Case Reports

The presence of the vermiform appendix within an inguinal hernia sac is termed an Amyand hernia. While the incidence of Amyand hernia in the general population is thought to be exceedingly rare, the presence of a left-sided Amyand hernia is even more rare due to the normal anatomical position of the appendix on the right side. Left-sided Amyand hernia presents a novel diagnosis that necessitates a high degree of clinical suspicion and special consideration during patient workup and operative treatment. We describe such a case and provide a review of all reports in the literature of this rare finding.

Case Presentation

A male aged 62 years presented to the emergency department of the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, in acute distress after experiencing 5 days of nausea and pain in his lower abdomen. The patient’s history was significant for cocaine abuse and a left-sided inguinal hernia that was repaired about 15 years prior to this visit. He reported having no bowel movements for the past 5 days and no other symptoms, including vomiting, hematemesis, and trauma to the abdomen. The patient’s abdominal pain was located in the suprapubic and periumbilical regions. Upon palpation of the lower abdomen, a firm, protruding mass was identified in the left lower quadrant and suspected to be a left-sided inguinal hernia.

A scout film and computed tomography (CT) scan of the abdomen taken on the same day that the patient presented to the emergency department confirmed the presence of a large left-sided inguinal hernia with possible bowel strangulation involving the colon (Figures 1, 2, and 3). The patient was diagnosed with an incarcerated recurrent left inguinal hernia and was taken emergently to the operating suite. General anesthesia and an ilioinguinal nerve block were performed. An inguinal incision was made on the left side, and the large hernia sac was identified and separated from the scrotum and spermatic cord structures.

Discussion

An Amyand hernia is an inguinal hernia in which the vermiform appendix is located within the hernial sac. Named after the French surgeon Claudius Amyand who first documented such a case during an appendectomy in 1735, the Amyand hernia is rare and is thought to occur in < 1% of inguinal hernias.¹ Given the normal anatomical position of the appendix on the right side of the body, most Amyand hernias occur in a right-sided inguinal hernia.

A literature review yielded 25 reported instances of a left-sided Amyand hernia (Table 1) including this report. The true age of incidence of Amyand hernia for each patient is difficult to determine, as many patients do not present until pain or discomfort reaches high levels, often many years after hernia formation. Additionally, some cases of left-sided Amyand hernia described herein, including our case, are recurrent cases of a previous hernia that have been surgically repaired.^2-20

Presentation of Amyand hernia often resembles that of a complicated inguinal hernia, acute appendicitis, or both. Hence, clinicians should consider this a possibility when patients present with signs and symptoms that could otherwise be thought to be originating from an incarcerated, strangulated, or recurrent hernia. Specifically, these signs and symptoms include a tender, nonreducible mass in the inguinal region, acute lower abdominal pain, nausea, or signs of intestinal obstruction such as failure to produce bowel movements.^4,17 Because of the unusual anatomy in patients presenting with left-sided Amyand hernia, tenderness at the McBurney point usually is absent and not a useful diagnostic tool to rule out acute appendicitis.

A literature review indicates that an Amyand hernia on either side tends to occur in males more often than it does in females. The rate of diagnosis of Amyand hernia also has been reported to be 3 times higher in children than it is in adults due to failure of the processus vaginalis to obliterate during development.²¹ Our literature review supports this finding, as 16 of the documented 25 cases of left-sided Amyand hernia were reported in males. Additionally, information regarding gender was not found in 6 cases, suggesting a potential for an even higher prevalence in males.

Explanations as to why the appendix is on the left side in these patients include developmental anomalies, such as situs inversus, intestinal rotation, mobile cecum, or an abnormally long appendix.^3,8 In our case, the likely causative culprit was a mobile cecum, as there was neither indication of intestinal malformation, rotation, nor of an abnormally long appendix during surgery. Additionally, pre-operative radiologic studies, clinical evaluation, and electrocardiogram did not suggest the presence of situs inversus.

Treatment of Amyand hernia usually follows the landmark classification algorithm set forth in 2007 by Losanoff and Basson (Table 2).²² This system stratifies treatment based on intraoperative findings of the appendix and surrounding structures, ranging from type 1, which involves a normal appendix within the hernia, to type 4, which includes acute appendicitis with additional abdominal pathology. Our patient presented with a type 1 Amyand hernia and appendectomy was foregone as per the guidelines; however, there have been numerous reported cases of surgeons opting for prophylactic appendectomy in the case of a normal appearing appendix and surrounding structures. The decision to act independent of the Losanoff and Basson classification underscores the lack of true standardization, namely, when it comes to a treatment approach for type 1 Amyand hernias. Nonetheless, many contend that indiscriminately performing appendectomies in all cases of left-sided Amyand hernia is useful as a prophylactic measure, as cases of future appendicitis in these patients will have atypical presentations based on the contralateral location of the appendix.^6,11,17

Others disagree, citing that prophylactic appendectomy in the case of a normal looking appendix is unnecessary and complicates an otherwise sterile surgery (clean wound classification) with the removal of an appendix containing fecal matter and gut microbiota (converted into a clean contaminated or a contaminated wound classification).¹⁷ Additionally, it is thought that in the cases of middle-aged or geriatric patients where the chances of appendicitis are far less, the risks of detriment from prophylactic appendectomy may outweigh the benefits. In these cases, a macroscopic view of the appendix based on visual examination during the operation should guide decision making.⁴

While the decision to remove a healthy-appearing appendix remains contentious, the decision for or against placement of a heterogenous hernia mesh has proven to be binary, with near universally accepted criteria. If signs of perforation or infection are present in the hernia sac, then surgeons will forego hernioplasty with mesh for simple herniorrhaphy. This contraindication for mesh placement is due to the increased risk of mesh infection, wound infection, and fistulae associated with the introduction of a foreign structure to an active infection site.²

While most cases of Amyand hernia are diagnosed intraoperatively, there have been documented cases of preoperative diagnosis using ultrasonography and CT imaging modalities.^19,23,24 In all cases, the presence of the vermiform appendix within the hernia sac can complicate diagnosis and treatment, and preoperative knowledge of this condition may help to guide physician decision making. Identifying Amyand hernia via CT scan is not only useful for alerting physicians of a potentially inflamed appendix within the hernia sac, but also may create opportunities for the use of other treatment modalities. For example, laparoscopic Amyand hernia reduction, an approach that was performed successfully and documented for the first time by Vermillion and colleagues, was made possible by preoperative diagnosis and can potentially result in improved patient outcomes.²⁵

Regardless, while standardization of treatment for Amyand hernia has not yet occurred, it is clear that improved preoperative diagnosis, especially in the case of an unanticipated left-sided Amyand hernia, can allow for better planning and use of a wider variety of treatment modalities. The main impediment to this approach is that suspected cases of appendicitis and inguinal hernias (the most common preoperative diagnoses of Amyand hernia) usually are diagnosed clinically without the need of additional imaging studies like CT or ultrasound. In accordance with the guiding principle of radiation safety of exposing patients to “as low as reasonably achievable” (ALARA) radiation and with consideration of expediency of care and cost efficiency, we recommend physicians continue to screen for and treat cases of potentially emergent appendicitis and/or inguinal hernia as per the conventional methodology. The best approach may involve increasing preoperative diagnoses of left-sided Amyand hernias via physician awareness of this rare finding, as well as evaluating imaging studies that have previously been obtained in order to narrow a broad differential diagnosis.

Conclusions

Left-sided Amyand hernia is an exceptionally rare condition whose preoperative diagnosis remains difficult to establish but whose treatment decision tree is significantly impacted by the condition.

The presence of the vermiform appendix within an inguinal hernia sac is termed an Amyand hernia. While the incidence of Amyand hernia in the general population is thought to be exceedingly rare, the presence of a left-sided Amyand hernia is even more rare due to the normal anatomical position of the appendix on the right side. Left-sided Amyand hernia presents a novel diagnosis that necessitates a high degree of clinical suspicion and special consideration during patient workup and operative treatment. We describe such a case and provide a review of all reports in the literature of this rare finding.

Case Presentation

A male aged 62 years presented to the emergency department of the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, in acute distress after experiencing 5 days of nausea and pain in his lower abdomen. The patient’s history was significant for cocaine abuse and a left-sided inguinal hernia that was repaired about 15 years prior to this visit. He reported having no bowel movements for the past 5 days and no other symptoms, including vomiting, hematemesis, and trauma to the abdomen. The patient’s abdominal pain was located in the suprapubic and periumbilical regions. Upon palpation of the lower abdomen, a firm, protruding mass was identified in the left lower quadrant and suspected to be a left-sided inguinal hernia.

A scout film and computed tomography (CT) scan of the abdomen taken on the same day that the patient presented to the emergency department confirmed the presence of a large left-sided inguinal hernia with possible bowel strangulation involving the colon (Figures 1, 2, and 3). The patient was diagnosed with an incarcerated recurrent left inguinal hernia and was taken emergently to the operating suite. General anesthesia and an ilioinguinal nerve block were performed. An inguinal incision was made on the left side, and the large hernia sac was identified and separated from the scrotum and spermatic cord structures.

Discussion

An Amyand hernia is an inguinal hernia in which the vermiform appendix is located within the hernial sac. Named after the French surgeon Claudius Amyand who first documented such a case during an appendectomy in 1735, the Amyand hernia is rare and is thought to occur in < 1% of inguinal hernias.¹ Given the normal anatomical position of the appendix on the right side of the body, most Amyand hernias occur in a right-sided inguinal hernia.

A literature review yielded 25 reported instances of a left-sided Amyand hernia (Table 1) including this report. The true age of incidence of Amyand hernia for each patient is difficult to determine, as many patients do not present until pain or discomfort reaches high levels, often many years after hernia formation. Additionally, some cases of left-sided Amyand hernia described herein, including our case, are recurrent cases of a previous hernia that have been surgically repaired.^2-20

Presentation of Amyand hernia often resembles that of a complicated inguinal hernia, acute appendicitis, or both. Hence, clinicians should consider this a possibility when patients present with signs and symptoms that could otherwise be thought to be originating from an incarcerated, strangulated, or recurrent hernia. Specifically, these signs and symptoms include a tender, nonreducible mass in the inguinal region, acute lower abdominal pain, nausea, or signs of intestinal obstruction such as failure to produce bowel movements.^4,17 Because of the unusual anatomy in patients presenting with left-sided Amyand hernia, tenderness at the McBurney point usually is absent and not a useful diagnostic tool to rule out acute appendicitis.

A literature review indicates that an Amyand hernia on either side tends to occur in males more often than it does in females. The rate of diagnosis of Amyand hernia also has been reported to be 3 times higher in children than it is in adults due to failure of the processus vaginalis to obliterate during development.²¹ Our literature review supports this finding, as 16 of the documented 25 cases of left-sided Amyand hernia were reported in males. Additionally, information regarding gender was not found in 6 cases, suggesting a potential for an even higher prevalence in males.

Explanations as to why the appendix is on the left side in these patients include developmental anomalies, such as situs inversus, intestinal rotation, mobile cecum, or an abnormally long appendix.^3,8 In our case, the likely causative culprit was a mobile cecum, as there was neither indication of intestinal malformation, rotation, nor of an abnormally long appendix during surgery. Additionally, pre-operative radiologic studies, clinical evaluation, and electrocardiogram did not suggest the presence of situs inversus.

Treatment of Amyand hernia usually follows the landmark classification algorithm set forth in 2007 by Losanoff and Basson (Table 2).²² This system stratifies treatment based on intraoperative findings of the appendix and surrounding structures, ranging from type 1, which involves a normal appendix within the hernia, to type 4, which includes acute appendicitis with additional abdominal pathology. Our patient presented with a type 1 Amyand hernia and appendectomy was foregone as per the guidelines; however, there have been numerous reported cases of surgeons opting for prophylactic appendectomy in the case of a normal appearing appendix and surrounding structures. The decision to act independent of the Losanoff and Basson classification underscores the lack of true standardization, namely, when it comes to a treatment approach for type 1 Amyand hernias. Nonetheless, many contend that indiscriminately performing appendectomies in all cases of left-sided Amyand hernia is useful as a prophylactic measure, as cases of future appendicitis in these patients will have atypical presentations based on the contralateral location of the appendix.^6,11,17

Others disagree, citing that prophylactic appendectomy in the case of a normal looking appendix is unnecessary and complicates an otherwise sterile surgery (clean wound classification) with the removal of an appendix containing fecal matter and gut microbiota (converted into a clean contaminated or a contaminated wound classification).¹⁷ Additionally, it is thought that in the cases of middle-aged or geriatric patients where the chances of appendicitis are far less, the risks of detriment from prophylactic appendectomy may outweigh the benefits. In these cases, a macroscopic view of the appendix based on visual examination during the operation should guide decision making.⁴

While the decision to remove a healthy-appearing appendix remains contentious, the decision for or against placement of a heterogenous hernia mesh has proven to be binary, with near universally accepted criteria. If signs of perforation or infection are present in the hernia sac, then surgeons will forego hernioplasty with mesh for simple herniorrhaphy. This contraindication for mesh placement is due to the increased risk of mesh infection, wound infection, and fistulae associated with the introduction of a foreign structure to an active infection site.²

While most cases of Amyand hernia are diagnosed intraoperatively, there have been documented cases of preoperative diagnosis using ultrasonography and CT imaging modalities.^19,23,24 In all cases, the presence of the vermiform appendix within the hernia sac can complicate diagnosis and treatment, and preoperative knowledge of this condition may help to guide physician decision making. Identifying Amyand hernia via CT scan is not only useful for alerting physicians of a potentially inflamed appendix within the hernia sac, but also may create opportunities for the use of other treatment modalities. For example, laparoscopic Amyand hernia reduction, an approach that was performed successfully and documented for the first time by Vermillion and colleagues, was made possible by preoperative diagnosis and can potentially result in improved patient outcomes.²⁵

Regardless, while standardization of treatment for Amyand hernia has not yet occurred, it is clear that improved preoperative diagnosis, especially in the case of an unanticipated left-sided Amyand hernia, can allow for better planning and use of a wider variety of treatment modalities. The main impediment to this approach is that suspected cases of appendicitis and inguinal hernias (the most common preoperative diagnoses of Amyand hernia) usually are diagnosed clinically without the need of additional imaging studies like CT or ultrasound. In accordance with the guiding principle of radiation safety of exposing patients to “as low as reasonably achievable” (ALARA) radiation and with consideration of expediency of care and cost efficiency, we recommend physicians continue to screen for and treat cases of potentially emergent appendicitis and/or inguinal hernia as per the conventional methodology. The best approach may involve increasing preoperative diagnoses of left-sided Amyand hernias via physician awareness of this rare finding, as well as evaluating imaging studies that have previously been obtained in order to narrow a broad differential diagnosis.

Conclusions

Left-sided Amyand hernia is an exceptionally rare condition whose preoperative diagnosis remains difficult to establish but whose treatment decision tree is significantly impacted by the condition.

The presence of the vermiform appendix within an inguinal hernia sac is termed an Amyand hernia. While the incidence of Amyand hernia in the general population is thought to be exceedingly rare, the presence of a left-sided Amyand hernia is even more rare due to the normal anatomical position of the appendix on the right side. Left-sided Amyand hernia presents a novel diagnosis that necessitates a high degree of clinical suspicion and special consideration during patient workup and operative treatment. We describe such a case and provide a review of all reports in the literature of this rare finding.

Case Presentation

A male aged 62 years presented to the emergency department of the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, in acute distress after experiencing 5 days of nausea and pain in his lower abdomen. The patient’s history was significant for cocaine abuse and a left-sided inguinal hernia that was repaired about 15 years prior to this visit. He reported having no bowel movements for the past 5 days and no other symptoms, including vomiting, hematemesis, and trauma to the abdomen. The patient’s abdominal pain was located in the suprapubic and periumbilical regions. Upon palpation of the lower abdomen, a firm, protruding mass was identified in the left lower quadrant and suspected to be a left-sided inguinal hernia.

A scout film and computed tomography (CT) scan of the abdomen taken on the same day that the patient presented to the emergency department confirmed the presence of a large left-sided inguinal hernia with possible bowel strangulation involving the colon (Figures 1, 2, and 3). The patient was diagnosed with an incarcerated recurrent left inguinal hernia and was taken emergently to the operating suite. General anesthesia and an ilioinguinal nerve block were performed. An inguinal incision was made on the left side, and the large hernia sac was identified and separated from the scrotum and spermatic cord structures.

Discussion

An Amyand hernia is an inguinal hernia in which the vermiform appendix is located within the hernial sac. Named after the French surgeon Claudius Amyand who first documented such a case during an appendectomy in 1735, the Amyand hernia is rare and is thought to occur in < 1% of inguinal hernias.¹ Given the normal anatomical position of the appendix on the right side of the body, most Amyand hernias occur in a right-sided inguinal hernia.

A literature review yielded 25 reported instances of a left-sided Amyand hernia (Table 1) including this report. The true age of incidence of Amyand hernia for each patient is difficult to determine, as many patients do not present until pain or discomfort reaches high levels, often many years after hernia formation. Additionally, some cases of left-sided Amyand hernia described herein, including our case, are recurrent cases of a previous hernia that have been surgically repaired.^2-20

Presentation of Amyand hernia often resembles that of a complicated inguinal hernia, acute appendicitis, or both. Hence, clinicians should consider this a possibility when patients present with signs and symptoms that could otherwise be thought to be originating from an incarcerated, strangulated, or recurrent hernia. Specifically, these signs and symptoms include a tender, nonreducible mass in the inguinal region, acute lower abdominal pain, nausea, or signs of intestinal obstruction such as failure to produce bowel movements.^4,17 Because of the unusual anatomy in patients presenting with left-sided Amyand hernia, tenderness at the McBurney point usually is absent and not a useful diagnostic tool to rule out acute appendicitis.

A literature review indicates that an Amyand hernia on either side tends to occur in males more often than it does in females. The rate of diagnosis of Amyand hernia also has been reported to be 3 times higher in children than it is in adults due to failure of the processus vaginalis to obliterate during development.²¹ Our literature review supports this finding, as 16 of the documented 25 cases of left-sided Amyand hernia were reported in males. Additionally, information regarding gender was not found in 6 cases, suggesting a potential for an even higher prevalence in males.

Explanations as to why the appendix is on the left side in these patients include developmental anomalies, such as situs inversus, intestinal rotation, mobile cecum, or an abnormally long appendix.^3,8 In our case, the likely causative culprit was a mobile cecum, as there was neither indication of intestinal malformation, rotation, nor of an abnormally long appendix during surgery. Additionally, pre-operative radiologic studies, clinical evaluation, and electrocardiogram did not suggest the presence of situs inversus.

Treatment of Amyand hernia usually follows the landmark classification algorithm set forth in 2007 by Losanoff and Basson (Table 2).²² This system stratifies treatment based on intraoperative findings of the appendix and surrounding structures, ranging from type 1, which involves a normal appendix within the hernia, to type 4, which includes acute appendicitis with additional abdominal pathology. Our patient presented with a type 1 Amyand hernia and appendectomy was foregone as per the guidelines; however, there have been numerous reported cases of surgeons opting for prophylactic appendectomy in the case of a normal appearing appendix and surrounding structures. The decision to act independent of the Losanoff and Basson classification underscores the lack of true standardization, namely, when it comes to a treatment approach for type 1 Amyand hernias. Nonetheless, many contend that indiscriminately performing appendectomies in all cases of left-sided Amyand hernia is useful as a prophylactic measure, as cases of future appendicitis in these patients will have atypical presentations based on the contralateral location of the appendix.^6,11,17

Others disagree, citing that prophylactic appendectomy in the case of a normal looking appendix is unnecessary and complicates an otherwise sterile surgery (clean wound classification) with the removal of an appendix containing fecal matter and gut microbiota (converted into a clean contaminated or a contaminated wound classification).¹⁷ Additionally, it is thought that in the cases of middle-aged or geriatric patients where the chances of appendicitis are far less, the risks of detriment from prophylactic appendectomy may outweigh the benefits. In these cases, a macroscopic view of the appendix based on visual examination during the operation should guide decision making.⁴

While the decision to remove a healthy-appearing appendix remains contentious, the decision for or against placement of a heterogenous hernia mesh has proven to be binary, with near universally accepted criteria. If signs of perforation or infection are present in the hernia sac, then surgeons will forego hernioplasty with mesh for simple herniorrhaphy. This contraindication for mesh placement is due to the increased risk of mesh infection, wound infection, and fistulae associated with the introduction of a foreign structure to an active infection site.²

While most cases of Amyand hernia are diagnosed intraoperatively, there have been documented cases of preoperative diagnosis using ultrasonography and CT imaging modalities.^19,23,24 In all cases, the presence of the vermiform appendix within the hernia sac can complicate diagnosis and treatment, and preoperative knowledge of this condition may help to guide physician decision making. Identifying Amyand hernia via CT scan is not only useful for alerting physicians of a potentially inflamed appendix within the hernia sac, but also may create opportunities for the use of other treatment modalities. For example, laparoscopic Amyand hernia reduction, an approach that was performed successfully and documented for the first time by Vermillion and colleagues, was made possible by preoperative diagnosis and can potentially result in improved patient outcomes.²⁵

Regardless, while standardization of treatment for Amyand hernia has not yet occurred, it is clear that improved preoperative diagnosis, especially in the case of an unanticipated left-sided Amyand hernia, can allow for better planning and use of a wider variety of treatment modalities. The main impediment to this approach is that suspected cases of appendicitis and inguinal hernias (the most common preoperative diagnoses of Amyand hernia) usually are diagnosed clinically without the need of additional imaging studies like CT or ultrasound. In accordance with the guiding principle of radiation safety of exposing patients to “as low as reasonably achievable” (ALARA) radiation and with consideration of expediency of care and cost efficiency, we recommend physicians continue to screen for and treat cases of potentially emergent appendicitis and/or inguinal hernia as per the conventional methodology. The best approach may involve increasing preoperative diagnoses of left-sided Amyand hernias via physician awareness of this rare finding, as well as evaluating imaging studies that have previously been obtained in order to narrow a broad differential diagnosis.

Conclusions

Left-sided Amyand hernia is an exceptionally rare condition whose preoperative diagnosis remains difficult to establish but whose treatment decision tree is significantly impacted by the condition.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Case Report

A 67-year-old woman presented with a painful expanding ulcer on the left leg and a new nearby ulcer of 2 months’ duration. She initially was seen 2 months prior for a wound on the left knee due to a fall as well as cellulitis, which was treated with intravenous vancomycin and ceftriaxone. Wound cultures were negative for bacteria, and she was discharged without antibiotics. She presented to the emergency department 1 month later for malodorous discharge of the first ulcer with zero systemic inflammatory response syndrome criteria; no fever; and no abnormal heart rate, respiratory rate, or leukocyte count. She was discharged with wound care. After 3 weeks, she returned with a second ulcer and worsening drainage but zero systemic inflammatory response syndrome criteria. She had a medical history of Crohn disease with 9-year remission, atrial fibrillation, pacemaker, mitral valve replacement, chronic obstructive pulmonary disease, and a 51 pack-year smoking history.

Physical examination of the left leg revealed a 3×3-cm deep lesion (ulcer A) on the distal left thigh located superomedial to the knee (Figure 1) as well as a 2×1-cm deep lesion (ulcer B) on the anteromedial knee with undermining and tunneling (Figure 2). A large amount of malodorous tan bloody discharge was present on both ulcers. There were no signs of induration or crepitus.Due to concerns of skin and soft tissue infection (SSTI) or osteomyelitis, a bone scan and wound and blood cultures were ordered. The patient was started on vancomycin and piperacillin-tazobactam in the emergency department, which later was augmented with cefepime. Trauma surgery scheduled debridement for the following morning with suspicion of necrotizing fasciitis. Additional consultations were requested, including infectious disease, wound care, and dermatology. Dermatology evaluated the wound, performed a punch biopsy, and canceled debridement due to unclear diagnosis. The clinical differential at that time included pyoderma gangrenosum (PG), atypical vasculitis, or infection. Additional workup revealed positive antineutrophil cytoplasmic antibodies but negative proteinase 3 and myeloperoxidase, disfavoring vasculitis. Wound cultures grew Staphylococcus aureus and Pseudomonas aeruginosa.

Comment

Pyoderma gangrenosum is a rare inflammatory skin condition that classically presents as tender papules or pustules evolving into painful ulcers, most commonly on the lower extremities. Pyoderma gangrenosum has a propensity to exhibit pathergy, the hyperreactivity of the skin in response to minor trauma. This phenomenon in PG manifests as the rapid evolution from pustule to ulceration with violaceous undermining borders.

Diagnosis of PG
Pyoderma gangrenosum has been described as a diagnosis of exclusion, as its findings frequently mimic SSTIs. Important findings to obtain are histology, history, ulcer morphology, and response to treatment.

In 2018, Maverakis et al¹ proposed diagnostic criteria for classic ulcerative PG (Table 1). A diagnosis of PG can be made if the patient meets 1 major criterion and 4 minor criteria. Our case met 0 major criteria and 5 minor criteria: history of inflammatory bowel disease (IBD); history of pustule ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, with at least 1 on an anterior lower leg; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Although our patient’s biopsy demonstrated a mixed infiltrate, PG was not excluded due to spontaneous resolution at the time of biopsy, emphasizing the need to biopsy subsequent new lesions if neutrophils are not initially seen.¹ Pyoderma gangrenosum frequently is associated with IBD, most often Crohn disease, as seen in our patient.^2-4 Although IBD classically is associated with smoking, studies have yet to conclude if smoking is a predictive factor of PG.⁵ Our patient presented with an initial ulcer that evolved into 2 ulcers, similar to a case of bilateral ulcers.⁶

Management of PG
A gold standard of treatment of PG does not exist, but the goal is to promote wound healing. Patients with limited disease typically can be managed with wound care and topical steroids or calcineurin inhibitors, though data on efficacy are limited. However, our patient had more extensive disease and needed to be treated with systemic therapy. First-line therapy for extensive disease includes oral prednisone or cyclosporine for patients who cannot tolerate systemic corticosteroids.¹² Second-line and adjunctive therapy options include dapsone, minocycline, methotrexate, and infliximab. Our patient was prescribed a 7-month course of dapsone with outpatient dermatology and demonstrated resolution of both ulcers. Dapsone was tapered from a daily dose of 100 mg to 50 mg to 25 mg to none over the course of 2 to 3 months. Close monitoring with wound care is recommended, and petroleum jelly can be used for dry skin around the lesion for comfort.

Conclusion

The diagnosis of PG is challenging because it relies heavily on clinical signs and often mimics SSTI. Gathering a detailed medical history is critical to make the diagnosis of PG. In a patient with associated features of PG, dermatologic consultation and biopsy of skin lesions should be considered. Physicians should evaluate for suspected PG prior to proceeding with surgical intervention to avoid unnecessary amputation. The diagnostic criteria for classic ulcerative PG are gaining wider acceptance and are a useful tool for clinicians.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

THE CASE

An 18-year-old woman with no significant past medical history presented to the emergency department complaining of midsternal chest pain and mild shortness of breath, which had been intermittent for the past several months. She denied any history of deep vein thrombosis or pulmonary embolism risk factors, such as oral contraceptive use.

Laboratory values were within normal limits. An electrocardiogram (EKG), however, showed T-wave inversions in leads V₁ and V₂, and physical examination revealed decreased breath sounds in the right lung base. A chest radiograph and subsequent chest computed tomography (CT) were ordered.

The initial radiograph (FIGURE 1) showed a large right anterior mediastinal mass; the CT revealed fat, fluid, soft tissue, and ossification within the mass (FIGURE 2). The CT also showed evidence of local mass effect on the right atrium, as well as compressive atelectasis in the adjacent right lung, contributing to the patient’s EKG abnormality and physical exam findings.

THE DIAGNOSIS

Based on the patient’s clinical history and imaging findings, which were consistent with a benign well-differentiated teratoma, she was given a diagnosis of anterior mediastinal teratoma.

DISCUSSION

Teratomas are tumors composed of pluripotent stem cells that carry elements from all 3 of the embryologic layers (ectoderm, mesoderm, and endoderm).¹ There are 3 classifications of teratomas: mature (well-differentiated), immature (poorly differentiated), and malignant.

Tumors of germ cell origin are rare within the anterior mediastinum, accounting for 1% to 3% of total reported cases.² Among anterior mediastinal masses, germ cell tumors such as teratomas, seminomas, and nonseminomatous tumors comprise approximately 15% of adult and 24% of pediatric anterior mediastinal tumors.³

It is reported that up to 60% of patients with mediastinal teratomas present with no signs or symptoms upon diagnosis.⁴ When the mass is large, patients can develop chest pain or shortness of breath relating to tumor mass effect. In rare instances, there can be hemoptysis or trichoptysis, pathognomonic for teratomas with bronchial communication.⁵ Physical exam findings are also nonspecific and may include decreased breath sounds secondary to compressive atelectasis with large tumor burden.

Continue to: Radiographic imaging...

Radiographic imaging is essential to elucidate the diagnosis. Chest radiograph can show an intrathoracic mass, and CT can provide further characterization, such as density and precise location.

Location of mass guides differential

Localizing an intrathoracic mass in the anterior, middle, or posterior mediastinum allows for narrowing of the differential diagnosis (TABLE⁶). The main diagnostic consideration for a middle mediastinal or hilar mass is primary carcinoma. Posterior mediastinal masses, on the other hand, are generally of benign etiology and may include neurogenic tumors, foregut duplication cysts, or, in rare cases, extramedullary hematopoiesis.

The differential diagnosis of anterior mediastinal masses can be separated into 4 main categories of disease, colloquially known as the “4 Ts”:

Teratoma. Mixed tissue densities seen on CT relate to the multiple tissue types originating from the embryologic germ cell layers.Frequently, there will be fat, fluid, and calcifications.

Thyroid pathology. A goiter or thyroid cancer can manifest with endocrine dysfunction, such as thyroid-stimulating hormone and T3/T4 abnormalities. A thyroid mass tends to sit more superiorly than do other anterior mediastinal masses and may be confirmed using a nuclear scan looking for increased radioactive iodine uptake.

Continue to: Thymoma

Thymoma. The diagnostic features include parathymic syndromes such as myasthenia gravis (30%-50% of thymoma cases^7,8) and pure red cell aplasia (5% of thymoma cases⁹).

“Terrible” lymphoma. The most effective way to differentiate an anterior mediastinal mass due to lymphadenopathy (secondary to lymphoma) is to perform a tissue sample biopsy.

Also consider, as part of the differential for anterior mediastinal masses, such things as mesenchymal tumors, Morgagni hernia (anterior diaphragmatic defect), and pericardial cysts (fluid attenuating and usually located at the right cardiophrenic angle).

Surgical resection is effective

The treatment for anterior mediastinal teratoma is surgical resection.¹⁰ A complete surgical resection is typically curative and provides adequate therapy for symptom resolution.

The standard surgical approach involves gaining access to the anterior mediastinum via a median sternotomy. When there is extensive tumor involvement of the hemithorax, clamshell thoracotomy is preferred, requiring incisions in both the left and right hemithoraxes.¹¹

Continue to: Our patient

Our patient underwent resection of the tumor; the subsequent pathology report for the specimen (FIGURE 3) confirmed the diagnosis. There was no abnormal enhancement or vascular invasion to suggest aggressive or malignant potential.

THE TAKEAWAY

Patients frequently present with nonspecific and vague chest complaints. This case points to the importance of obtaining a thorough clinical history and conducting a complete physical examination to guide additional work-up and radiographic imaging.

CORRESPONDENCE
Cassie Tran, MD, 320 E North Avenue, Pittsburgh, PA 15212; [email protected]

THE CASE

An 18-year-old woman with no significant past medical history presented to the emergency department complaining of midsternal chest pain and mild shortness of breath, which had been intermittent for the past several months. She denied any history of deep vein thrombosis or pulmonary embolism risk factors, such as oral contraceptive use.

Laboratory values were within normal limits. An electrocardiogram (EKG), however, showed T-wave inversions in leads V₁ and V₂, and physical examination revealed decreased breath sounds in the right lung base. A chest radiograph and subsequent chest computed tomography (CT) were ordered.

The initial radiograph (FIGURE 1) showed a large right anterior mediastinal mass; the CT revealed fat, fluid, soft tissue, and ossification within the mass (FIGURE 2). The CT also showed evidence of local mass effect on the right atrium, as well as compressive atelectasis in the adjacent right lung, contributing to the patient’s EKG abnormality and physical exam findings.

THE DIAGNOSIS

Based on the patient’s clinical history and imaging findings, which were consistent with a benign well-differentiated teratoma, she was given a diagnosis of anterior mediastinal teratoma.

DISCUSSION

Teratomas are tumors composed of pluripotent stem cells that carry elements from all 3 of the embryologic layers (ectoderm, mesoderm, and endoderm).¹ There are 3 classifications of teratomas: mature (well-differentiated), immature (poorly differentiated), and malignant.

Tumors of germ cell origin are rare within the anterior mediastinum, accounting for 1% to 3% of total reported cases.² Among anterior mediastinal masses, germ cell tumors such as teratomas, seminomas, and nonseminomatous tumors comprise approximately 15% of adult and 24% of pediatric anterior mediastinal tumors.³

It is reported that up to 60% of patients with mediastinal teratomas present with no signs or symptoms upon diagnosis.⁴ When the mass is large, patients can develop chest pain or shortness of breath relating to tumor mass effect. In rare instances, there can be hemoptysis or trichoptysis, pathognomonic for teratomas with bronchial communication.⁵ Physical exam findings are also nonspecific and may include decreased breath sounds secondary to compressive atelectasis with large tumor burden.

Continue to: Radiographic imaging...

Radiographic imaging is essential to elucidate the diagnosis. Chest radiograph can show an intrathoracic mass, and CT can provide further characterization, such as density and precise location.

Location of mass guides differential

Localizing an intrathoracic mass in the anterior, middle, or posterior mediastinum allows for narrowing of the differential diagnosis (TABLE⁶). The main diagnostic consideration for a middle mediastinal or hilar mass is primary carcinoma. Posterior mediastinal masses, on the other hand, are generally of benign etiology and may include neurogenic tumors, foregut duplication cysts, or, in rare cases, extramedullary hematopoiesis.

The differential diagnosis of anterior mediastinal masses can be separated into 4 main categories of disease, colloquially known as the “4 Ts”:

Teratoma. Mixed tissue densities seen on CT relate to the multiple tissue types originating from the embryologic germ cell layers.Frequently, there will be fat, fluid, and calcifications.

Thyroid pathology. A goiter or thyroid cancer can manifest with endocrine dysfunction, such as thyroid-stimulating hormone and T3/T4 abnormalities. A thyroid mass tends to sit more superiorly than do other anterior mediastinal masses and may be confirmed using a nuclear scan looking for increased radioactive iodine uptake.

Continue to: Thymoma

Thymoma. The diagnostic features include parathymic syndromes such as myasthenia gravis (30%-50% of thymoma cases^7,8) and pure red cell aplasia (5% of thymoma cases⁹).

“Terrible” lymphoma. The most effective way to differentiate an anterior mediastinal mass due to lymphadenopathy (secondary to lymphoma) is to perform a tissue sample biopsy.

Also consider, as part of the differential for anterior mediastinal masses, such things as mesenchymal tumors, Morgagni hernia (anterior diaphragmatic defect), and pericardial cysts (fluid attenuating and usually located at the right cardiophrenic angle).

Surgical resection is effective

The treatment for anterior mediastinal teratoma is surgical resection.¹⁰ A complete surgical resection is typically curative and provides adequate therapy for symptom resolution.

The standard surgical approach involves gaining access to the anterior mediastinum via a median sternotomy. When there is extensive tumor involvement of the hemithorax, clamshell thoracotomy is preferred, requiring incisions in both the left and right hemithoraxes.¹¹

Continue to: Our patient

Our patient underwent resection of the tumor; the subsequent pathology report for the specimen (FIGURE 3) confirmed the diagnosis. There was no abnormal enhancement or vascular invasion to suggest aggressive or malignant potential.

THE TAKEAWAY

Patients frequently present with nonspecific and vague chest complaints. This case points to the importance of obtaining a thorough clinical history and conducting a complete physical examination to guide additional work-up and radiographic imaging.

CORRESPONDENCE
Cassie Tran, MD, 320 E North Avenue, Pittsburgh, PA 15212; [email protected]

THE CASE

An 18-year-old woman with no significant past medical history presented to the emergency department complaining of midsternal chest pain and mild shortness of breath, which had been intermittent for the past several months. She denied any history of deep vein thrombosis or pulmonary embolism risk factors, such as oral contraceptive use.

Laboratory values were within normal limits. An electrocardiogram (EKG), however, showed T-wave inversions in leads V₁ and V₂, and physical examination revealed decreased breath sounds in the right lung base. A chest radiograph and subsequent chest computed tomography (CT) were ordered.

The initial radiograph (FIGURE 1) showed a large right anterior mediastinal mass; the CT revealed fat, fluid, soft tissue, and ossification within the mass (FIGURE 2). The CT also showed evidence of local mass effect on the right atrium, as well as compressive atelectasis in the adjacent right lung, contributing to the patient’s EKG abnormality and physical exam findings.

THE DIAGNOSIS

Based on the patient’s clinical history and imaging findings, which were consistent with a benign well-differentiated teratoma, she was given a diagnosis of anterior mediastinal teratoma.

DISCUSSION

Teratomas are tumors composed of pluripotent stem cells that carry elements from all 3 of the embryologic layers (ectoderm, mesoderm, and endoderm).¹ There are 3 classifications of teratomas: mature (well-differentiated), immature (poorly differentiated), and malignant.

Tumors of germ cell origin are rare within the anterior mediastinum, accounting for 1% to 3% of total reported cases.² Among anterior mediastinal masses, germ cell tumors such as teratomas, seminomas, and nonseminomatous tumors comprise approximately 15% of adult and 24% of pediatric anterior mediastinal tumors.³

It is reported that up to 60% of patients with mediastinal teratomas present with no signs or symptoms upon diagnosis.⁴ When the mass is large, patients can develop chest pain or shortness of breath relating to tumor mass effect. In rare instances, there can be hemoptysis or trichoptysis, pathognomonic for teratomas with bronchial communication.⁵ Physical exam findings are also nonspecific and may include decreased breath sounds secondary to compressive atelectasis with large tumor burden.

Continue to: Radiographic imaging...

Radiographic imaging is essential to elucidate the diagnosis. Chest radiograph can show an intrathoracic mass, and CT can provide further characterization, such as density and precise location.

Location of mass guides differential

Localizing an intrathoracic mass in the anterior, middle, or posterior mediastinum allows for narrowing of the differential diagnosis (TABLE⁶). The main diagnostic consideration for a middle mediastinal or hilar mass is primary carcinoma. Posterior mediastinal masses, on the other hand, are generally of benign etiology and may include neurogenic tumors, foregut duplication cysts, or, in rare cases, extramedullary hematopoiesis.

The differential diagnosis of anterior mediastinal masses can be separated into 4 main categories of disease, colloquially known as the “4 Ts”:

Teratoma. Mixed tissue densities seen on CT relate to the multiple tissue types originating from the embryologic germ cell layers.Frequently, there will be fat, fluid, and calcifications.

Thyroid pathology. A goiter or thyroid cancer can manifest with endocrine dysfunction, such as thyroid-stimulating hormone and T3/T4 abnormalities. A thyroid mass tends to sit more superiorly than do other anterior mediastinal masses and may be confirmed using a nuclear scan looking for increased radioactive iodine uptake.

Continue to: Thymoma

Thymoma. The diagnostic features include parathymic syndromes such as myasthenia gravis (30%-50% of thymoma cases^7,8) and pure red cell aplasia (5% of thymoma cases⁹).

“Terrible” lymphoma. The most effective way to differentiate an anterior mediastinal mass due to lymphadenopathy (secondary to lymphoma) is to perform a tissue sample biopsy.

Also consider, as part of the differential for anterior mediastinal masses, such things as mesenchymal tumors, Morgagni hernia (anterior diaphragmatic defect), and pericardial cysts (fluid attenuating and usually located at the right cardiophrenic angle).

Surgical resection is effective

The treatment for anterior mediastinal teratoma is surgical resection.¹⁰ A complete surgical resection is typically curative and provides adequate therapy for symptom resolution.

The standard surgical approach involves gaining access to the anterior mediastinum via a median sternotomy. When there is extensive tumor involvement of the hemithorax, clamshell thoracotomy is preferred, requiring incisions in both the left and right hemithoraxes.¹¹

Continue to: Our patient

Our patient underwent resection of the tumor; the subsequent pathology report for the specimen (FIGURE 3) confirmed the diagnosis. There was no abnormal enhancement or vascular invasion to suggest aggressive or malignant potential.

THE TAKEAWAY

Patients frequently present with nonspecific and vague chest complaints. This case points to the importance of obtaining a thorough clinical history and conducting a complete physical examination to guide additional work-up and radiographic imaging.

CORRESPONDENCE
Cassie Tran, MD, 320 E North Avenue, Pittsburgh, PA 15212; [email protected]

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major challenges to both clinicians and pathologists.¹ Clinically, the lesions may appear as subtle bland papules, nodules, or plaques. They can be easily mistaken for benign growths, leading to a delayed diagnosis. Consequently, most DMMs at the time of diagnosis tend to be thick, with a mean Breslow depth ranging from 2.0 to 6.5 mm.² Histopathologic evaluation has its difficulties. At scanning magnification, these tumors may show low cellularity, mimicking a benign proliferation. It is well recognized that S-100 and other tumor markers lack specificity for DMM, which can be positive in a range of neural tumors and other cell types.² In some amelanotic tumors, DMM becomes virtually indistinguishable from benign peripheral sheath tumors such as neurofribroma.³

Desmoplastic melanoma is exceedingly uncommon in the United States, with an estimated annual incidence rate of 2.0 cases per million.² Typical locations of presentation include sun-exposed skin, with the head and neck regions representing more than half of reported cases.² Desmoplastic melanoma largely is a disease of fair-skinned patients, with 95.5% of cases in the United States occurring in white non-Hispanic individuals. Advancing age, male gender, and head and neck location are associated with an increased risk for DMM-specific death.² It is important that new or changing lesions in the correct cohort and location are biopsied promptly. We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor.

Case Report

A 51-year-old White man with a history of prostate cancer, a personal and family history of melanoma, and benign neurofibromas presented with a 6-mm, pink, well-demarcated, soft papule on the left lateral neck (Figure 1). The lesion had been stable for many years but began growing more rapidly 1 to 2 years prior to presentation. The lesion was asymptomatic, and he denied changes in color or texture. There also was no bleeding or ulceration. A review of systems was unremarkable. A shave biopsy of the lesion revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma on low power (Figure 2). However, overlying the tumor was a confluent proliferation positive for MART-1 and S-100, which was consistent with a diagnosis of melanoma in situ (Figure 3). Higher-power evaluation of the dermal proliferation showed both bland and hyperchromatic spindled and epithelioid cells (Figure 4), with rare mitotic figures highlighted by PHH3, an uncommon finding in neurofibromas (Figure 5). The dermal spindle cells were positive for S-100 and p75 and negative for Melan-A. Epithelial membrane antigen highlighted a faint sheath surrounding the dermal component. Ki-67 revealed a mildly increased proliferative index in the dermal component. The diagnosis of DMM was made after outside dermatopathology consultation was in agreement. However, the possibility of a melanoma in situ growing in association with an underlying neurofibroma remained a diagnostic consideration histologically. The lesion was widely excised.

Comment

Differential for DMM
Early DMMs may not show sufficient cytologic atypia to permit obvious distinction from neurofibromas, which becomes problematic when encountering a spindle cell proliferation within severely sun-damaged skin, or even more so when an intraepidermal population of melanocytes is situated above a dermal population of slender, spindled, S-100–positive cells, as seen in our patient.⁴ For these challenging scenarios, Yeh and McCalmont⁴ have proposed evaluating for a CD34 “fingerprint” pattern. This pattern typically is widespread in neurofibroma but absent or limited in DMM, and it is a useful adjunct in the differential diagnosis when conventional immunohistochemistry has little contribution.

There are several case reports in the literature of DMM mimicking other benign or malignant proliferations. In 2012, Jou et al⁵ described a case of a 62-year-old White man who presented with an oral nodule consistent with fibrous inflammatory hyperplasia clinically. Incisional biopsy later confirmed the diagnosis of amelanotic DMM.⁵ Similar case reports have been described in which the diagnosis of DMM was later found to resemble a sarcoma and malignant peripheral nerve sheath tumor.^6,7

Diagnosis of DMM
The prototypical DMM is an asymmetrical and deeply infiltrative spindle cell lesion in severely sun-damaged skin. By definition, the individual melanocytes are separated by connective tissue components, giving the tumor a paucicellular appearance.¹ Although the low cellularity can give a deceptively bland scanning aspect, on high-power examination there usually are identifiable atypical spindled cells with enlarged, elongated, and hyperchromatic nuclei. S-100 typically is diffusely positive in DMM, though occasional cases show more limited staining.⁸ Other commonly used and more specific markers of melanocytic differentiation, including HMB45 and Melan-A, typically are negative in the paucicellular spindle cell components.⁹ Desmoplastic melanoma can be further categorized by the degree of fibrosis within a particular tumor. If fibrosis is prominent throughout the entire tumor, it is named pure DMM. On the other hand, fibrosis may only represent a portion of an otherwise nondesmoplastic melanoma, which is known as combined DMM.¹⁰

Conclusion

We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically. Although a bland-appearing lesion, key clinical features prompting a biopsy in our patient included recent growth of the lesion, a personal history of melanoma, the patient’s fair skin type, a history of heavy sun exposure, and the location of the lesion. According to Busam,¹¹ an associated melanoma in situ component is identified in 80% to 85% of DMM cases. Detection of a melanoma in situ component associated with a malignant spindle cell tumor can help establish the diagnosis of DMM. In the absence of melanoma in situ, a strong diffuse immunoreactivity for S-100 and lack of epithelial markers support the diagnosis.¹¹ After review of the literature, our case likely represents DMM as opposed to a melanoma in situ developing within a neurofibroma.