Nonmelanoma Skin Cancer

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

Fibroepithelioma of Pinkus (FeP), or Pinkus tumor, is a rare tumor with a presentation similar to benign neoplasms such as acrochordons and seborrheic keratoses. Classically, FeP presents as a nontender, solitary, flesh-colored, firm, dome-shaped papule or plaque with a predilection for the lumbosacral region rather than sun-exposed areas. This tumor typically develops in fair-skinned older adults, more often in females.¹

The association between cutaneous lesions and internal malignancies is well known to include dermatoses such as erythema repens in patients with lung cancer, or tripe palms and acanthosis nigricans in patients with gastrointestinal malignancy. Outside of paraneoplastic presentations, many syndromes have unique constellations of clinical findings that require the clinician to investigate for internal malignancy. Cancer-associated genodermatoses such as Birt-Hogg-Dubé, neurofibromatosis, and Cowden syndrome have key findings to alert the provider of potential internal malignancies.² Given the rarity and relative novelty of FeP, few studies have been performed that evaluate for an association with internal malignancies.

There potentially is a common pathophysiologic mechanism between FeP and other benign and malignant tumors. Some have noted a possible common embryonic origin, such as Merkel cells, and even a common gene mutation involving tumor protein p53 or PTCH1 gene.^3,4 Carcinoembryonic antigen is a glycoprotein often found in association with gastrointestinal tract tumors and also is elevated in some cases of FeP.⁵ A single-center retrospective study performed by Longo et al³ demonstrated an association between FeP and gastrointestinal malignancy by calculating a percentage of those with FeP who also had gastrointestinal tract tumors. Moreover, they noted that FeP preceded gastrointestinal tract tumors by up to 1 to 2 years. Using the results of this study, they suggested that a similar pathogenesis underlies the association between FeP and gastrointestinal malignancy, but a shared pathogenesis has not yet been elucidated.³

With a transition to preventive medicine and age-adjusted malignancy screening in the US medical community, the findings of FeP as a marker of gastrointestinal tract tumors could alter current recommendations of routine skin examinations and colorectal cancer screening. This study investigates the association between FeP and internal malignancy, especially gastrointestinal tract tumors.

Methods

Patient Selection—A single-center, retrospective, case-control study was designed to investigate an association between FeP and internal malignancy. The study protocol was approved by the institutional review board of the Naval Medical Center San Diego, California, in compliance with all applicable federal regulations governing the protection of human subjects. A medical record review was initiated using the Department of Defense (DoD) electronic health record to identify patients with a history of FeP. The query used a natural language search for patients who had received a histopathology report that included Fibroepithelioma of Pinkus, Pinkus, or Pinkus tumor within the diagnosis or comment section for pathology specimens processed at our institution (Naval Medical Center San Diego). A total of 45 patients evaluated at Naval Medical Center San Diego had biopsy specimens that met inclusion criteria. Only 42 electronic medical records were available to review between January 1, 2003, and March 1, 2020. Three patients were excluded from the study for absent or incomplete medical records.

Study Procedures—Data extracted by researchers were analyzed for statistical significance. All available data in current electronic health records prior to the FeP diagnosis until March 1, 2020, was reviewed for other documented malignancy or colonoscopy data. Data extracted included age, sex, date of diagnosis of FeP, location of FeP, social history, and medical and surgical history to identify prior malignancy. Colorectal cancer screening results were drawn from original reports, gastrointestinal clinic notes, biopsy results, and/or primary care provider documentation of colonoscopy results. If the exact date of internal tumor diagnosis could not be determined but the year was known, the value “July, year” was utilized as the diagnosis date.

Statistical Analysis—Data were reviewed for validity, and the Shapiro-Wilk test was used to test for normality. Graphical visualization assisted in reviewing the distribution of the data in relation to the internal tumors. The Fisher exact test was performed to test for associations, while continuous variables were assessed using the Student t test or the nonparametric Mann-Whitney U test. Analysis was conducted with StataCorp. 2017 Stata Statistical Software: Release 15 (StataCorp LLC). Significance was set at P<.05. 

Patient Demographics—Of the 42 patients with FeP included in this study, 28 (66.7%) were male and 14 (33.3%) were female. The overall mean age at FeP diagnosis was 56.83 years. The mean age (SD) at FeP diagnosis for males was 59.21 (19.00) years and 52.07 (21.61) for females (P=.2792)(Table 1). Other pertinent medical history, including alcohol and tobacco use, obesity, and diabetes mellitus, is included in Table 1.

Characterization of Tumors—The classification of the number of patients with any other nonskin neoplasm is presented in Table 2. Fifteen (35.7%) patients had 1 or more gastrointestinal tubular adenomas. Three patients were found to have colorectal adenocarcinoma. Karsenti et al⁶ published a large study of colonic adenoma detection rates in the World Journal of Gastroenterology stratified by age and found that the incidence of adenoma for those aged 55 to 59 years was 28.3% vs 35.7% in our study (P=.2978 [Fisher exact test]).

Given the number of gastrointestinal tract tumors detected, most of which were found during routine surveillance, and a prior study⁶ suggesting a relationship between FeP and gastrointestinal tract tumors, we analyzed the temporal relationship between the date of gastrointestinal tract tumor diagnosis and the date of FeP diagnosis to assess if gastrointestinal tract tumor or FeP might predict the onset of the other (Figure 1). By assigning a temporal category to each gastrointestinal tract tumor as occurring either before or after the FeP diagnosis by 0 to 3 years, 3 to 10 years, 10 to 15 years, and 15 or more years, the box plot in Figure 1 shows that gastrointestinal adenoma development had no significant temporal relationship to the presence of FeP, excluding any outliers (shown as dots). Additionally, in Figure 1, the same concept was applied to assess the relationship between the dates of all gastrointestinal tract tumors—benign, precancerous, or malignant—and the date of FeP diagnosis, which again showed that FeP and gastrointestinal tract tumors did not predict the onset of the other. Figure 2 showed the same for all nonskin tumor diagnoses and again demonstrated that FeP and all other nondermatologic tumors did not predict the onset of the other.

Comment

Malignancy Potential—The malignant potential of FeP—characterized as a trichoblastoma (an adnexal tumor) or a basal cell carcinoma (BCC) variant—has been documented.¹ Haddock and Cohen¹ noted that FeP can be considered as an intermediate variant between BCC and trichoblastomas. Furthermore, they questioned the relevance of differentiating FeP as benign or malignant.¹ There are additional elements of FeP that currently are unknown, which can be partially attributed to its rarity. If we can clarify a more accurate pathogenic model of FeP, then common mutational pathways with other malignancies may be identified.

Screening for Malignancy in FeP Patients—Until recently, FeP has not been demonstrated to be associated with other cancers or to have increased metastatic potential.¹ In a 1985 case series of 2 patients, FeP was found to be specifically overlying infiltrating ductal carcinoma of the breast. After a unilateral mastectomy, examination of the overlying skin of the breast showed a solitary, lightly pigmented nodule, which was identified as an FeP after histopathologic evaluation.⁷ There have been limited investigations of whether FeP is simply a solitary tumor or a harbinger for other malignancies, despite a study by Longo et al³ that attempted to establish this temporal relationship. They recommended that patients with FeP be clinically evaluated and screened for gastrointestinal tract tumors.³ Based on these recommendations, textbooks for dermatopathology now highlight the possible correlation of FeP and gastrointestinal malignancy,⁸ which may lead to earlier and unwarranted screening.

Comparison to the General Population—Although our analysis showed a portion of patients with FeP have gastrointestinal tract tumors, we do not detect a significant difference from the general population. The average age at the time of FeP diagnosis in our study was 56.83 years compared with the average age of 64.0 years by Longo et al,³ where they found an association with gastrointestinal adenocarcinoma and neuroendocrine tumors. As the rate of gastrointestinal adenoma and malignancy increases with age, the older population in the study by Longo et al³ may have developed colorectal cancer independent of FeP development. However, the rate of gastrointestinal or other malignancies in their study was substantially higher than that of the general population. The Longo et al³ study found that 22 of 49 patients developed nondermatologic malignancies within 2 years of FeP diagnosis. Additionally, no data were provided in the study regarding precancerous lesions.

In our study population, benign gastrointestinal tract tumors, specifically tubular adenomas, were noted in 35.7% of patients with FeP compared with 28.3% of the general population in the same age group reported by Karsenti et al.⁶ Although limited by our sample size, our study demonstrated that patients with FeP diagnosis showed no significant difference in age-stratified incidence of tubular adenoma compared with the general population (P=.2978). Figures 1 and 2 showed no obvious temporal relationship between the development of FeP and the diagnosis of gastrointestinal tumor—either precancerous or malignant lesions—suggesting that diagnosis of one does not indicate the presence of the other.

Relationship With Colonoscopy Results—By analyzing those patients with FeP who specifically had documented colonoscopy results, we did not find a correlation between FeP and gastrointestinal tubular adenoma or carcinoma at any time during the patients’ available records. Although some patients may have had undocumented colonoscopies performed outside the DoD medical system, most had evidence that these procedures were being performed by transcription into primary care provider notes, uploaded gastroenterologist clinical notes, or colonoscopy reports. It is unlikely a true colorectal or other malignancy would remain undocumented over years within the electronic medical record.

Study Limitations—Because of the nature of electronic medical records at multiple institutions, the quality and/or the quantity of medical documentation is not standardized across all patients. Not all pathology reports may include FeP as the primary diagnosis or description, as FeP may simply be reported as BCC. Despite thorough data extraction by physicians, we were limited to the data available within our electronic medical records. Colonoscopies and other specialty care often were performed by civilian providers. Documentation regarding where patients were referred for such procedures outside the DoD was not available unless reports were transmitted to the DoD or transcribed by primary care providers. Incomplete records may make it more difficult to identify and document the number and characteristics of patients’ tubular adenomas. Therefore, a complete review of civilian records was not possible, causing some patients’ medical records to be documented for a longer period of their lives than for others.

Conclusion

Our data demonstrated no statistically significant temporal relationship between the development of FeP and other benign or malignant tumors. Additionally, the prevalence of tubular adenoma or gastrointestinal malignancy is not substantially higher in those with FeP than the age-adjusted population. Current guidelines recommend that patients with FeP should be treated and return for follow up at regular intervals, similar to patients with a history of BCC. This study does not establish FeP as a risk factor for development of any type of cancer that would require earlier or more frequent intervals beyond the established age-appropriate screening guidelines.

Given the discrepancies in our findings with the previous study,³ future investigations on FeP and associated tumors should focus on integrated health care systems with longitudinal data sets for all age-appropriate cancer screenings in a larger sample size. Another related study is needed to evaluate the pathophysiologic mechanisms of FeP development relative to known cancer lines.

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of skin-homing T-cell neoplasms with a wide array of clinical presentations, immunohistopathologic subtypes, and prognoses. The age-adjusted incidence of CTCL in the United States is 6.4 per million individuals.¹ In the early stages of CTCL, the malignant lymphocytes are isolated to the skin, while more advanced disease involves metastatic spread to the lymphatic and peripheral blood compartments. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising roughly 50% of all cases. The etiology of CTCL and MF remains poorly understood and no unifying driver mutation has been identified.² However, recent sequencing efforts have revealed recurrent genomics alterations primarily in 3 pathways: constitutive T-cell activation, resistance to apoptosis/cell-cycle dysregulation, and DNA structural/gene expression dysregulation.^3-8 These studies, among others, support the assertion that CTCL may be an epigenetic phenomenon.^9-14

Most patients with MF will experience an indolent course of skin-limited disease with a favorable prognosis and a 5-year survival rate of 88%.^15-17 A large study of patients with MF (N=525) followed for more than 40 years determined that approximately 20% of early-stage (IA-IIA) patients with MF progress to develop tumors, metastasis to the lymphatic tissue, and/or leukemic blood disease.¹⁸

Cutaneous T-cell lymphoma is a chronic disease, and most treatment responses are partial and short-lived. Allogenic hematopoietic transplantation is the only potentially curative option, and all other therapies are aimed at arresting progression and achieving remission.¹⁹ Skin-directed therapies include topical steroids, topical nitrogen mustard, phototherapy, and radiation. Systemic therapies such as oral retinoids, chemotherapy, and immunotherapy may be used alone or in combination with skin-directed therapies based on the overall disease stage and clinical presentation. Unfortunately, complete response (CR) to therapy is rare and fleeting, and most patients require multiple sequential treatments over their lifetimes.²⁰

Across all stages of CTCL, there is a therapeutic push to combination and immune-based therapies to achieve more durable responses. The imidazoquinolines are a family of toll-like receptor (TLR) agonists including imiquimod (TLR7) and resiquimod (TLR7 and TLR8). Imiquimod (IMQ) is a topical immunomodulator, which increases the local cytotoxic helper T-cell profile (T_H1 marked by IFN-α, tumor necrosis factor α, IL-1α, IL-6, and IL-8), thereby enhancing both humoral and innate immune responses targeting tumor cells.^21-23 Several small studies evaluating topical TLR agonists have documented efficacy in patients with early and advanced stages of CTCL.^24-34

Skin-directed chemotherapy using 5-fluorouracil (5-FU) has shown activity against many cutaneous malignancies. 5-Fluorouracil is an antimetabolite drug that inhibits thymidylate synthase, resulting in interrupted DNA and RNA synthesis and leading to an apoptotic cell death (Figure 1). It has been administered via intravenous, oral (prodrug), intralesional (IL), and topical routes with well-documented success in treating cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and precancerous actinic keratosis.³⁵ As a topical, 5-FU has been shown to provide a good response in 6 patients with early MF.³⁶ In late-stage MF, 5-FU has been used in combination with methotrexate as an infusion.³⁷ We present a single-center case series of 9 patients with CTCL who received combination IL 5-FU and IMQ cream 5%.

Methods

Patient Selection—Patients were selected from our multidisciplinary CTCL subspecialty clinic at the Inova Schar Cancer Institute (Fairfax, Virginia). Patients with single to few recalcitrant CTCL plaques or tumors that were symptomatic or otherwise bothersome were included. All patients had at least 2 prior skin-directed therapies that failed, and many had advanced-stage disease requiring systemic therapy. All patients provided verbal consent.

Study Materials and Evaluations—Patients received IL injections of 5-FU 50 mg/mL. The volume injected was approximately 0.2 cc per cubic centimeter of lesion tissue. Injections were repeated at 2- to 3-week intervals until the target lesions achieved an acute hemorrhagic phase characterized by erosion, flattening, and crust formation. The total number of serial injections administered ranged from 1 to 5. The patients concomitantly treated all lesions with IMQ cream 5% daily for a duration of 2 to 3 months.

Medical photography and physical examination were performed every 2 to 3 weeks until the hemorrhagic phase resolved and treated sites re-epithelialized. Index lesions were assessed using the Composite Assessment of Index Lesion Severity (CAILS) score by a single investigator for all patients.³⁸ Scores were retrospectively assigned using the investigator’s detailed physical examination descriptions and extensive medical photography. Any hyperpigmentation was scored as residual disease, despite the fair interpretation of it as procedure-related postinflammatory dyspigmentation. Complete response was strictly defined as a CAILS score of 0. The patients were screened for possible systemic effects of IMQ, including the presence of fever, chills, fatigue, and myalgia. Patients were evaluated every 6 to 12 weeks as a standing follow-up.

Statistical Analysis—Reductions were calculated using local regression from baseline to the 4- to 7-week follow-up. Patients with multiple lesions had their CAILS score averaged at ea

Results

Nine patients aged 28 to 91 years (median age, 66 years) with CTCL stages IA to IVA2, who had lesions located throughout their body, achieved CR; 3 patients were female (Table 1). The most common phenotype was CD8⁺ (n=3). All patients had at least 2 prior skin-directed therapies at treatment sites that failed, and 1 patient had 7 prior treatments that failed. Prior treatments included a variety of modalities, including all standard-of-care options and enrollment in clinical trials. One patient died from pneumonia following CR (Table 2). Seven patients had previously received systemic therapy for CTCL, and 1 patient was stable on romidepsin during our study. In patients who received more than 1 injection of 5-FU—1 injection: 3 patients; 2 injections: 3 patients; 3 injections: 1 patient; 4 injections: 1 patient; 5 injections: 1 patient—injections were spaced by 2 to 3 weeks. There was 1 patient who initially had an inadequate dosing of IL 5-FU and was restarted 14 months later; this was the patient with 5 total injections. This occurred in one of the first patients in the study, who presented with a facial lesion. The investigator used approximately 0.02 cc per cubic centimeter (dose reduction of nearly 90%), which was inadequate and did not achieve the requisite hemorrhagic phase.

Treatment was well tolerated overall. In all cases, a hemorrhagic phase was achieved, characterized by erosion and crusting that was rated as mildly uncomfortable by 7 patients and moderately uncomfortable by 2 patients. In total, 15 lesions in all 9 patients achieved a CR within 24 weeks of the final injection. The longest treatment course required 12 weeks of therapy with IMQ and 5 IL injections of 5-FU. The fastest CR was achieved in patient 6 within 6 weeks following a single IL injection of 5-FU and 2 applications of IMQ. The average time to CR was 14.78 weeks (95% CI, 1.75-27.81)(Figure 2), and the time to CR ranged from 4 to 24 weeks. On average, patients achieved more than 50% reduction in CAILS score by 3.53 weeks (95% CI, 1.55-5.51) and nearly a 4-fold (74.7%) reduction at the time of initial follow-up (occurring at 4–7 weeks). By 7 weeks, patient 3 had the most modest improvement in CAILS score with a 2.75-fold reduction, while patient 5 had the largest decrease with a 5-fold reduction. Figure 3 shows representative clinical photographs of 2 patients before and after treatment, with all patients having similar results.

Comment

Cutaneous T-cell lymphoma is a chronic skin cancer with a pattern of limited response to therapy and frequent recurrence. Currently available skin-directed therapies function as temporizing measures rather than curative treatments. Immunotherapy offers the promise of lasting disease control even after cessation of treatment, as it may essentially awaken cutaneous immune surveillance to malignant lymphocytes.

Several small observational studies have evaluated topical IMQ and TLR agonist therapy in CTCL. The construct of prior reports varies widely, including many different pretreatments, dosing schemes, and follow-up periods.^24-33 Dosing intervals with IMQ ranged from daily to 3 times per week and treatment duration from 2 weeks to 1 year. Complete response rates from 50% to 100% were reported, and partial responses were observed in all but 1 patient, with recurrence-free follow-up ranging from 6 months to 8 years. Comparatively, combining IL 5-FU and IMQ appears to be at least as effective as IMQ alone or in other sequential treatments and combinations.^24-33

Resiquimod, an experimental TLR7/8 agonist, has shown promising results in CTCL. Rook et al³⁴ conducted a phase 1 trial of topical resiquimod in 12 early-stage patients with CTCL, all of whom responded to therapy. Two patients achieved CR, and 9 achieved a partial response, including 5 patients with the folliculotropic subtype. Interestingly, an abscopal effect was observed in 92% (11/12) of patients. Molecular evidence of reduction of the malignant clone was observed in 90% of patients via high-throughput sequencing of lesional tissue.³⁴ These exciting findings suggest that topical immune therapy with TLR agonists may achieve robust, sustained, and possibly global disease control in CTCL.

Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced T_H1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.

In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.

Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al³⁶ reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.

Conclusion

Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

A California woman developed skin cancer after getting a cut during a manicure. Now, she and her doctor are spreading the word about her ordeal as a lesson that speed and persistence in seeking treatment are the keys that make her type of cancer – squamous cell carcinoma – completely curable.

“She cut me, and the cut wasn’t just a regular cuticle cut. She cut me deep, and that was one of the first times that happened to me,” Grace Garcia, 50, told TODAY.com, recalling the November 2021 incident.

Ms. Garcia had been getting her nails done regularly for 20 years, she said, but happened to go to a different salon than her usual spot because she couldn’t get an appointment during the busy pre-Thanksgiving season. She doesn’t recall whether the technician opened packaging that signals unused tools.

She put antibiotic ointment on the cut, but it didn’t heal after a few days. Eventually, the skin closed and a darkened bump formed. It was painful. She went to her doctor, who said it was a “callus from writing,” she told TODAY.com. But it was on her ring finger, which didn’t seem connected to writing. Her doctor said to keep an eye on it. 

Five months after the cut occurred, she mentioned it during a gynecology appointment and was referred to a dermatologist, who also advised keeping an eye on it. A wart developed. She went back to her primary care physician and then to another dermatologist. The spot was biopsied.

Squamous cell carcinoma is a common type of skin cancer, according to the American Academy of Dermatology. It can have many causes, but the cause in Ms. Garcia’s case was both very common and very rare: human papillomavirus, or HPV. HPV is a virus that infects millions of people every year, but it’s not a typical cause of skin cancer.

“It’s pretty rare for several reasons. Generally speaking, the strains that cause cancer from an HPV standpoint tend to be more sexually transmitted,” dermatologist Teo Soleymani told TODAY.com. “In Grace’s case, she had an injury, which became the portal of entry. So that thick skin that we have on our hands and feet that acts as a natural barrier against infections and things like that was no longer the case, and the virus was able to infect her skin.”

Dr. Soleymani said Ms. Garcia’s persistence to get answers likely saved her from losing a finger.

“Your outcomes are entirely dictated by how early you catch them, and very often they’re completely curable,” he said. “Her persistence – not only was she able to have a great outcome, she probably saved herself from having her finger amputated.”

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

To the Editor:

Surgical wounds on the lower leg are challenging to manage because venous stasis, bacterial colonization, and high tension may contribute to protracted healing. Advances in technology led to the development of novel, polymer-based wound-healing modalities that hold promise for the management of these wounds.

A 75-year-old man presented with a well-differentiated squamous cell carcinoma with a 3-mm depth of invasion on the left pretibial region. His comorbidities were notable for hypertension, hypercholesterolemia, varicose veins, myocardial infarction, peripheral vascular disease, and a 32 pack-year cigarette smoking history. Current medications included clopidogrel bisulfate and warfarin sodium to manage a recently placed coronary artery stent.

The tumor was cleared after 2 stages of Mohs micrographic surgery with excision down to tibialis anterior fascia (Figure 1A). The resultant defect measured 43×33 mm in area and 9 mm in depth (wound size, 12,771 mm³). Reconstructive options were discussed, including random-pattern flap repair and skin graft. Given the patient’s risk of bleeding, the decision was made to forego a flap repair. Additionally, the patient was a heavy smoker and could not comply with the wound care and elevation and ambulation restrictions required for optimal skin graft care. Therefore, a decision was made to proceed with secondary intention healing using a methacrylate polymer powder dressing.

After achieving hemostasis, a novel 10-mg sterile, biologically inert methacrylate polymer powder dressing was poured over the wound in a uniform layer to fill and seal the entire wound surface (Figure 1B). Sterile normal saline 0.1 mL was sprayed onto the powder to activate particle aggregation. No secondary dressing was used, and the patient was permitted to get the dressing wet after 48 hours.

The dressing was changed in a similar fashion 4 weeks after application, following gentle debridement with gauze and normal saline. Eight weeks after surgery, the wound exhibited healthy granulation tissue and measured 5×6 mm in area and 2 mm in depth (wound size, 60 mm³), which represented a 99.5% reduction in wound size (Figure 1C). The dressing was not painful, and there were no reported adverse effects. The patient continued to smoke and ambulate fully throughout this period. No antibiotics were used.

Methacrylate polymer powder dressings are a novel and sophisticated dressing modality with great promise for the management of surgical wounds on the lower limb. The dressing is a sterile powder consisting of 84.8% poly-2-hydroxyethylmethacrylate, 14.9% poly-2-hydroxypropylmethacrylate, and 0.3% sodium deoxycholate. These hydrophilic polymers have a covalent methacrylate backbone with a hydroxyl aliphatic side chain. When saline or wound exudate contacts the powder, the spheres hydrate and nonreversibly aggregate to form a moist, flexible dressing that conforms to the topography of the wound and seals it (Figure 2).¹

Once the spheres have aggregated, they are designed to orient in a honeycomb formation with 4- to 10-nm openings that serve as capillary channels (Figure 3). This porous architecture of the polymer is essential for adequate moisture management. It allows for vapor transpiration at a rate of 12 L/m² per day, which ensures the capillary flow from the moist wound surface is evenly distributed through the dressing, contributing to its 68% water content. Notably, this approximately three-fifths water composition is similar to the water makeup of human skin. Optimized moisture management is theorized to enhance epithelial migration, stimulate angiogenesis, retain growth factors, promote autolytic debridement, and maintain ideal voltage and oxygen gradients for wound healing. The risk for infection is not increased by the existence of these pores, as their small size does not allow for bacterial migration.¹

This case demonstrates the effectiveness of using a methacrylate polymer powder dressing to promote timely wound healing in a poorly vascularized lower leg surgical wound. The low maintenance, user-friendly dressing was changed at monthly intervals, which spared the patient the inconvenience and pain associated with the repeated application of more conventional primary and secondary dressings. The dressing was well tolerated and resulted in a 99.5% reduction in wound size. Further studies are needed to investigate the utility of this promising technology.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

Overall survival has improved in patients with Kaposi’s sarcoma since the introduction of antiretroviral therapy (ART), but those with HIV infection can expect to live shorter lives than their uninfected counterparts, based on the first such analysis of the American College of Surgeons’ National Cancer Database.

One-year overall survival for all patients with Kaposi’s sarcoma (KS), 74.9% in 2004-2007, rose by 6.4 percentage points to 81.3% in 2016-2018, with the use of ART for HIV starting in 2008. Two-year survival was up by an even larger 8.3 percentage points: 68.0% to 76.3%, said Amar D. Desai of New Jersey Medical School, Newark, and Shari R. Lipner, MD, of Weill Cornell Medicine, New York.

Since HIV-infected patients represented a much lower 46.7% of the Kaposi’s population in 2016-2018 than in 2004-2007 (70.5%), “better outcomes for all KS patients likely reflects advancements in ART, preventing many HIV+ patients from progressing to AIDS, changes in clinical practice with earlier treatment start, and more off-label treatments,” they wrote in the Journal of the American Academy of Dermatology.

Overall survival rates for the 10,027 patients with KS with data available in the National Cancer Database were 77.9% at 1 year and 72.4% at 2 years. HIV status had a significant (P < .0074) effect over the entire study period: One-year survival rates were 88.9% for HIV-negative and 74.5% for HIV-positive patients, and 2-year rates were 83.0% (HIV-negative) and 69.3% (HIV-positive), the investigators reported in what they called “the largest analysis since the advent of antiretroviral therapy for HIV in 2008.”

The improvement in overall survival, along with the continued differences in survival between HIV infected and noninfected patients, indicate that “dermatologists, as part of a multidisciplinary team including oncologists and infectious disease physicians, can play significant roles in early KS diagnosis,” Mr. Desai and Dr. Lipner said.

Mr. Desai had no conflicts of interest to report. Dr. Lipner has served as a consultant for Ortho-Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

To the Editor:

Angiosarcoma is a malignancy of the vascular endothelium that most commonly presents on the skin.¹ Patients diagnosed with cutaneous angiosarcoma, which is a rare and aggressive malignancy, have a 5-year survival rate of approximately 30%.^2,3 Angiosarcoma can be seen in the setting of chronic lymphedema; radiation therapy; and sporadically in elderly patients, where it is commonly seen on the head and neck. Presentation on the head and neck has been associated with worse outcomes, with a projected overall 10-year survival rate of 13.8%; the survival rate is lower if the tumor is surgically unresectable or larger in size. Metastasis can occur via both lymphatic and hematogenous routes, with pulmonary and hepatic metastases most frequently observed.¹ Prognostications of poor outcomes for patients with head and neck cutaneous angiosarcoma via a 5-year survival rate were identified in a meta-analysis and included the following: patient age older than 70 years, larger tumors, tumor location of scalp vs face, nonsurgical treatments, and lack of clear margins on histology.²

Treatment of angiosarcoma historically has encompassed both surgical resection and adjuvant radiation therapy with suboptimal success. Evidence supporting various treatment regimens remains sparse due to the low incidence of the neoplasm. Although surgical resection is the only documented curative treatment, cutaneous angiosarcomas frequently are found to have positive surgical margins and require adjuvant radiation. Use of high-dose radiation (>50 Gy) with application over a wide treatment area such as total scalp irradiation is recommended.⁴ Although radiation has been found to diminish local recurrence rates, it has not substantially affected rates of distant disease recurrence.¹ Cytotoxic chemotherapy has clinical utility in minimizing progression, but standard regimens afford a progression-free survival of only months.³ Adjuvant treatment with paclitaxel has been shown to have improved efficacy in scalp angiosarcoma vs other visceral sites, showing a nonprogression rate of 42% at 4 months after treatment.⁵ More recently, targeted chemotherapeutics, including the vascular endothelial growth factor inhibitor bevacizumab and tyrosine kinase inhibitor sorafenib, have shown some survival benefit, but it is unclear if these agents are superior to traditional cytotoxic agents.^4,6-10 A phase 2 study of paclitaxel administered weekly with or without bevacizumab showed similar progression-free survival and overall survival, albeit at the expense of added toxicity experienced by participants in the combined group.¹⁰

The addition of the nonselective β-adrenergic blocker propranolol to the treatment armamentarium, which was pursued due to its utility in the treatment of benign infantile hemangioma and demonstrated ability to limit the expression of adrenergic receptors in angiosarcoma, has gained clinical attention for possible augmentation of cutaneous angiosarcoma therapy.^11-14 Propranolol has been shown to reduce metastasis in other neoplasms—both vascular and nonvascular—and may play a role as an adjuvant treatment to current therapies in angiosarcoma.^15-20 We report a patient with cutaneous angiosarcoma (T2 classification) with disease-free survival of nearly 6 years without evidence of recurrence in the setting of continuous propranolol use supplementary to chemotherapy and radiation.

A 78-year-old man with a history of multiple basal cell carcinomas, hypertension, and remote smoking history presented to the dermatology clinic with an enlarging red-brown plaque on the scalp of 2 months’ duration. The lesion had grown rapidly to involve the forehead, right temple, preauricular region, and parietal scalp. At presentation, the tumor measured more than 20 cm in diameter at its greatest point (Figure 1). Physical examination revealed a 6-mm purple nodule within the lesion on the patient’s right parietal scalp. No clinical lymphadenopathy was appreciated at the time of diagnosis. Punch biopsies of the right parietal scalp nodule and right temple patch showed findings consistent with angiosarcoma with diffuse cytoplasmic staining of CD31 in atypical endothelial cells and no staining for human herpesvirus 8 (Figure 2). Concurrent computed tomography of the head showed thickening of the right epidermis, dermis, and deeper scalp tissues, but there was no evidence of skull involvement. Computed tomography of the thorax, abdomen, and pelvis showed no evidence of metastatic disease. After a diagnostic workup, the patient was diagnosed with T2bN0M0 angiosarcoma.

The lesion was determined to be nonresectable due to the extent of the patient’s cutaneous disease. The patient was started on a regimen of paclitaxel, scalp radiation, and oral propranolol. Propranolol 40 mg twice daily was initiated at the time of diagnosis with a plan to continue indefinitely. Starting 1 month after staging, the patient completed 10 weekly cycles of paclitaxel, and he was treated with 60 Gy of scalp radiation in 30 fractions, starting with the second cycle of paclitaxel. He tolerated both well with no reported adverse events. Repeat computed tomography performed 1 month after completion of chemotherapy and radiation showed no evidence of a mass or fluid collection in subcutaneous scalp tissues and no evidence of metastatic disease. This correlated with an observed clinical regression at 1 month and complete clinical response at 5 months with residual hemosiderin and radiation changes. The area of prior disease involvement subsequently evolved from violet to dusky gray in appearance to an eventual complete resolution 26 months after diagnosis, accompanied by atrophic radiation-induced sequelae (Figure 3).

The patient’s postchemotherapy course was complicated by hospitalization for a suspected malignant pleural effusion. Analysis revealed growing ground-glass opacities and nodules in the right lower lung lobe. A thoracentesis with cytology studies was negative for malignancy. Continued monitoring over 19 months demonstrated eventual resolution of those findings. He experienced notable complication from local radiation therapy to the scalp with chronic cutaneous ulceration refractory to wound care and surgical intervention. The patient did not exhibit additional signs or symptoms concerning for recurrence or metastasis and was followed by dermatology and oncology until he died nearly 5 years after initial diagnosis due to complications from acute hypoxic respiratory failure secondary to COVID-19. The last imaging obtained showed no convincing evidence of metastasis, though spinal imaging within a month of his death showed lesions favored to represent benign angiomatous growths. His survival after diagnosis ultimately reached 57 months without confirmed disease recurrence and cause of death unrelated to malignancy history, which is a markedly long documented survival for this extent of disease.

Cutaneous angiosarcoma is an aggressive yet rare malignancy without effective treatments for prolonging survival or eradicating disease. Cutaneous angiosarcoma of the head and neck has a reported 10-year survival rate of 13.8%.¹ Although angiosarcoma in any location holds a bleak prognosis, cutaneous angiosarcoma of the scalp with a T2 classification has a 2-year survival rate of 0%. Moreover, even if remission is achieved, disease is highly recurrent, typically within months with the current standard of care.^3,21,22

Emerging evidence for the possible role of β-adrenergic receptor blockade in the treatment of malignant vascular neoplasms is promising. Microarrays from a host of vascular growths have demonstrated expression of β-adrenergic receptors in 77% of sampled angiosarcoma specimens in addition to strong expression in infantile hemangiomas, hemangiomas, hemangioendotheliomas, and vascular malformations.¹⁹ Research findings have further verified the validity of this approach with the demonstration of b₁-, b₂-, and b₃- adrenergic receptor expression by angiosarcoma cell lines. Propranolol subsequently was shown to effectively target proliferation of these cells and induce apoptosis in a dose-dependent manner and moreover be synergistic in effect with other chemotherapies.¹⁵ Several genes have exhibited differential expression between control tumor cells and propranolol-treated cells. Specifically, target genes including AXL (a receptor tyrosine kinase associated with cell adhesion, proliferation, and apoptosis and found to upregulated in melanoma and leukemia) and ERBB receptor feedback inhibitor 1 (receptor tyrosine kinase, with ERBB family members commonly overexpressed or mutated in the setting malignancy) have been posited as possible explanatory factors in the observed angiosarcoma response to propranolol.²³

Several cases describing propranolol use as an adjunctive therapy for angiosarcoma suggest a beneficial role in clinical medicine. One case report described propranolol monotherapy for lesion to our patient, with a resultant reduction in Ki-67 as a measure of proliferative index within 1 week of initiating propranolol therapy.¹³ Propranolol also has been shown to halt or slow progression of metastatic disease in visceral and metastatic angiosarcomas.^12-14 In combination with oral etoposide and cyclophosphamide, maintenance propranolol therapy in 7 cases of advanced cutaneous angiosarcoma resulted in 1 complete response and 3 very good partial responses, with a median progression-free survival of 11 months.¹¹ Larger-scale studies have not been published, but the growing number of case reports and case series warrants further investigation of the utility of propranolol as an adjunct to current therapies in advanced angiosarcoma.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.