Article

Evidence-based cognitive-behavioral therapies for posttraumatic stress disorder (PTSD) may employ cognitive restructuring. This psychotherapeutic technique entails recognizing and correcting maladaptive, inaccurate thoughts that perpetuate illness.¹ For example, a clinician helps a patient recognize that the negative thought “Nobody loves me” following a romantic breakup is an overgeneralization. The patient is taught to self-correct this to “While my ex-girlfriend doesn’t love me, others do. It only feels like nobody loves me.”²

We introduce the acronym I STEP to help clinicians recognize several common distorted thoughts in PTSD. These tend to occur within stereotyped themes in PTSD,³ as outlined and illustrated below. Recognizing distorted thoughts in these patients will help clinicians understand and address psychological distress following trauma.

Intimacy/In-touch. Intimacy involves comfort in relationships, including but not limited to sexual intimacy. This requires being in touch emotionally with self and others. In trauma involving loss, fear of further loss may impair intimacy with others. Difficulty with self-intimacy impairs commitment to life’s goals and prompts unhelpful avoidance behaviors, such as difficulty being alone or self-injurious use of drugs or alcohol. Comfort in spending some portion of time alone with one’s thoughts and emotions is a life skill necessary to attain optimum function. Patients who are unable to tolerate their own emotions without constant company might have excessive anxiety when social supports are otherwise occupied. Such patients might seek excessive and repeated reassurance rather than learning to tolerate their own emotions and thoughts. They would then find it difficult to engage successfully in solo activities.

Safety. After trauma, patients may view themselves and others as unsafe, and may overestimate risk. For example, a pedestrian who is struck by a vehicle may believe that crossing a street will again result in getting hit by a car without appreciating that people frequently cross streets without injury or that crossing cautiously is an essential life skill. Parents who have suffered from trauma may unduly believe that their children are in danger when engaging in an activity generally considered to be safe. This may create challenges in parenting and impede their children’s ability to develop a sense of independence.

Trust. Trauma victims may unfairly blame themselves, leading them to mistrust their own judgment. Such patients may have difficulty making decisions confidently and independently, such as choosing a job or a romantic partner. When traumatized by another person or people, it can be difficult to maintain positive views of others or to accept others’ positive behaviors as genuine. For example, a common reaction following rape may be a generalized mistrust of all men.

Esteem. Patients’ self-esteem may suffer following trauma due to irrational self-blame or believing the “just world hypothesis”—the idea that bad things only happen to bad people. For example, a patient who suffers an assault by an acquaintance might think “I must be stupid if I couldn’t figure out that my friend was dangerous.”

Power. Traumatic events usually occur outside of one’s control. Survivors of trauma may lose confidence in their ability to control any aspect of their lives. Conversely, they may attempt to gain control of all of life’s circumstances, including those that are beyond anyone’s control. Control can be applied to emotions, behaviors, or events. A driver struck by a vehicle may think “I can’t control other drivers, so I have no power to control my safety while driving,” and hence give up driving. While there are things that are beyond our control, this extreme thought ignores things that we can control, such as wearing seatbelts or having the vehicle’s brakes regularly serviced.

Evidence-based cognitive-behavioral therapies for posttraumatic stress disorder (PTSD) may employ cognitive restructuring. This psychotherapeutic technique entails recognizing and correcting maladaptive, inaccurate thoughts that perpetuate illness.¹ For example, a clinician helps a patient recognize that the negative thought “Nobody loves me” following a romantic breakup is an overgeneralization. The patient is taught to self-correct this to “While my ex-girlfriend doesn’t love me, others do. It only feels like nobody loves me.”²

We introduce the acronym I STEP to help clinicians recognize several common distorted thoughts in PTSD. These tend to occur within stereotyped themes in PTSD,³ as outlined and illustrated below. Recognizing distorted thoughts in these patients will help clinicians understand and address psychological distress following trauma.

Intimacy/In-touch. Intimacy involves comfort in relationships, including but not limited to sexual intimacy. This requires being in touch emotionally with self and others. In trauma involving loss, fear of further loss may impair intimacy with others. Difficulty with self-intimacy impairs commitment to life’s goals and prompts unhelpful avoidance behaviors, such as difficulty being alone or self-injurious use of drugs or alcohol. Comfort in spending some portion of time alone with one’s thoughts and emotions is a life skill necessary to attain optimum function. Patients who are unable to tolerate their own emotions without constant company might have excessive anxiety when social supports are otherwise occupied. Such patients might seek excessive and repeated reassurance rather than learning to tolerate their own emotions and thoughts. They would then find it difficult to engage successfully in solo activities.

Safety. After trauma, patients may view themselves and others as unsafe, and may overestimate risk. For example, a pedestrian who is struck by a vehicle may believe that crossing a street will again result in getting hit by a car without appreciating that people frequently cross streets without injury or that crossing cautiously is an essential life skill. Parents who have suffered from trauma may unduly believe that their children are in danger when engaging in an activity generally considered to be safe. This may create challenges in parenting and impede their children’s ability to develop a sense of independence.

Trust. Trauma victims may unfairly blame themselves, leading them to mistrust their own judgment. Such patients may have difficulty making decisions confidently and independently, such as choosing a job or a romantic partner. When traumatized by another person or people, it can be difficult to maintain positive views of others or to accept others’ positive behaviors as genuine. For example, a common reaction following rape may be a generalized mistrust of all men.

Esteem. Patients’ self-esteem may suffer following trauma due to irrational self-blame or believing the “just world hypothesis”—the idea that bad things only happen to bad people. For example, a patient who suffers an assault by an acquaintance might think “I must be stupid if I couldn’t figure out that my friend was dangerous.”

Power. Traumatic events usually occur outside of one’s control. Survivors of trauma may lose confidence in their ability to control any aspect of their lives. Conversely, they may attempt to gain control of all of life’s circumstances, including those that are beyond anyone’s control. Control can be applied to emotions, behaviors, or events. A driver struck by a vehicle may think “I can’t control other drivers, so I have no power to control my safety while driving,” and hence give up driving. While there are things that are beyond our control, this extreme thought ignores things that we can control, such as wearing seatbelts or having the vehicle’s brakes regularly serviced.

Evidence-based cognitive-behavioral therapies for posttraumatic stress disorder (PTSD) may employ cognitive restructuring. This psychotherapeutic technique entails recognizing and correcting maladaptive, inaccurate thoughts that perpetuate illness.¹ For example, a clinician helps a patient recognize that the negative thought “Nobody loves me” following a romantic breakup is an overgeneralization. The patient is taught to self-correct this to “While my ex-girlfriend doesn’t love me, others do. It only feels like nobody loves me.”²

We introduce the acronym I STEP to help clinicians recognize several common distorted thoughts in PTSD. These tend to occur within stereotyped themes in PTSD,³ as outlined and illustrated below. Recognizing distorted thoughts in these patients will help clinicians understand and address psychological distress following trauma.

Intimacy/In-touch. Intimacy involves comfort in relationships, including but not limited to sexual intimacy. This requires being in touch emotionally with self and others. In trauma involving loss, fear of further loss may impair intimacy with others. Difficulty with self-intimacy impairs commitment to life’s goals and prompts unhelpful avoidance behaviors, such as difficulty being alone or self-injurious use of drugs or alcohol. Comfort in spending some portion of time alone with one’s thoughts and emotions is a life skill necessary to attain optimum function. Patients who are unable to tolerate their own emotions without constant company might have excessive anxiety when social supports are otherwise occupied. Such patients might seek excessive and repeated reassurance rather than learning to tolerate their own emotions and thoughts. They would then find it difficult to engage successfully in solo activities.

Safety. After trauma, patients may view themselves and others as unsafe, and may overestimate risk. For example, a pedestrian who is struck by a vehicle may believe that crossing a street will again result in getting hit by a car without appreciating that people frequently cross streets without injury or that crossing cautiously is an essential life skill. Parents who have suffered from trauma may unduly believe that their children are in danger when engaging in an activity generally considered to be safe. This may create challenges in parenting and impede their children’s ability to develop a sense of independence.

Trust. Trauma victims may unfairly blame themselves, leading them to mistrust their own judgment. Such patients may have difficulty making decisions confidently and independently, such as choosing a job or a romantic partner. When traumatized by another person or people, it can be difficult to maintain positive views of others or to accept others’ positive behaviors as genuine. For example, a common reaction following rape may be a generalized mistrust of all men.

Esteem. Patients’ self-esteem may suffer following trauma due to irrational self-blame or believing the “just world hypothesis”—the idea that bad things only happen to bad people. For example, a patient who suffers an assault by an acquaintance might think “I must be stupid if I couldn’t figure out that my friend was dangerous.”

Power. Traumatic events usually occur outside of one’s control. Survivors of trauma may lose confidence in their ability to control any aspect of their lives. Conversely, they may attempt to gain control of all of life’s circumstances, including those that are beyond anyone’s control. Control can be applied to emotions, behaviors, or events. A driver struck by a vehicle may think “I can’t control other drivers, so I have no power to control my safety while driving,” and hence give up driving. While there are things that are beyond our control, this extreme thought ignores things that we can control, such as wearing seatbelts or having the vehicle’s brakes regularly serviced.

With the COVID-19 pandemic turning the world on its head, we have seen more first-episode psychotic breaks and quick deterioration in previously stable patients. Early in the pandemic, care was particularly complicated for psychiatric patients who had been infected with the virus. Many of these patients required immediate psychiatric hospitalization. At that time, many community hospital psychiatric inpatient units did not have the capacity, staffing, or infrastructure to safely admit such patients, so they needed to be managed on a medical unit. Here, I discuss the case of a COVID-19–positive woman with psychiatric illness who we managed while she was in quarantine on a medical unit.

Case report

Early in the COVID-19 pandemic, Ms. B, a 35-year-old teacher with a history of depression, was evaluated in the emergency department for bizarre behavior and paranoid delusions regarding her family. Initial laboratory and imaging testing was negative for any potential medical causes of her psychiatric symptoms. Psychiatric hospitalization was recommended, but before Ms. B could be transferred to the psychiatric unit, she tested positive for COVID-19. At that time, our community hospital did not have a designated wing on our psychiatric unit for patients infected with COVID-19. Thus, Ms. B was admitted to the medical floor, where she was quarantined in her room. She would need to remain asymptomatic and test negative for COVID-19 before she could be transferred to the psychiatric unit.

Upon arriving at the medical unit, Ms. B was hostile and uncooperative. She frequently attempted to leave her room and required restraints throughout the day. Our consultation-liaison (CL) team was consulted to assist in managing her. During the initial interview, we noticed that she had covered all 4 walls of her room with papers filled with handwritten notes. Ms. B had cut her gown to expose her stomach and legs. She had pressured speech, tangential thinking, and was religiously preoccupied. She denied any visual and auditory hallucinations, but her persecutory delusions involving her family persisted. We believed that her signs and symptoms were consistent with a manic episode from underlying, and likely undiagnosed, bipolar I disorder that was precipitated by her COVID-19 infection.

We first addressed Ms. B’s and the staff’s safety by transferring her to a larger room with a vestibule at the end of the hallway so she had more room to walk and minimal exposure to the stimuli of the medical unit. We initiated one-on-one observation to redirect her and prevent elopement. We incentivized her cooperation with staff by providing her with paper, pencils, reading material, and phone privileges. We started oral risperidone 2 mg twice daily and lorazepam 2 mg 3 times daily for short-term behavioral control and acute treatment of her symptoms, with the goal of deferring additional treatment decisions to the inpatient psychiatry team after she was transferred to the psychiatric unit. Ms. B’s agitation and impulsivity improved. She began participating with the medical team and was eventually transferred out of our medical unit to a psychiatric unit at a different facility.

COVID-19 and psychiatric illness: Clinical concerns

While infection from COVID-19 and widespread social distancing of the general population have been linked to depression and anxiety, manic and psychotic symptoms secondary to the COVID-19 pandemic have not been well described. The association between influenza infection and psychosis has been reported since the Spanish Flu pandemic,¹ but there is limited data on the association between COVID-19 and psychosis. A review of 14 studies found that 0.9% to 4% of people exposed to a virus during an epidemic or pandemic develop psychosis or psychotic symptoms.¹ Psychosis was associated with viral exposure, treatments used to manage the infection (steroid therapy), and psychosocial stress. This study also found that treatment with low doses of antipsychotic medication—notably aripiprazole—seemed to have been effective.¹

Nonetheless, it is important to keep in mind a thorough differential diagnosis and rule out any potential organic etiologies in a COVID-19–positive patient who presents with psychiatric symptoms.² For Ms. B, we began by ruling out drug-induced psychosis and electrolyte imbalance, and obtained brain imaging to rule out malignancy. We considered an interictal behavior syndrome of temporal lobe epilepsy, a neuropsychiatric disorder characterized by alterations in sexual behavior, religiosity, and extensive and compulsive writing and drawing.³ Neurology was consulted to evaluate the patient and possibly use EEG to detect interictal spikes, a tall task given the patient’s restlessness and paranoia. Ultimately, we determined the patient was most likely exhibiting symptoms of previously undetected bipolar disorder.

Managing patients with psychiatric illness on a medical floor during a pandemic such as COVID-19 requires the psychiatrist to truly serve as a consultant and liaison between the patient and the treatment team.⁴ Clinical management should address both infection control and psychiatric symptoms.⁵ We visited with Ms. B frequently, provided psychoeducation, engaged her in treatment, and updated her on the treatment plan.

As the medical world continues to adjust to treating patients during the pandemic, CL psychiatrists may be tasked with managing patients with acute psychiatric illness on the medical unit while they await transfer to a psychiatric unit. A creative, multifaceted, and team-based approach is key to ensure effective care and safety for all involved.

With the COVID-19 pandemic turning the world on its head, we have seen more first-episode psychotic breaks and quick deterioration in previously stable patients. Early in the pandemic, care was particularly complicated for psychiatric patients who had been infected with the virus. Many of these patients required immediate psychiatric hospitalization. At that time, many community hospital psychiatric inpatient units did not have the capacity, staffing, or infrastructure to safely admit such patients, so they needed to be managed on a medical unit. Here, I discuss the case of a COVID-19–positive woman with psychiatric illness who we managed while she was in quarantine on a medical unit.

Case report

Early in the COVID-19 pandemic, Ms. B, a 35-year-old teacher with a history of depression, was evaluated in the emergency department for bizarre behavior and paranoid delusions regarding her family. Initial laboratory and imaging testing was negative for any potential medical causes of her psychiatric symptoms. Psychiatric hospitalization was recommended, but before Ms. B could be transferred to the psychiatric unit, she tested positive for COVID-19. At that time, our community hospital did not have a designated wing on our psychiatric unit for patients infected with COVID-19. Thus, Ms. B was admitted to the medical floor, where she was quarantined in her room. She would need to remain asymptomatic and test negative for COVID-19 before she could be transferred to the psychiatric unit.

Upon arriving at the medical unit, Ms. B was hostile and uncooperative. She frequently attempted to leave her room and required restraints throughout the day. Our consultation-liaison (CL) team was consulted to assist in managing her. During the initial interview, we noticed that she had covered all 4 walls of her room with papers filled with handwritten notes. Ms. B had cut her gown to expose her stomach and legs. She had pressured speech, tangential thinking, and was religiously preoccupied. She denied any visual and auditory hallucinations, but her persecutory delusions involving her family persisted. We believed that her signs and symptoms were consistent with a manic episode from underlying, and likely undiagnosed, bipolar I disorder that was precipitated by her COVID-19 infection.

We first addressed Ms. B’s and the staff’s safety by transferring her to a larger room with a vestibule at the end of the hallway so she had more room to walk and minimal exposure to the stimuli of the medical unit. We initiated one-on-one observation to redirect her and prevent elopement. We incentivized her cooperation with staff by providing her with paper, pencils, reading material, and phone privileges. We started oral risperidone 2 mg twice daily and lorazepam 2 mg 3 times daily for short-term behavioral control and acute treatment of her symptoms, with the goal of deferring additional treatment decisions to the inpatient psychiatry team after she was transferred to the psychiatric unit. Ms. B’s agitation and impulsivity improved. She began participating with the medical team and was eventually transferred out of our medical unit to a psychiatric unit at a different facility.

COVID-19 and psychiatric illness: Clinical concerns

While infection from COVID-19 and widespread social distancing of the general population have been linked to depression and anxiety, manic and psychotic symptoms secondary to the COVID-19 pandemic have not been well described. The association between influenza infection and psychosis has been reported since the Spanish Flu pandemic,¹ but there is limited data on the association between COVID-19 and psychosis. A review of 14 studies found that 0.9% to 4% of people exposed to a virus during an epidemic or pandemic develop psychosis or psychotic symptoms.¹ Psychosis was associated with viral exposure, treatments used to manage the infection (steroid therapy), and psychosocial stress. This study also found that treatment with low doses of antipsychotic medication—notably aripiprazole—seemed to have been effective.¹

Nonetheless, it is important to keep in mind a thorough differential diagnosis and rule out any potential organic etiologies in a COVID-19–positive patient who presents with psychiatric symptoms.² For Ms. B, we began by ruling out drug-induced psychosis and electrolyte imbalance, and obtained brain imaging to rule out malignancy. We considered an interictal behavior syndrome of temporal lobe epilepsy, a neuropsychiatric disorder characterized by alterations in sexual behavior, religiosity, and extensive and compulsive writing and drawing.³ Neurology was consulted to evaluate the patient and possibly use EEG to detect interictal spikes, a tall task given the patient’s restlessness and paranoia. Ultimately, we determined the patient was most likely exhibiting symptoms of previously undetected bipolar disorder.

Managing patients with psychiatric illness on a medical floor during a pandemic such as COVID-19 requires the psychiatrist to truly serve as a consultant and liaison between the patient and the treatment team.⁴ Clinical management should address both infection control and psychiatric symptoms.⁵ We visited with Ms. B frequently, provided psychoeducation, engaged her in treatment, and updated her on the treatment plan.

As the medical world continues to adjust to treating patients during the pandemic, CL psychiatrists may be tasked with managing patients with acute psychiatric illness on the medical unit while they await transfer to a psychiatric unit. A creative, multifaceted, and team-based approach is key to ensure effective care and safety for all involved.

With the COVID-19 pandemic turning the world on its head, we have seen more first-episode psychotic breaks and quick deterioration in previously stable patients. Early in the pandemic, care was particularly complicated for psychiatric patients who had been infected with the virus. Many of these patients required immediate psychiatric hospitalization. At that time, many community hospital psychiatric inpatient units did not have the capacity, staffing, or infrastructure to safely admit such patients, so they needed to be managed on a medical unit. Here, I discuss the case of a COVID-19–positive woman with psychiatric illness who we managed while she was in quarantine on a medical unit.

Case report

Early in the COVID-19 pandemic, Ms. B, a 35-year-old teacher with a history of depression, was evaluated in the emergency department for bizarre behavior and paranoid delusions regarding her family. Initial laboratory and imaging testing was negative for any potential medical causes of her psychiatric symptoms. Psychiatric hospitalization was recommended, but before Ms. B could be transferred to the psychiatric unit, she tested positive for COVID-19. At that time, our community hospital did not have a designated wing on our psychiatric unit for patients infected with COVID-19. Thus, Ms. B was admitted to the medical floor, where she was quarantined in her room. She would need to remain asymptomatic and test negative for COVID-19 before she could be transferred to the psychiatric unit.

Upon arriving at the medical unit, Ms. B was hostile and uncooperative. She frequently attempted to leave her room and required restraints throughout the day. Our consultation-liaison (CL) team was consulted to assist in managing her. During the initial interview, we noticed that she had covered all 4 walls of her room with papers filled with handwritten notes. Ms. B had cut her gown to expose her stomach and legs. She had pressured speech, tangential thinking, and was religiously preoccupied. She denied any visual and auditory hallucinations, but her persecutory delusions involving her family persisted. We believed that her signs and symptoms were consistent with a manic episode from underlying, and likely undiagnosed, bipolar I disorder that was precipitated by her COVID-19 infection.

We first addressed Ms. B’s and the staff’s safety by transferring her to a larger room with a vestibule at the end of the hallway so she had more room to walk and minimal exposure to the stimuli of the medical unit. We initiated one-on-one observation to redirect her and prevent elopement. We incentivized her cooperation with staff by providing her with paper, pencils, reading material, and phone privileges. We started oral risperidone 2 mg twice daily and lorazepam 2 mg 3 times daily for short-term behavioral control and acute treatment of her symptoms, with the goal of deferring additional treatment decisions to the inpatient psychiatry team after she was transferred to the psychiatric unit. Ms. B’s agitation and impulsivity improved. She began participating with the medical team and was eventually transferred out of our medical unit to a psychiatric unit at a different facility.

COVID-19 and psychiatric illness: Clinical concerns

While infection from COVID-19 and widespread social distancing of the general population have been linked to depression and anxiety, manic and psychotic symptoms secondary to the COVID-19 pandemic have not been well described. The association between influenza infection and psychosis has been reported since the Spanish Flu pandemic,¹ but there is limited data on the association between COVID-19 and psychosis. A review of 14 studies found that 0.9% to 4% of people exposed to a virus during an epidemic or pandemic develop psychosis or psychotic symptoms.¹ Psychosis was associated with viral exposure, treatments used to manage the infection (steroid therapy), and psychosocial stress. This study also found that treatment with low doses of antipsychotic medication—notably aripiprazole—seemed to have been effective.¹

Nonetheless, it is important to keep in mind a thorough differential diagnosis and rule out any potential organic etiologies in a COVID-19–positive patient who presents with psychiatric symptoms.² For Ms. B, we began by ruling out drug-induced psychosis and electrolyte imbalance, and obtained brain imaging to rule out malignancy. We considered an interictal behavior syndrome of temporal lobe epilepsy, a neuropsychiatric disorder characterized by alterations in sexual behavior, religiosity, and extensive and compulsive writing and drawing.³ Neurology was consulted to evaluate the patient and possibly use EEG to detect interictal spikes, a tall task given the patient’s restlessness and paranoia. Ultimately, we determined the patient was most likely exhibiting symptoms of previously undetected bipolar disorder.

Managing patients with psychiatric illness on a medical floor during a pandemic such as COVID-19 requires the psychiatrist to truly serve as a consultant and liaison between the patient and the treatment team.⁴ Clinical management should address both infection control and psychiatric symptoms.⁵ We visited with Ms. B frequently, provided psychoeducation, engaged her in treatment, and updated her on the treatment plan.

As the medical world continues to adjust to treating patients during the pandemic, CL psychiatrists may be tasked with managing patients with acute psychiatric illness on the medical unit while they await transfer to a psychiatric unit. A creative, multifaceted, and team-based approach is key to ensure effective care and safety for all involved.

On February 22, the US Preventive Services Task Force (USPSTF) posted draft recommendations on the use of statins as a method of primary prevention of cardiovascular disease (CVD).¹ This is an update to their 2016 recommendations and reaffirms the guidance published at that time.

What’s recommended. The recommendations have 3 parts and are intended for adults with no evidence or previous diagnosis of CVD.

• Statins should be prescribed for those who meet 3 criteria: (1) are ages 40 through 75 years; (2) have 1 or more CVD risk factors (high blood pressure, dyslipidemia, diabetes, tobacco use); and (3) have a calculated 10-year risk of a CVD event of 10% or greater. (The American College of Cardiology/American Heart Association ASCVD Risk Calculator, recommended by the USPSTF, can be found at www.cvriskcalculator.com/.) This is a “B” recommendation.¹
• Selectively offer a statin, based on a discussion of benefits and risks and patient preferences, to those who meet criteria 1 and 2 above but who have a calculated CVD risk of 7.5% to 10%. This is a “C” recommendation.¹
• For those ages 76 years and older, there is insufficient evidence to assess benefits and harms of statin use. The USPSTF therefore issued an “I” statement for this group.¹

What to prescribe. The USPSTF feels that moderate-intensity statin therapy is a reasonable approach for most people who use statins for primary CVD prevention. This would equate to atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20 to 40 mg daily.¹

A few notes on the evidence. Data from 22 studies were included in the evidence review upon which the recommendations are based. The mean duration of follow-up was 3 years. The number needed to treat to prevent 1 stroke was about 256; to prevent 1 myocardial infarction, 112; and to prevent all CVD events, 78.²

What others recommend. These recommendations are mostly consistent with those of the American College of Cardiology and the American Heart Association, except that those organizations recommend initiating statins in all those with a 10-year CVD risk ≥ 7.5%.¹

On February 22, the US Preventive Services Task Force (USPSTF) posted draft recommendations on the use of statins as a method of primary prevention of cardiovascular disease (CVD).¹ This is an update to their 2016 recommendations and reaffirms the guidance published at that time.

What’s recommended. The recommendations have 3 parts and are intended for adults with no evidence or previous diagnosis of CVD.

• Statins should be prescribed for those who meet 3 criteria: (1) are ages 40 through 75 years; (2) have 1 or more CVD risk factors (high blood pressure, dyslipidemia, diabetes, tobacco use); and (3) have a calculated 10-year risk of a CVD event of 10% or greater. (The American College of Cardiology/American Heart Association ASCVD Risk Calculator, recommended by the USPSTF, can be found at www.cvriskcalculator.com/.) This is a “B” recommendation.¹
• Selectively offer a statin, based on a discussion of benefits and risks and patient preferences, to those who meet criteria 1 and 2 above but who have a calculated CVD risk of 7.5% to 10%. This is a “C” recommendation.¹
• For those ages 76 years and older, there is insufficient evidence to assess benefits and harms of statin use. The USPSTF therefore issued an “I” statement for this group.¹

What to prescribe. The USPSTF feels that moderate-intensity statin therapy is a reasonable approach for most people who use statins for primary CVD prevention. This would equate to atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20 to 40 mg daily.¹

A few notes on the evidence. Data from 22 studies were included in the evidence review upon which the recommendations are based. The mean duration of follow-up was 3 years. The number needed to treat to prevent 1 stroke was about 256; to prevent 1 myocardial infarction, 112; and to prevent all CVD events, 78.²

What others recommend. These recommendations are mostly consistent with those of the American College of Cardiology and the American Heart Association, except that those organizations recommend initiating statins in all those with a 10-year CVD risk ≥ 7.5%.¹

On February 22, the US Preventive Services Task Force (USPSTF) posted draft recommendations on the use of statins as a method of primary prevention of cardiovascular disease (CVD).¹ This is an update to their 2016 recommendations and reaffirms the guidance published at that time.

What’s recommended. The recommendations have 3 parts and are intended for adults with no evidence or previous diagnosis of CVD.

• Statins should be prescribed for those who meet 3 criteria: (1) are ages 40 through 75 years; (2) have 1 or more CVD risk factors (high blood pressure, dyslipidemia, diabetes, tobacco use); and (3) have a calculated 10-year risk of a CVD event of 10% or greater. (The American College of Cardiology/American Heart Association ASCVD Risk Calculator, recommended by the USPSTF, can be found at www.cvriskcalculator.com/.) This is a “B” recommendation.¹
• Selectively offer a statin, based on a discussion of benefits and risks and patient preferences, to those who meet criteria 1 and 2 above but who have a calculated CVD risk of 7.5% to 10%. This is a “C” recommendation.¹
• For those ages 76 years and older, there is insufficient evidence to assess benefits and harms of statin use. The USPSTF therefore issued an “I” statement for this group.¹

What to prescribe. The USPSTF feels that moderate-intensity statin therapy is a reasonable approach for most people who use statins for primary CVD prevention. This would equate to atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20 to 40 mg daily.¹

A few notes on the evidence. Data from 22 studies were included in the evidence review upon which the recommendations are based. The mean duration of follow-up was 3 years. The number needed to treat to prevent 1 stroke was about 256; to prevent 1 myocardial infarction, 112; and to prevent all CVD events, 78.²

What others recommend. These recommendations are mostly consistent with those of the American College of Cardiology and the American Heart Association, except that those organizations recommend initiating statins in all those with a 10-year CVD risk ≥ 7.5%.¹

Patients diagnosed with advanced hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2-) breast cancer have significantly improved outcomes with the combination of a cyclin-dependent kinase (CDK) 4/6 inhibitor and endocrine therapy compared with endocrine therapy alone.

Dr Sara Hurvitz, director of the Breast Cancer Clinical Trials Program at UCLA, discusses the efficacy, tolerability, and patient quality-of-life factors to consider when deciding which of the three available CDK4/6 inhibitors — palbociclib, ribociclib, or abemaciclib — is appropriate for your patient in the frontline setting.

Reporting on data from the ongoing MONALEESA, MONARCH, and PALOMA trials, Dr Hurvitz spotlights the differences and similarities between agents that may help steer treatment decisions for pre- or perimenopausal patients

--

Associate Professor, David Geffen School of Medicine at UCLA; Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit; Co-director, Santa Monica-UCLA Outpatient Oncology Practices; Director, Breast Cancer Clinical Trials Program, UCLA, Los Angeles, California

Sara A. Hurvitz, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ambrx; Amgen; Arvinas; Bayer; BioMarin; Cascadian Therapeutics; Daiichi Sankyo; Dignitana; Genentech/Roche; Gilead Sciences; GlaxoSmithKline; Immunomedics; Lilly; MacroGenics; Merrimack; Novartis; OBI Pharma; Pfizer; Phoenix Molecular Designs; Pieris; Puma Biotechnology; Radius; Samumed; Sanofi; Seattle Genetics; Zymeworks

Has been reimbursed for travel, accommodations, or other expenses by Lilly

Patients diagnosed with advanced hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2-) breast cancer have significantly improved outcomes with the combination of a cyclin-dependent kinase (CDK) 4/6 inhibitor and endocrine therapy compared with endocrine therapy alone.

Dr Sara Hurvitz, director of the Breast Cancer Clinical Trials Program at UCLA, discusses the efficacy, tolerability, and patient quality-of-life factors to consider when deciding which of the three available CDK4/6 inhibitors — palbociclib, ribociclib, or abemaciclib — is appropriate for your patient in the frontline setting.

Reporting on data from the ongoing MONALEESA, MONARCH, and PALOMA trials, Dr Hurvitz spotlights the differences and similarities between agents that may help steer treatment decisions for pre- or perimenopausal patients

--

Associate Professor, David Geffen School of Medicine at UCLA; Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit; Co-director, Santa Monica-UCLA Outpatient Oncology Practices; Director, Breast Cancer Clinical Trials Program, UCLA, Los Angeles, California

Sara A. Hurvitz, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ambrx; Amgen; Arvinas; Bayer; BioMarin; Cascadian Therapeutics; Daiichi Sankyo; Dignitana; Genentech/Roche; Gilead Sciences; GlaxoSmithKline; Immunomedics; Lilly; MacroGenics; Merrimack; Novartis; OBI Pharma; Pfizer; Phoenix Molecular Designs; Pieris; Puma Biotechnology; Radius; Samumed; Sanofi; Seattle Genetics; Zymeworks

Has been reimbursed for travel, accommodations, or other expenses by Lilly

Patients diagnosed with advanced hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2-) breast cancer have significantly improved outcomes with the combination of a cyclin-dependent kinase (CDK) 4/6 inhibitor and endocrine therapy compared with endocrine therapy alone.

Dr Sara Hurvitz, director of the Breast Cancer Clinical Trials Program at UCLA, discusses the efficacy, tolerability, and patient quality-of-life factors to consider when deciding which of the three available CDK4/6 inhibitors — palbociclib, ribociclib, or abemaciclib — is appropriate for your patient in the frontline setting.

Reporting on data from the ongoing MONALEESA, MONARCH, and PALOMA trials, Dr Hurvitz spotlights the differences and similarities between agents that may help steer treatment decisions for pre- or perimenopausal patients

--

Associate Professor, David Geffen School of Medicine at UCLA; Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit; Co-director, Santa Monica-UCLA Outpatient Oncology Practices; Director, Breast Cancer Clinical Trials Program, UCLA, Los Angeles, California

Sara A. Hurvitz, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ambrx; Amgen; Arvinas; Bayer; BioMarin; Cascadian Therapeutics; Daiichi Sankyo; Dignitana; Genentech/Roche; Gilead Sciences; GlaxoSmithKline; Immunomedics; Lilly; MacroGenics; Merrimack; Novartis; OBI Pharma; Pfizer; Phoenix Molecular Designs; Pieris; Puma Biotechnology; Radius; Samumed; Sanofi; Seattle Genetics; Zymeworks

Has been reimbursed for travel, accommodations, or other expenses by Lilly

What is your approach to differentiating EPI from other pancreatic conditions when making a diagnosis?

Dr. Kothari: Exocrine pancreatic insufficiency, or EPI, is a condition largely defined by malabsorption as the result of inadequate digestive enzymes. The resulting symptoms from maldigestion include bloating, malodorous gas, abdominal pain, changes in bowel habits, and weight change. EPI can be caused by intrinsic pancreatic disorders (such as chronic pancreatitis, acute pancreatitis, cystic fibrosis or pancreatic cancer) or from extra-pancreatic diseases (including the result of gastrointestinal surgery). Thus, EPI should be considered a consequence of an already existing gastrointestinal disorder.

Can you a speak a little bit more about the signs and symptoms or characteristics that are most common in patients with EPI?

Dr. Kothari: The symptoms of EPI can range from bloating and abdominal pain with mild to overt steatorrhea with greasy and oily stools that are difficult to flush with malodorous flatulence, weight loss, and symptoms of vitamin and micronutrient deficiency. The pathophysiology of these symptoms results from inadequate enzymes which are needed for digestion. Particularly, lipase is the major enzyme needed for fat digestion and thus when not present leads to fat maldigestion resulting in symptoms. Furthermore, undigested fats result in alterations in gut motility which can further exacerbate symptoms to include nausea, vomiting, early satiety and inadequate stool evacuation.

Patients who have fat malabsorption, particularly for pancreatic insufficiency, can also have malnutrition as a result of inadequate absorption of nutrients and micronutrients. Particularly, we think about fat-soluble vitamins-- vitamin A, vitamin E, vitamin D, and vitamin K and in the initial evaluation of patients with established EPI, one could consider evaluation of comorbid bone disease.

How crucial is having the correct interpretation of the clinical presentation to pinpointing the diagnosis?

Dr. Kothari: This is a great question because, with exocrine pancreatic insufficiency as there is growing publicity for the disorder and because symptoms can be rather non-specific when mild, it is important to be informed on how best to make this diagnosis. Thus, it is important to review the predisposing conditions that may lead to the diagnosis of EPI. These conditions include cystic fibrosis, chronic pancreatitis, acute pancreatitis, previous pancreatic surgery, history of pancreatic cancer (or suspicion for new pancreatic cancer), history of diabetes, celiac disease, history of luminal surgeries (including bariatric surgery), and inflammatory bowel disease. Further, since EPI can be a result of intrinsic pancreatic pathologies, it is critical to consider the risk factors for chronic pancreatitis which include alcohol and tobacco ingestion, prior episodes of recurrent acute pancreatitis, genetic conditions that may predispose patients to chronic pancreatitis, including cystic fibrosis, and hereditary conditions that also result in pancreatitis. As clinicians, it is our role to obtain an accurate history to best gauge the risk factors for EPI.

After reviewing risk factors, we then must review the clinical presentation to know if the symptoms could be from EPI which include bloating, gas, abdominal pain, weight changes, changes in bowel habits and consequences of vitamin deficiencies. Since the symptoms of mild EPI can be similar to other GI conditions such as SIBO, celiac disease, and functional bowel disorders, gauging whether a patient has risk factors for EPI will help the clinician understand how likely a diagnosis of EPI may be and if and what testing would be appropriate.

In my practice, I consider diagnostic testing in patients who may be at risk for EPI and have mild symptoms such malodorous gas, bloating and mild steatorrhea. For patient with clear evidence of steatorrhea (weight loss and vitamin deficiencies) and have strong risk factors for EPI (i.e. heavy alcohol and tobacco and/or a history of recurrent or severe acute pancreatitis), I might consider imaging and/or empiric therapies as to expedite care.

How difficult is it to diagnose EPI and what steps do you take to ensure that you prescribe patients with the proper therapy?

Dr. Kothari: The diagnosis of pancreatic insufficiency, in my mind, needs to start with assessing the pre-test probability of the patient having EPI, since testing could lead to a false positive.

The test of choice in most scenarios for diagnosing pancreatic insufficiency is a stool test known as the fecal elastase. It is a measurement of pancreatic elastase in the stool. The test itself is a concentration. For any condition that results in a dilute stool sample, that'll result in a falsely low value that can give a patient a false positive test. Now, this can be corrected  by the lab concentrating the stool sample before running the test, but that testing center needs to know how to do that.

The other assumption that we make with this stool test is that we assume that the elastase is a stable molecule that can traverse all the gut and be collected adequately. And for any reason, if that enzyme is degraded for any reason, it's also going to provide a low test, a low result, resulting in a false positive.

If they have risk factors for chronic pancreatitis or pancreatic disease and they're presenting with symptoms of EPI, then the usual test that I'll choose is dedicated pancreatic imaging such as an MRI or dedicated CT pancreatic imaging, or endoscopic ultrasound. If we clinch a diagnosis of chronic pancreatitis and they have symptoms of pancreatic insufficiency, I think that’s enough to presume a diagnosis of exocrine pancreatic insufficiency and start treatment.

On the other hand, in patients who do not have risk factors for pancreatic disease but there remains some clinical suspicion for exocrine pancreatic insufficiency, then it may be reasonable to check a fecal elastase to rule out pancreatic insufficiency. If the test results are low, then follow-up dedicated pancreas imaging would be the next step in delineating intrinsic pancreatic conditions form extra-pancreatic causes.  If pancreas imaging effectively rules out pancreatic disease then I consider checking for celiac disease, ruling out small intestinal bacterial overgrowth and considering assessment of luminal motility (either with a capsule or small bowel follow through). Although functional neuroendocrine tumors have been previously considered a cause of EPI, these tumors tend to present with secretory diarrhea which typically present differently (and often more dramatically) than other causes of EPI. Thus, I do not routinely check vasoactive hormone levels.

I think the American Gastroenterological Association has great patient education documents for our patients. Thus, I would encourage our colleagues to use the AGA for their resources for our patients on EPI.

What is your approach to differentiating EPI from other pancreatic conditions when making a diagnosis?

Dr. Kothari: Exocrine pancreatic insufficiency, or EPI, is a condition largely defined by malabsorption as the result of inadequate digestive enzymes. The resulting symptoms from maldigestion include bloating, malodorous gas, abdominal pain, changes in bowel habits, and weight change. EPI can be caused by intrinsic pancreatic disorders (such as chronic pancreatitis, acute pancreatitis, cystic fibrosis or pancreatic cancer) or from extra-pancreatic diseases (including the result of gastrointestinal surgery). Thus, EPI should be considered a consequence of an already existing gastrointestinal disorder.

Can you a speak a little bit more about the signs and symptoms or characteristics that are most common in patients with EPI?

Dr. Kothari: The symptoms of EPI can range from bloating and abdominal pain with mild to overt steatorrhea with greasy and oily stools that are difficult to flush with malodorous flatulence, weight loss, and symptoms of vitamin and micronutrient deficiency. The pathophysiology of these symptoms results from inadequate enzymes which are needed for digestion. Particularly, lipase is the major enzyme needed for fat digestion and thus when not present leads to fat maldigestion resulting in symptoms. Furthermore, undigested fats result in alterations in gut motility which can further exacerbate symptoms to include nausea, vomiting, early satiety and inadequate stool evacuation.

Patients who have fat malabsorption, particularly for pancreatic insufficiency, can also have malnutrition as a result of inadequate absorption of nutrients and micronutrients. Particularly, we think about fat-soluble vitamins-- vitamin A, vitamin E, vitamin D, and vitamin K and in the initial evaluation of patients with established EPI, one could consider evaluation of comorbid bone disease.

How crucial is having the correct interpretation of the clinical presentation to pinpointing the diagnosis?

Dr. Kothari: This is a great question because, with exocrine pancreatic insufficiency as there is growing publicity for the disorder and because symptoms can be rather non-specific when mild, it is important to be informed on how best to make this diagnosis. Thus, it is important to review the predisposing conditions that may lead to the diagnosis of EPI. These conditions include cystic fibrosis, chronic pancreatitis, acute pancreatitis, previous pancreatic surgery, history of pancreatic cancer (or suspicion for new pancreatic cancer), history of diabetes, celiac disease, history of luminal surgeries (including bariatric surgery), and inflammatory bowel disease. Further, since EPI can be a result of intrinsic pancreatic pathologies, it is critical to consider the risk factors for chronic pancreatitis which include alcohol and tobacco ingestion, prior episodes of recurrent acute pancreatitis, genetic conditions that may predispose patients to chronic pancreatitis, including cystic fibrosis, and hereditary conditions that also result in pancreatitis. As clinicians, it is our role to obtain an accurate history to best gauge the risk factors for EPI.

After reviewing risk factors, we then must review the clinical presentation to know if the symptoms could be from EPI which include bloating, gas, abdominal pain, weight changes, changes in bowel habits and consequences of vitamin deficiencies. Since the symptoms of mild EPI can be similar to other GI conditions such as SIBO, celiac disease, and functional bowel disorders, gauging whether a patient has risk factors for EPI will help the clinician understand how likely a diagnosis of EPI may be and if and what testing would be appropriate.

In my practice, I consider diagnostic testing in patients who may be at risk for EPI and have mild symptoms such malodorous gas, bloating and mild steatorrhea. For patient with clear evidence of steatorrhea (weight loss and vitamin deficiencies) and have strong risk factors for EPI (i.e. heavy alcohol and tobacco and/or a history of recurrent or severe acute pancreatitis), I might consider imaging and/or empiric therapies as to expedite care.

How difficult is it to diagnose EPI and what steps do you take to ensure that you prescribe patients with the proper therapy?

Dr. Kothari: The diagnosis of pancreatic insufficiency, in my mind, needs to start with assessing the pre-test probability of the patient having EPI, since testing could lead to a false positive.

The test of choice in most scenarios for diagnosing pancreatic insufficiency is a stool test known as the fecal elastase. It is a measurement of pancreatic elastase in the stool. The test itself is a concentration. For any condition that results in a dilute stool sample, that'll result in a falsely low value that can give a patient a false positive test. Now, this can be corrected  by the lab concentrating the stool sample before running the test, but that testing center needs to know how to do that.

The other assumption that we make with this stool test is that we assume that the elastase is a stable molecule that can traverse all the gut and be collected adequately. And for any reason, if that enzyme is degraded for any reason, it's also going to provide a low test, a low result, resulting in a false positive.

If they have risk factors for chronic pancreatitis or pancreatic disease and they're presenting with symptoms of EPI, then the usual test that I'll choose is dedicated pancreatic imaging such as an MRI or dedicated CT pancreatic imaging, or endoscopic ultrasound. If we clinch a diagnosis of chronic pancreatitis and they have symptoms of pancreatic insufficiency, I think that’s enough to presume a diagnosis of exocrine pancreatic insufficiency and start treatment.

On the other hand, in patients who do not have risk factors for pancreatic disease but there remains some clinical suspicion for exocrine pancreatic insufficiency, then it may be reasonable to check a fecal elastase to rule out pancreatic insufficiency. If the test results are low, then follow-up dedicated pancreas imaging would be the next step in delineating intrinsic pancreatic conditions form extra-pancreatic causes.  If pancreas imaging effectively rules out pancreatic disease then I consider checking for celiac disease, ruling out small intestinal bacterial overgrowth and considering assessment of luminal motility (either with a capsule or small bowel follow through). Although functional neuroendocrine tumors have been previously considered a cause of EPI, these tumors tend to present with secretory diarrhea which typically present differently (and often more dramatically) than other causes of EPI. Thus, I do not routinely check vasoactive hormone levels.

I think the American Gastroenterological Association has great patient education documents for our patients. Thus, I would encourage our colleagues to use the AGA for their resources for our patients on EPI.

What is your approach to differentiating EPI from other pancreatic conditions when making a diagnosis?

Dr. Kothari: Exocrine pancreatic insufficiency, or EPI, is a condition largely defined by malabsorption as the result of inadequate digestive enzymes. The resulting symptoms from maldigestion include bloating, malodorous gas, abdominal pain, changes in bowel habits, and weight change. EPI can be caused by intrinsic pancreatic disorders (such as chronic pancreatitis, acute pancreatitis, cystic fibrosis or pancreatic cancer) or from extra-pancreatic diseases (including the result of gastrointestinal surgery). Thus, EPI should be considered a consequence of an already existing gastrointestinal disorder.

Can you a speak a little bit more about the signs and symptoms or characteristics that are most common in patients with EPI?

Dr. Kothari: The symptoms of EPI can range from bloating and abdominal pain with mild to overt steatorrhea with greasy and oily stools that are difficult to flush with malodorous flatulence, weight loss, and symptoms of vitamin and micronutrient deficiency. The pathophysiology of these symptoms results from inadequate enzymes which are needed for digestion. Particularly, lipase is the major enzyme needed for fat digestion and thus when not present leads to fat maldigestion resulting in symptoms. Furthermore, undigested fats result in alterations in gut motility which can further exacerbate symptoms to include nausea, vomiting, early satiety and inadequate stool evacuation.

Patients who have fat malabsorption, particularly for pancreatic insufficiency, can also have malnutrition as a result of inadequate absorption of nutrients and micronutrients. Particularly, we think about fat-soluble vitamins-- vitamin A, vitamin E, vitamin D, and vitamin K and in the initial evaluation of patients with established EPI, one could consider evaluation of comorbid bone disease.

How crucial is having the correct interpretation of the clinical presentation to pinpointing the diagnosis?

Dr. Kothari: This is a great question because, with exocrine pancreatic insufficiency as there is growing publicity for the disorder and because symptoms can be rather non-specific when mild, it is important to be informed on how best to make this diagnosis. Thus, it is important to review the predisposing conditions that may lead to the diagnosis of EPI. These conditions include cystic fibrosis, chronic pancreatitis, acute pancreatitis, previous pancreatic surgery, history of pancreatic cancer (or suspicion for new pancreatic cancer), history of diabetes, celiac disease, history of luminal surgeries (including bariatric surgery), and inflammatory bowel disease. Further, since EPI can be a result of intrinsic pancreatic pathologies, it is critical to consider the risk factors for chronic pancreatitis which include alcohol and tobacco ingestion, prior episodes of recurrent acute pancreatitis, genetic conditions that may predispose patients to chronic pancreatitis, including cystic fibrosis, and hereditary conditions that also result in pancreatitis. As clinicians, it is our role to obtain an accurate history to best gauge the risk factors for EPI.

After reviewing risk factors, we then must review the clinical presentation to know if the symptoms could be from EPI which include bloating, gas, abdominal pain, weight changes, changes in bowel habits and consequences of vitamin deficiencies. Since the symptoms of mild EPI can be similar to other GI conditions such as SIBO, celiac disease, and functional bowel disorders, gauging whether a patient has risk factors for EPI will help the clinician understand how likely a diagnosis of EPI may be and if and what testing would be appropriate.

In my practice, I consider diagnostic testing in patients who may be at risk for EPI and have mild symptoms such malodorous gas, bloating and mild steatorrhea. For patient with clear evidence of steatorrhea (weight loss and vitamin deficiencies) and have strong risk factors for EPI (i.e. heavy alcohol and tobacco and/or a history of recurrent or severe acute pancreatitis), I might consider imaging and/or empiric therapies as to expedite care.

How difficult is it to diagnose EPI and what steps do you take to ensure that you prescribe patients with the proper therapy?

Dr. Kothari: The diagnosis of pancreatic insufficiency, in my mind, needs to start with assessing the pre-test probability of the patient having EPI, since testing could lead to a false positive.

The test of choice in most scenarios for diagnosing pancreatic insufficiency is a stool test known as the fecal elastase. It is a measurement of pancreatic elastase in the stool. The test itself is a concentration. For any condition that results in a dilute stool sample, that'll result in a falsely low value that can give a patient a false positive test. Now, this can be corrected  by the lab concentrating the stool sample before running the test, but that testing center needs to know how to do that.

The other assumption that we make with this stool test is that we assume that the elastase is a stable molecule that can traverse all the gut and be collected adequately. And for any reason, if that enzyme is degraded for any reason, it's also going to provide a low test, a low result, resulting in a false positive.

If they have risk factors for chronic pancreatitis or pancreatic disease and they're presenting with symptoms of EPI, then the usual test that I'll choose is dedicated pancreatic imaging such as an MRI or dedicated CT pancreatic imaging, or endoscopic ultrasound. If we clinch a diagnosis of chronic pancreatitis and they have symptoms of pancreatic insufficiency, I think that’s enough to presume a diagnosis of exocrine pancreatic insufficiency and start treatment.

On the other hand, in patients who do not have risk factors for pancreatic disease but there remains some clinical suspicion for exocrine pancreatic insufficiency, then it may be reasonable to check a fecal elastase to rule out pancreatic insufficiency. If the test results are low, then follow-up dedicated pancreas imaging would be the next step in delineating intrinsic pancreatic conditions form extra-pancreatic causes.  If pancreas imaging effectively rules out pancreatic disease then I consider checking for celiac disease, ruling out small intestinal bacterial overgrowth and considering assessment of luminal motility (either with a capsule or small bowel follow through). Although functional neuroendocrine tumors have been previously considered a cause of EPI, these tumors tend to present with secretory diarrhea which typically present differently (and often more dramatically) than other causes of EPI. Thus, I do not routinely check vasoactive hormone levels.

I think the American Gastroenterological Association has great patient education documents for our patients. Thus, I would encourage our colleagues to use the AGA for their resources for our patients on EPI.

Correct answer: B. Absence of ganglion cells on rectal biopsy. 
 
Rationale  
Hirschsprung's disease occurs in approximately 1 out of 5,000 live births and is caused by absence of ganglion cells in the myenteric plexus of the intestine. The condition arises from failure of the neural crest cells to fully migrate caudally along the intestine during early gestation, resulting in a distal portion of the intestine being aganglionic. Rectal and distal sigmoid involvement is seen in around 85% of cases, with the other 15 percent involving more proximal intestine. It can rarely involve the entire colon and small intestine. Ganglion cells inhibit local smooth muscles, resulting in the characteristic inability for aganglionic bowel to relax. This lack of inhibition gives rise to the absence of rectoanal inhibitory reflex (RAIRs) during anorectal manometry. The lack of inhibition also produces a transition zone on contrast enema, with the distal aganglionic bowel being narrow and the more proximal bowel containing ganglia being dilated. Lack of meconium passage in the first 48 hours of life raises concern for Hirschsprung's disease. Other causes for possible failure to pass meconium include cystic fibrosis, anorectal malformation, small left colon syndrome, meconium plug syndrome and megacystis-microcolon-intestinal hypoperistalsis syndrome.  
 
References 
Kenny, S et al. Semin Pediatr Surg. 2010 Aug;19(3):194-200. 
Wyllie R et al. Pediatric Gastrointestinal and Liver Disease. 4th edition. Elsevier Saunders, Philadelphia, 2011.

Correct answer: B. Absence of ganglion cells on rectal biopsy. 
 
Rationale  
Hirschsprung's disease occurs in approximately 1 out of 5,000 live births and is caused by absence of ganglion cells in the myenteric plexus of the intestine. The condition arises from failure of the neural crest cells to fully migrate caudally along the intestine during early gestation, resulting in a distal portion of the intestine being aganglionic. Rectal and distal sigmoid involvement is seen in around 85% of cases, with the other 15 percent involving more proximal intestine. It can rarely involve the entire colon and small intestine. Ganglion cells inhibit local smooth muscles, resulting in the characteristic inability for aganglionic bowel to relax. This lack of inhibition gives rise to the absence of rectoanal inhibitory reflex (RAIRs) during anorectal manometry. The lack of inhibition also produces a transition zone on contrast enema, with the distal aganglionic bowel being narrow and the more proximal bowel containing ganglia being dilated. Lack of meconium passage in the first 48 hours of life raises concern for Hirschsprung's disease. Other causes for possible failure to pass meconium include cystic fibrosis, anorectal malformation, small left colon syndrome, meconium plug syndrome and megacystis-microcolon-intestinal hypoperistalsis syndrome.  
 
References 
Kenny, S et al. Semin Pediatr Surg. 2010 Aug;19(3):194-200. 
Wyllie R et al. Pediatric Gastrointestinal and Liver Disease. 4th edition. Elsevier Saunders, Philadelphia, 2011.

Correct answer: B. Absence of ganglion cells on rectal biopsy. 
 
Rationale  
Hirschsprung's disease occurs in approximately 1 out of 5,000 live births and is caused by absence of ganglion cells in the myenteric plexus of the intestine. The condition arises from failure of the neural crest cells to fully migrate caudally along the intestine during early gestation, resulting in a distal portion of the intestine being aganglionic. Rectal and distal sigmoid involvement is seen in around 85% of cases, with the other 15 percent involving more proximal intestine. It can rarely involve the entire colon and small intestine. Ganglion cells inhibit local smooth muscles, resulting in the characteristic inability for aganglionic bowel to relax. This lack of inhibition gives rise to the absence of rectoanal inhibitory reflex (RAIRs) during anorectal manometry. The lack of inhibition also produces a transition zone on contrast enema, with the distal aganglionic bowel being narrow and the more proximal bowel containing ganglia being dilated. Lack of meconium passage in the first 48 hours of life raises concern for Hirschsprung's disease. Other causes for possible failure to pass meconium include cystic fibrosis, anorectal malformation, small left colon syndrome, meconium plug syndrome and megacystis-microcolon-intestinal hypoperistalsis syndrome.  
 
References 
Kenny, S et al. Semin Pediatr Surg. 2010 Aug;19(3):194-200. 
Wyllie R et al. Pediatric Gastrointestinal and Liver Disease. 4th edition. Elsevier Saunders, Philadelphia, 2011.

Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Wednesday, March 30. Day 3 of SGS.

The final day of #SGS2022 began with the last round of oral and video presentations on topics including: the efficacy and safety of restrictive blood transfusion protocols in gynecologic surgical patients, restricted opioid use following midurethral sling procedures, and the efficacy of trigger point injections for myofascial pelvic pain. Next, the prestigious Distinguished Surgeon Award was presented to Dr. Jeffrey Cornella, professor of Obstetrics and Gynecology at Mayo Clinic College of Medicine, for his contributions to the field of gynecologic surgery.

This was followed by the passing of the presidential gavel from current SGS president Dr. Carl Zimmerman to incoming president Dr. Cheryl Iglesia, Director of Female Pelvic Medicine and Reconstructive Surgery at MedStar Washington Hospital Center, Washington DC, and Director of the National Center for Advanced Pelvic Surgery (NCAPS) at Medstar Health. Dr. Iglesia has been internationally and nationally recognized for her work in advancing the field of pelvic surgery and urogynecology through extensive research, clinical excellence, and support of medical education.

Needless to say, #SGS2022 was a huge success! While many of us are sad to leave San Antonio today, we are returning to our respective programs feeling motivated and rejuvenated. There is nothing more inspiring than spending time with such a highly committed group of physicians who strive to improve patient care through their excellent contributions to research and medical education. I am grateful for the new mentors, colleagues, and friends I have met at this meeting.

Thank you to the Society of Gynecologic Surgeons and OBG Management for giving me the opportunity to reflect on my experience at #SGS2022, as well as the companies that support the Fellows Scholar program.

I can’t wait to attend the 49th Annual Scientific Meeting in Tuscon, Arizona, in 2023!

Tuesday, March 29, 2022. Day 2 of SGS.

The second day of #SGS2022 began with several academic roundtables on a variety of topics including hysteroscopy, uterine-preserving prolapse surgeries, how to select patients for vaginal hysterectomy, and the role of minimally invasive surgery in transabdominal cerclage. The general session continued with more outstanding poster and video presentations that were followed by the annual presidential address. SGS president Dr. Carl Zimmerman spoke about the changing surgical landscape and SGS’s commitment to improving surgical education: “The women of America and the world deserve better.” He went on to announce the creation of a presidential task force on surgical training, whose members will include: Dr. Ted Anderson, Dr. Emily Weber LeBrun, and Dr. Mike Moen.

This year’s TeLinde Lecture was given by the executive director of the American College of Surgeons, Dr. Dr. Patricia Turner. Her talk was entitled, “Surgeons: More to Unite Us Than Divide Us.” Dr. Turner began by reminding us of the shared history between general surgery and gynecologic surgery. In fact, the American College of Surgeons was founded by gynecologist Dr. Franklin H. Martin. She went on to thoughtfully discuss the need to rethink surgical training and the way we assess surgical trainees. She highlighted the importance of collaboration between all surgical specialties to improve surgical education, improve outcomes, and advocate for patients. “In order to heal all, we have to have ALL surgeons at the table.”

Today’s general session was concluded with a panel discussion on “Operating Room Safety and Efficiency” in which Dr. Kenneth Catchpole, Dr. Teodor Grantcharov, and Dr. Jason Wright shared some interesting ideas on how we can improve patient care in the operating room. The afternoon continued with a number of social activities, providing an opportunity to enjoy the beautiful landscape of San Antonio, Texas, including: a tour of Eisenhower park, kayaking on the Guadelupe River, and the SGS golf tournament.

The fun continued into the evening at the annual “SGS’ Got Talent” in which participants could be spotted in cowboy hats, bandanas, and boots. The night was filled with food, drinks, laughter, and line dancing! #SGS2022

 

Monday, March 28, 2022. Day 1 of SGS.

“How do you become brave? How do you become an advocate? How do you make a change?” These are just some of the questions asked during our thought-provoking early morning session entitled, “Healthcare Inequity Awareness—A Conversation to Empower Providers and Enhance the Patient Experience” at this year’s annual scientific meeting of the Society of Gynecologic Surgeons #SGS2022. The panelists, which included Dr. Olivia Cardenas-Trowers, Dr. Maria Florian-Rodriguez, and Dr. Tristi Muir, emphasized the importance of acknowledging our own bias as physicians, as well as the role structural racism plays in the health care access and outcomes of our patients. We were reminded that “Diversity, Equity, Inclusion (aka DEI) is a journey. It is progress over time, not over night.”

Following the early morning panel, the 48th annual scientific meeting officially began with a brief welcome and recognition of new SGS members by current president Dr. Carl Zimmerman and scientific program committee chair Dr. Oz Harmanli. The rest of the morning session was filled with outstanding oral and video presentations on topics ranging from the role of oophorectomy in patients with breast cancer, creating simulation models to enhance medical education, and tips for navigating the altered retroperitoneum.

Next, the Mark D. Walters endowed lecture was given by Dr. Marta A. Crispens, entitled “Restructuring Gynecologic Surgical Education: It’s a Matter of Equity.” In her exceptionally powerful address, Dr. Crispens began by discussing the historical context in which the fields of obstetrics and gynecology were combined and comparing it to a shift in current practice toward a national decrease in number of hysterectomies and an increase in the complexity of surgical cases. She highlighted the well-studied fact that low-volume surgeons have higher complication rates and that many new ObGyn residency graduates perform only 3 to 4 hysterectomies annually during the first few years of practice. Finally, she asserted that, by separating the practices of obstetrics and gynecology, we can improve surgical education and the quality of surgical care for our patients. The audience’s enthusiasm was undeniable, resulting in resounding applause and a standing ovation.

The afternoon was filled with unique opportunities for fellows, including: the Fellow’s Pelvic Research Network (FPRN) meeting, an incredibly informative panel on how to navigate the first year out of fellowship with Dr. Mireille Truong, Dr. Christine Foley, and Dr. Jon Pennycuff, and finally, the Mentorship Mingle.

The first day was concluded with the President’s Award Ceremony in which Dr. John DeLancey was presented with the illustrious President’s Award, followed by the President’s Reception with food, drinks, and lively conversation. Looking forward to day 2 of #SGS2022. @gynsurgery

Wednesday, March 30. Day 3 of SGS.

The final day of #SGS2022 began with the last round of oral and video presentations on topics including: the efficacy and safety of restrictive blood transfusion protocols in gynecologic surgical patients, restricted opioid use following midurethral sling procedures, and the efficacy of trigger point injections for myofascial pelvic pain. Next, the prestigious Distinguished Surgeon Award was presented to Dr. Jeffrey Cornella, professor of Obstetrics and Gynecology at Mayo Clinic College of Medicine, for his contributions to the field of gynecologic surgery.

This was followed by the passing of the presidential gavel from current SGS president Dr. Carl Zimmerman to incoming president Dr. Cheryl Iglesia, Director of Female Pelvic Medicine and Reconstructive Surgery at MedStar Washington Hospital Center, Washington DC, and Director of the National Center for Advanced Pelvic Surgery (NCAPS) at Medstar Health. Dr. Iglesia has been internationally and nationally recognized for her work in advancing the field of pelvic surgery and urogynecology through extensive research, clinical excellence, and support of medical education.

Needless to say, #SGS2022 was a huge success! While many of us are sad to leave San Antonio today, we are returning to our respective programs feeling motivated and rejuvenated. There is nothing more inspiring than spending time with such a highly committed group of physicians who strive to improve patient care through their excellent contributions to research and medical education. I am grateful for the new mentors, colleagues, and friends I have met at this meeting.

Thank you to the Society of Gynecologic Surgeons and OBG Management for giving me the opportunity to reflect on my experience at #SGS2022, as well as the companies that support the Fellows Scholar program.

I can’t wait to attend the 49th Annual Scientific Meeting in Tuscon, Arizona, in 2023!

Tuesday, March 29, 2022. Day 2 of SGS.

The second day of #SGS2022 began with several academic roundtables on a variety of topics including hysteroscopy, uterine-preserving prolapse surgeries, how to select patients for vaginal hysterectomy, and the role of minimally invasive surgery in transabdominal cerclage. The general session continued with more outstanding poster and video presentations that were followed by the annual presidential address. SGS president Dr. Carl Zimmerman spoke about the changing surgical landscape and SGS’s commitment to improving surgical education: “The women of America and the world deserve better.” He went on to announce the creation of a presidential task force on surgical training, whose members will include: Dr. Ted Anderson, Dr. Emily Weber LeBrun, and Dr. Mike Moen.

This year’s TeLinde Lecture was given by the executive director of the American College of Surgeons, Dr. Dr. Patricia Turner. Her talk was entitled, “Surgeons: More to Unite Us Than Divide Us.” Dr. Turner began by reminding us of the shared history between general surgery and gynecologic surgery. In fact, the American College of Surgeons was founded by gynecologist Dr. Franklin H. Martin. She went on to thoughtfully discuss the need to rethink surgical training and the way we assess surgical trainees. She highlighted the importance of collaboration between all surgical specialties to improve surgical education, improve outcomes, and advocate for patients. “In order to heal all, we have to have ALL surgeons at the table.”

Today’s general session was concluded with a panel discussion on “Operating Room Safety and Efficiency” in which Dr. Kenneth Catchpole, Dr. Teodor Grantcharov, and Dr. Jason Wright shared some interesting ideas on how we can improve patient care in the operating room. The afternoon continued with a number of social activities, providing an opportunity to enjoy the beautiful landscape of San Antonio, Texas, including: a tour of Eisenhower park, kayaking on the Guadelupe River, and the SGS golf tournament.

The fun continued into the evening at the annual “SGS’ Got Talent” in which participants could be spotted in cowboy hats, bandanas, and boots. The night was filled with food, drinks, laughter, and line dancing! #SGS2022

 

Monday, March 28, 2022. Day 1 of SGS.

“How do you become brave? How do you become an advocate? How do you make a change?” These are just some of the questions asked during our thought-provoking early morning session entitled, “Healthcare Inequity Awareness—A Conversation to Empower Providers and Enhance the Patient Experience” at this year’s annual scientific meeting of the Society of Gynecologic Surgeons #SGS2022. The panelists, which included Dr. Olivia Cardenas-Trowers, Dr. Maria Florian-Rodriguez, and Dr. Tristi Muir, emphasized the importance of acknowledging our own bias as physicians, as well as the role structural racism plays in the health care access and outcomes of our patients. We were reminded that “Diversity, Equity, Inclusion (aka DEI) is a journey. It is progress over time, not over night.”

Following the early morning panel, the 48th annual scientific meeting officially began with a brief welcome and recognition of new SGS members by current president Dr. Carl Zimmerman and scientific program committee chair Dr. Oz Harmanli. The rest of the morning session was filled with outstanding oral and video presentations on topics ranging from the role of oophorectomy in patients with breast cancer, creating simulation models to enhance medical education, and tips for navigating the altered retroperitoneum.

Next, the Mark D. Walters endowed lecture was given by Dr. Marta A. Crispens, entitled “Restructuring Gynecologic Surgical Education: It’s a Matter of Equity.” In her exceptionally powerful address, Dr. Crispens began by discussing the historical context in which the fields of obstetrics and gynecology were combined and comparing it to a shift in current practice toward a national decrease in number of hysterectomies and an increase in the complexity of surgical cases. She highlighted the well-studied fact that low-volume surgeons have higher complication rates and that many new ObGyn residency graduates perform only 3 to 4 hysterectomies annually during the first few years of practice. Finally, she asserted that, by separating the practices of obstetrics and gynecology, we can improve surgical education and the quality of surgical care for our patients. The audience’s enthusiasm was undeniable, resulting in resounding applause and a standing ovation.

The afternoon was filled with unique opportunities for fellows, including: the Fellow’s Pelvic Research Network (FPRN) meeting, an incredibly informative panel on how to navigate the first year out of fellowship with Dr. Mireille Truong, Dr. Christine Foley, and Dr. Jon Pennycuff, and finally, the Mentorship Mingle.

The first day was concluded with the President’s Award Ceremony in which Dr. John DeLancey was presented with the illustrious President’s Award, followed by the President’s Reception with food, drinks, and lively conversation. Looking forward to day 2 of #SGS2022. @gynsurgery

Wednesday, March 30. Day 3 of SGS.

The final day of #SGS2022 began with the last round of oral and video presentations on topics including: the efficacy and safety of restrictive blood transfusion protocols in gynecologic surgical patients, restricted opioid use following midurethral sling procedures, and the efficacy of trigger point injections for myofascial pelvic pain. Next, the prestigious Distinguished Surgeon Award was presented to Dr. Jeffrey Cornella, professor of Obstetrics and Gynecology at Mayo Clinic College of Medicine, for his contributions to the field of gynecologic surgery.

This was followed by the passing of the presidential gavel from current SGS president Dr. Carl Zimmerman to incoming president Dr. Cheryl Iglesia, Director of Female Pelvic Medicine and Reconstructive Surgery at MedStar Washington Hospital Center, Washington DC, and Director of the National Center for Advanced Pelvic Surgery (NCAPS) at Medstar Health. Dr. Iglesia has been internationally and nationally recognized for her work in advancing the field of pelvic surgery and urogynecology through extensive research, clinical excellence, and support of medical education.

Needless to say, #SGS2022 was a huge success! While many of us are sad to leave San Antonio today, we are returning to our respective programs feeling motivated and rejuvenated. There is nothing more inspiring than spending time with such a highly committed group of physicians who strive to improve patient care through their excellent contributions to research and medical education. I am grateful for the new mentors, colleagues, and friends I have met at this meeting.

Thank you to the Society of Gynecologic Surgeons and OBG Management for giving me the opportunity to reflect on my experience at #SGS2022, as well as the companies that support the Fellows Scholar program.

I can’t wait to attend the 49th Annual Scientific Meeting in Tuscon, Arizona, in 2023!

Tuesday, March 29, 2022. Day 2 of SGS.

The second day of #SGS2022 began with several academic roundtables on a variety of topics including hysteroscopy, uterine-preserving prolapse surgeries, how to select patients for vaginal hysterectomy, and the role of minimally invasive surgery in transabdominal cerclage. The general session continued with more outstanding poster and video presentations that were followed by the annual presidential address. SGS president Dr. Carl Zimmerman spoke about the changing surgical landscape and SGS’s commitment to improving surgical education: “The women of America and the world deserve better.” He went on to announce the creation of a presidential task force on surgical training, whose members will include: Dr. Ted Anderson, Dr. Emily Weber LeBrun, and Dr. Mike Moen.

This year’s TeLinde Lecture was given by the executive director of the American College of Surgeons, Dr. Dr. Patricia Turner. Her talk was entitled, “Surgeons: More to Unite Us Than Divide Us.” Dr. Turner began by reminding us of the shared history between general surgery and gynecologic surgery. In fact, the American College of Surgeons was founded by gynecologist Dr. Franklin H. Martin. She went on to thoughtfully discuss the need to rethink surgical training and the way we assess surgical trainees. She highlighted the importance of collaboration between all surgical specialties to improve surgical education, improve outcomes, and advocate for patients. “In order to heal all, we have to have ALL surgeons at the table.”

Today’s general session was concluded with a panel discussion on “Operating Room Safety and Efficiency” in which Dr. Kenneth Catchpole, Dr. Teodor Grantcharov, and Dr. Jason Wright shared some interesting ideas on how we can improve patient care in the operating room. The afternoon continued with a number of social activities, providing an opportunity to enjoy the beautiful landscape of San Antonio, Texas, including: a tour of Eisenhower park, kayaking on the Guadelupe River, and the SGS golf tournament.

The fun continued into the evening at the annual “SGS’ Got Talent” in which participants could be spotted in cowboy hats, bandanas, and boots. The night was filled with food, drinks, laughter, and line dancing! #SGS2022

 

Monday, March 28, 2022. Day 1 of SGS.

“How do you become brave? How do you become an advocate? How do you make a change?” These are just some of the questions asked during our thought-provoking early morning session entitled, “Healthcare Inequity Awareness—A Conversation to Empower Providers and Enhance the Patient Experience” at this year’s annual scientific meeting of the Society of Gynecologic Surgeons #SGS2022. The panelists, which included Dr. Olivia Cardenas-Trowers, Dr. Maria Florian-Rodriguez, and Dr. Tristi Muir, emphasized the importance of acknowledging our own bias as physicians, as well as the role structural racism plays in the health care access and outcomes of our patients. We were reminded that “Diversity, Equity, Inclusion (aka DEI) is a journey. It is progress over time, not over night.”

Following the early morning panel, the 48th annual scientific meeting officially began with a brief welcome and recognition of new SGS members by current president Dr. Carl Zimmerman and scientific program committee chair Dr. Oz Harmanli. The rest of the morning session was filled with outstanding oral and video presentations on topics ranging from the role of oophorectomy in patients with breast cancer, creating simulation models to enhance medical education, and tips for navigating the altered retroperitoneum.

Next, the Mark D. Walters endowed lecture was given by Dr. Marta A. Crispens, entitled “Restructuring Gynecologic Surgical Education: It’s a Matter of Equity.” In her exceptionally powerful address, Dr. Crispens began by discussing the historical context in which the fields of obstetrics and gynecology were combined and comparing it to a shift in current practice toward a national decrease in number of hysterectomies and an increase in the complexity of surgical cases. She highlighted the well-studied fact that low-volume surgeons have higher complication rates and that many new ObGyn residency graduates perform only 3 to 4 hysterectomies annually during the first few years of practice. Finally, she asserted that, by separating the practices of obstetrics and gynecology, we can improve surgical education and the quality of surgical care for our patients. The audience’s enthusiasm was undeniable, resulting in resounding applause and a standing ovation.

The afternoon was filled with unique opportunities for fellows, including: the Fellow’s Pelvic Research Network (FPRN) meeting, an incredibly informative panel on how to navigate the first year out of fellowship with Dr. Mireille Truong, Dr. Christine Foley, and Dr. Jon Pennycuff, and finally, the Mentorship Mingle.

The first day was concluded with the President’s Award Ceremony in which Dr. John DeLancey was presented with the illustrious President’s Award, followed by the President’s Reception with food, drinks, and lively conversation. Looking forward to day 2 of #SGS2022. @gynsurgery