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Derm Dx

What Is This Large Growth on the Foot?

November 2016

A 65-year-old African American man with a past medical history significant for hepatocellular carcinoma and liver transplant on 6 mg tacrolimus daily was seen for follow-up of a large lesion on the plantar surface of the left foot that had been present for the past 2 years. On physical examination, there was a macerated plaque with areas of thick filiform hyperkeratosis on the plantar surface of the left foot (Figures 1 and 2). What is your diagnosis? Scroll Down

        

 

 

 

 

 

DIAGNOSIS:

Verruca plantaris are caused by infection of the epidermis with human papillomavirus (HPV). HPV is a circular double-stranded DNA virus that belongs to the family Papillomaviridae. There are more than 120 types of HPV. The virus is introduced in the skin and mucosal epithelia at specific sites after minimal trauma and can persist asymptomatically or cause benign and malignant warts (papillomas).1,2 A large population-based study of skin pathology in the United States found the prevalence of nongenital warts to be 0.85%. The prevalence rate (15.5) was greatest among individuals aged 12 to 17 years followed by 13.1 among children aged 6 to 11 years and 12.4 among adults aged 18 to 24 years.3,4

Clinical Presentation
Verruca plantaris are epidermal proliferations of the skin due to infection with HPV manifesting as thick hyperkeratotic plaques. Lesions may be single or multiple and are located on the soles of the feet, often at pressure points such as the heel or underneath the metatarsal heads. These lesions are highly vascularized and rough to the touch.5,6 HPV-1, HPV-2, and HPV-4 are most commonly associated with verruca plantaris (Table).

The virus is transmitted through direct skin-to-skin contact or indirectly through contact with contaminated surfaces or objects. Transmission is facilitated by breaks in the skin and from activities that cause maceration of the skin such as swimming.7 In many cases, verruca plantaris resolve spontaneously in about 1 to 2 years, but infections may persist in immunocompromised individuals.1 Immunosuppressed patients, such as transplant patients are also at an increased risk for the development of multiple verruca.8 Patients typically seek treatment for cosmetic purposes or because of pain with weight bearing or pressure.

Diagnosis of verruca plantaris is typically based on clinical examination.3 Myrmecia are deep palmoplantar warts commonly associated with HPV-1 and characterized by a central keratotic plug surrounded by a harder rim of keratin.9 These lesions are painful upon application of lateral pressure and bleed when pared down to expose tiny red-black puncta representative of thrombosed capillaries.7 Superficial mosaic verruca are associated with HPV-2 and HPV-4, typically present as multiple and confluent lesions that form a thick layer, and are painless.9

Differential Diagnosis
The differential diagnosis for verruca plantaris includes plantar corns and calluses. Dermoscopically, verruca plantaris appear as a verrucous and yellow tinged area composed of a variable number of irregularly distributed red-black dots or streaks.10 Corns typically have a translucent central core, whereas calluses appear as a homogenous opacity under the dermatoscope.11

Histology
Histologic analysis of verruca plantaris demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies. Myrmecia demonstrate a unique histologic appearance characterized by endophytic growth, hyperacanthosis, and papillomatosis. The cornified layer is thick and compact with some red blood cells. There is abundant parakeratosis and intracytoplasmic eosinophilic inclusion bodies of HPV-1 viral particles.9 Superficial mosaic verruca are characterized by exophytic growth and hyperacanthosis with papillomatosis. The stratum granulosum is composed of vacuolated cells and intracytoplasmic basophilic keratohyalin granules.9,12

Verruca Plantaris and Verrucous Carcinoma
Verrucous carcinoma was first described in 1948 by Ackerman as an indolent and well-differentiated squamous cell carcinoma that rarely metastasizes.13 First described in the oral cavity, there are 3 main clinicopathologic types of  verrucous carcinoma named according to anatomic location and involving the oral mucosa (oral papillomatosis), anogenital region (giant condyloma acuminatum of Buschke and Lowenstein), and the plantar surface (epithelioma cuniculatum [EC]).14,15 While the pathogenesis of verrucous carcinoma is largely unknown, HPV infection is thought to contribute to the development of all types. Exposure to tobacco products has been associated with verrucous carcinoma involving the oral cavity.15

EC was first described by Aird and colleagues16 in 1954; the incidence is unknown. Males are predominantly affected (79%-89%) and tumors typically occur in the fifth decade of life.15 HPV-6, HPV-11, HPV-16, and HPV-18 have been associated with tumor development (Table). Other etiological factors include trauma, radiation exposure, chronic irritation, arsenic ingestion, and immunosuppression.17,18 It is well known that immunosuppressed organ transplant patients are at an increased risk for the development of skin cancer and verrucae.18-21 There are a number of cases describing EC in transplant patients on immunosuppressive therapy and in other immunosuppressed individuals.22,23

EC classically presents as a fungating, exophytic mass in a patient with a history of recalcitrant plantar warts. The disease follows a chronic course, often evolving from a discrete focal lesion.23 Diagnosis is often delayed as lesions develop slowly and may initially be misdiagnosed as plantar verrucae. A clue to diagnosis is that these lesions typically fail to respond to the standard therapeutic modalities for plantar verrucae.24 Tissue biopsy of the lesion may then aid in reaching the correct diagnosis. EC is characterized histologically by well-differentiated squamous epithelia, minimal cellular atypia, and blunt epidermal projections surrounded by edematous stroma.14,25 There is hyperkeratosis and parakeratosis as well as multiple keratin filled cysts and crypts.17,23,26

Characteristic clinical findings may also be useful. EC lesions have multiple sinuses and keratin-filled crypts that drain a malodorous fluid and occur on the soles of the feet at weight-bearing areas. The tumor has a tendency to invade locally, involving deeper structures such as plantar fascia, tendon, and bone.22 Although mortality is low, morbidity is significant due to skin and soft tissue destruction as well as involvement of muscle and bone.

Management of Verruca Plantaris
There are a number of different therapeutic options for patients with plantar verrucae including pharmacologic agents that are destructive, antimitotic, or via immunotherapeutic effect. First-line therapy is with destructive agents including salicylic acid, an organic acid that destroys HPV-infected epidermal cells.6 Treatment with salicylic acid is optimized when patients first soak the lesion in warm water and pare the lesion down. Cantharidin, a vesicant no longer marketed in the United States, is an effective destructive agent that causes mitochondrial cell death, acantholysis, and blistering 24 to 48 hours after application. Second-line therapy is with liquid nitrogen cryotherapy. Intralesional or topical application of the antimitotic agent bleomycin is used in the treatment of recalcitrant cutaneous warts.5,27 Bleomycin creates double strand breaks in DNA causing apoptosis. Immunotherapy involves intradermal injection of Candida antigens directly into the lesion to stimulate the host’s natural cell-mediated immune response and lead to clearance of HPV. Imiquimod 5% cream is another immunotherapeutic agent that inhibits HPV replication through upregulation of host factors such as tumor necrosis factor.28 Immunotherapy is a first-line treatment option in immunocompromised patients and a second-line therapy in patients who have failed cryotherapy.27

Topical therapies typically fail in the management of EC. It is common for EC to initially be misdiagnosed as verruca plantaris, and in these patients, lesions continue to evolve with use of topical agents. In such cases, biopsy is necessary to establish an accurate diagnosis and recommend an appropriate management plan. Treatment of EC involves wide local excision. Amputation may sometimes be necessary if the EC has significantly involved deep structures. Radiation is contraindicated due to high potential for recurrence.18

Our Patient
Our patient, who presented with a large lesion on the plantar surface of the left foot (Figures 1 and 2), had a past medical history significant for hepatocellular carcinoma followed by liver transplant and was on antirejection medication, tacrolimus at a dose of 6 mg daily. An initial punch biopsy showed classical features of verruca plantaris 2 years prior to his presentation to our clinic for follow up.

He was treated with epsom salt soaks, gentian violet, and imiquimod 5% cream 3 times a week while waiting for an appointment at the podiatric medicine department for therapeutic debridements and further evaluation. Minimal improvement was seen at a 1-year follow-up visit, and the left plantar foot had developed a macerated verrucous plaque with areas of thick filiform hyperkeratosis. Deep excisional biopsy was performed to rule out verrucous carcinoma. The patient’s history of organ transplantation on immunosuppressive therapy and history of recalcitrant plantar wart with malodorous exudate was concerning for possible EC. An incisional biopsy revealed verruca vulgaris and the patient was advised to keep regular follow-up appointments with the podiatric medicine department for debridements to be followed by use of imiquimod 5% cream. Vinegar soaks twice a day followed by sandpaper to thickened areas was also recommended. The malodorous drainage was attributed to infection and the patient was given metronidazole cream to apply to the affected area. Appropriate antibiotic coverage use per culture results was also recommended. The patient continues to be followed mutually by the dermatology and podiatric medicine clinics.

Conclusion
Plantar verrucae are commonly caused by HPV-1, HPV-2, and HPV-4. Lesions typically develop at pressure points on the heel or underneath the metatarsal heads and are painful with application of lateral pressure. Histologic analysis demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies (Figures 3 and 4). Infection with certain HPV types predisposes individuals to the development of EC. There is also a large body of evidence supporting an increased risk for the development of EC, verrucae, and other types of skin disease in organ transplant patients on immunosuppressive therapy. Treatment of plantar verrucae is with destructive agents such as salicylic acid, although newer approaches involving immunotherapeutic agents such as imiquimod 5% cream may also be effective. Management of EC involves wide local excision and/or amputation as conservative measures typically fail.

Stephanie Chapman is an MD Candidate 2017 at Michigan State University, College of Human Medicine in East Lansing, MI.
Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Disclosure: The authors report no relevant financial relationships.   

Acknowledgement: We thank Celine Mestel, MD, PhD, and Stephanie Gallitano, MD, for helping with the preparation of this manuscript and taking histology pictures.

References
1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.     
2. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70-79.    
3. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.
4. Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1-74 years. United States, 1971-1974. Vital Health Stat 11. 1978;(212):i-v, 1-72.
5. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014;348:g3339.
6. Micali G, Dall’Oglio F, Nasca M, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am J Clin Dermatol. 2004;5(5):311-317.
7. Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445(1-2):21-34.
8. Marks JG Jr, Miller JJ. Lookingbill & Marks’ Principles of Dermatology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
9. Laurent R, Kienzler JL, Croissant O, Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type 1 (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101-111.
10. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216(1):14-23.
11. Bae JM, Kang H, Kim HO, Park YM. Differential diagnosis of plantar wart from corn, callus, and healed wart with the aid of dermoscopy. Br J Dermatol. 2009;160(1):220-222.
12. Gross G, Pfister H, Hagedorn M, Gissmann L. Correlation between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol. 1982;78(2):160-164.
13. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23(4):670-678.

 

 

A 65-year-old African American man with a past medical history significant for hepatocellular carcinoma and liver transplant on 6 mg tacrolimus daily was seen for follow-up of a large lesion on the plantar surface of the left foot that had been present for the past 2 years. On physical examination, there was a macerated plaque with areas of thick filiform hyperkeratosis on the plantar surface of the left foot (Figures 1 and 2).

        

 

 

 

What is your diagnosis? 

DIAGNOSIS:

Verruca plantaris are caused by infection of the epidermis with human papillomavirus (HPV). HPV is a circular double-stranded DNA virus that belongs to the family Papillomaviridae. There are more than 120 types of HPV. The virus is introduced in the skin and mucosal epithelia at specific sites after minimal trauma and can persist asymptomatically or cause benign and malignant warts (papillomas).1,2 A large population-based study of skin pathology in the United States found the prevalence of nongenital warts to be 0.85%. The prevalence rate (15.5) was greatest among individuals aged 12 to 17 years followed by 13.1 among children aged 6 to 11 years and 12.4 among adults aged 18 to 24 years.3,4

Clinical Presentation
Verruca plantaris are epidermal proliferations of the skin due to infection with HPV manifesting as thick hyperkeratotic plaques. Lesions may be single or multiple and are located on the soles of the feet, often at pressure points such as the heel or underneath the metatarsal heads. These lesions are highly vascularized and rough to the touch.5,6 HPV-1, HPV-2, and HPV-4 are most commonly associated with verruca plantaris (Table).

The virus is transmitted through direct skin-to-skin contact or indirectly through contact with contaminated surfaces or objects. Transmission is facilitated by breaks in the skin and from activities that cause maceration of the skin such as swimming.7 In many cases, verruca plantaris resolve spontaneously in about 1 to 2 years, but infections may persist in immunocompromised individuals.1 Immunosuppressed patients, such as transplant patients are also at an increased risk for the development of multiple verruca.8 Patients typically seek treatment for cosmetic purposes or because of pain with weight bearing or pressure.

Diagnosis of verruca plantaris is typically based on clinical examination.3 Myrmecia are deep palmoplantar warts commonly associated with HPV-1 and characterized by a central keratotic plug surrounded by a harder rim of keratin.9 These lesions are painful upon application of lateral pressure and bleed when pared down to expose tiny red-black puncta representative of thrombosed capillaries.7 Superficial mosaic verruca are associated with HPV-2 and HPV-4, typically present as multiple and confluent lesions that form a thick layer, and are painless.9

Differential Diagnosis
The differential diagnosis for verruca plantaris includes plantar corns and calluses. Dermoscopically, verruca plantaris appear as a verrucous and yellow tinged area composed of a variable number of irregularly distributed red-black dots or streaks.10 Corns typically have a translucent central core, whereas calluses appear as a homogenous opacity under the dermatoscope.11

Histology
Histologic analysis of verruca plantaris demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies. Myrmecia demonstrate a unique histologic appearance characterized by endophytic growth, hyperacanthosis, and papillomatosis. The cornified layer is thick and compact with some red blood cells. There is abundant parakeratosis and intracytoplasmic eosinophilic inclusion bodies of HPV-1 viral particles.9 Superficial mosaic verruca are characterized by exophytic growth and hyperacanthosis with papillomatosis. The stratum granulosum is composed of vacuolated cells and intracytoplasmic basophilic keratohyalin granules.9,12

Verruca Plantaris and Verrucous Carcinoma
Verrucous carcinoma was first described in 1948 by Ackerman as an indolent and well-differentiated squamous cell carcinoma that rarely metastasizes.13 First described in the oral cavity, there are 3 main clinicopathologic types of  verrucous carcinoma named according to anatomic location and involving the oral mucosa (oral papillomatosis), anogenital region (giant condyloma acuminatum of Buschke and Lowenstein), and the plantar surface (epithelioma cuniculatum [EC]).14,15 While the pathogenesis of verrucous carcinoma is largely unknown, HPV infection is thought to contribute to the development of all types. Exposure to tobacco products has been associated with verrucous carcinoma involving the oral cavity.15

EC was first described by Aird and colleagues16 in 1954; the incidence is unknown. Males are predominantly affected (79%-89%) and tumors typically occur in the fifth decade of life.15 HPV-6, HPV-11, HPV-16, and HPV-18 have been associated with tumor development (Table). Other etiological factors include trauma, radiation exposure, chronic irritation, arsenic ingestion, and immunosuppression.17,18 It is well known that immunosuppressed organ transplant patients are at an increased risk for the development of skin cancer and verrucae.18-21 There are a number of cases describing EC in transplant patients on immunosuppressive therapy and in other immunosuppressed individuals.22,23

EC classically presents as a fungating, exophytic mass in a patient with a history of recalcitrant plantar warts. The disease follows a chronic course, often evolving from a discrete focal lesion.23 Diagnosis is often delayed as lesions develop slowly and may initially be misdiagnosed as plantar verrucae. A clue to diagnosis is that these lesions typically fail to respond to the standard therapeutic modalities for plantar verrucae.24 Tissue biopsy of the lesion may then aid in reaching the correct diagnosis. EC is characterized histologically by well-differentiated squamous epithelia, minimal cellular atypia, and blunt epidermal projections surrounded by edematous stroma.14,25 There is hyperkeratosis and parakeratosis as well as multiple keratin filled cysts and crypts.17,23,26

Characteristic clinical findings may also be useful. EC lesions have multiple sinuses and keratin-filled crypts that drain a malodorous fluid and occur on the soles of the feet at weight-bearing areas. The tumor has a tendency to invade locally, involving deeper structures such as plantar fascia, tendon, and bone.22 Although mortality is low, morbidity is significant due to skin and soft tissue destruction as well as involvement of muscle and bone.

Management of Verruca Plantaris
There are a number of different therapeutic options for patients with plantar verrucae including pharmacologic agents that are destructive, antimitotic, or via immunotherapeutic effect. First-line therapy is with destructive agents including salicylic acid, an organic acid that destroys HPV-infected epidermal cells.6 Treatment with salicylic acid is optimized when patients first soak the lesion in warm water and pare the lesion down. Cantharidin, a vesicant no longer marketed in the United States, is an effective destructive agent that causes mitochondrial cell death, acantholysis, and blistering 24 to 48 hours after application. Second-line therapy is with liquid nitrogen cryotherapy. Intralesional or topical application of the antimitotic agent bleomycin is used in the treatment of recalcitrant cutaneous warts.5,27 Bleomycin creates double strand breaks in DNA causing apoptosis. Immunotherapy involves intradermal injection of Candida antigens directly into the lesion to stimulate the host’s natural cell-mediated immune response and lead to clearance of HPV. Imiquimod 5% cream is another immunotherapeutic agent that inhibits HPV replication through upregulation of host factors such as tumor necrosis factor.28 Immunotherapy is a first-line treatment option in immunocompromised patients and a second-line therapy in patients who have failed cryotherapy.27

Topical therapies typically fail in the management of EC. It is common for EC to initially be misdiagnosed as verruca plantaris, and in these patients, lesions continue to evolve with use of topical agents. In such cases, biopsy is necessary to establish an accurate diagnosis and recommend an appropriate management plan. Treatment of EC involves wide local excision. Amputation may sometimes be necessary if the EC has significantly involved deep structures. Radiation is contraindicated due to high potential for recurrence.18

Our Patient
Our patient, who presented with a large lesion on the plantar surface of the left foot (Figures 1 and 2), had a past medical history significant for hepatocellular carcinoma followed by liver transplant and was on antirejection medication, tacrolimus at a dose of 6 mg daily. An initial punch biopsy showed classical features of verruca plantaris 2 years prior to his presentation to our clinic for follow up.

He was treated with epsom salt soaks, gentian violet, and imiquimod 5% cream 3 times a week while waiting for an appointment at the podiatric medicine department for therapeutic debridements and further evaluation. Minimal improvement was seen at a 1-year follow-up visit, and the left plantar foot had developed a macerated verrucous plaque with areas of thick filiform hyperkeratosis. Deep excisional biopsy was performed to rule out verrucous carcinoma. The patient’s history of organ transplantation on immunosuppressive therapy and history of recalcitrant plantar wart with malodorous exudate was concerning for possible EC. An incisional biopsy revealed verruca vulgaris and the patient was advised to keep regular follow-up appointments with the podiatric medicine department for debridements to be followed by use of imiquimod 5% cream. Vinegar soaks twice a day followed by sandpaper to thickened areas was also recommended. The malodorous drainage was attributed to infection and the patient was given metronidazole cream to apply to the affected area. Appropriate antibiotic coverage use per culture results was also recommended. The patient continues to be followed mutually by the dermatology and podiatric medicine clinics.

Conclusion
Plantar verrucae are commonly caused by HPV-1, HPV-2, and HPV-4. Lesions typically develop at pressure points on the heel or underneath the metatarsal heads and are painful with application of lateral pressure. Histologic analysis demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies (Figures 3 and 4). Infection with certain HPV types predisposes individuals to the development of EC. There is also a large body of evidence supporting an increased risk for the development of EC, verrucae, and other types of skin disease in organ transplant patients on immunosuppressive therapy. Treatment of plantar verrucae is with destructive agents such as salicylic acid, although newer approaches involving immunotherapeutic agents such as imiquimod 5% cream may also be effective. Management of EC involves wide local excision and/or amputation as conservative measures typically fail.

Stephanie Chapman is an MD Candidate 2017 at Michigan State University, College of Human Medicine in East Lansing, MI.
Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Disclosure: The authors report no relevant financial relationships.   

Acknowledgement: We thank Celine Mestel, MD, PhD, and Stephanie Gallitano, MD, for helping with the preparation of this manuscript and taking histology pictures.

References
1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.     
2. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70-79.    
3. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.
4. Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1-74 years. United States, 1971-1974. Vital Health Stat 11. 1978;(212):i-v, 1-72.
5. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014;348:g3339.
6. Micali G, Dall’Oglio F, Nasca M, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am J Clin Dermatol. 2004;5(5):311-317.
7. Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445(1-2):21-34.
8. Marks JG Jr, Miller JJ. Lookingbill & Marks’ Principles of Dermatology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
9. Laurent R, Kienzler JL, Croissant O, Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type 1 (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101-111.
10. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216(1):14-23.
11. Bae JM, Kang H, Kim HO, Park YM. Differential diagnosis of plantar wart from corn, callus, and healed wart with the aid of dermoscopy. Br J Dermatol. 2009;160(1):220-222.
12. Gross G, Pfister H, Hagedorn M, Gissmann L. Correlation between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol. 1982;78(2):160-164.
13. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23(4):670-678.

 

 

A 65-year-old African American man with a past medical history significant for hepatocellular carcinoma and liver transplant on 6 mg tacrolimus daily was seen for follow-up of a large lesion on the plantar surface of the left foot that had been present for the past 2 years. On physical examination, there was a macerated plaque with areas of thick filiform hyperkeratosis on the plantar surface of the left foot (Figures 1 and 2).

        

 

 

 

What is your diagnosis? 

,

A 65-year-old African American man with a past medical history significant for hepatocellular carcinoma and liver transplant on 6 mg tacrolimus daily was seen for follow-up of a large lesion on the plantar surface of the left foot that had been present for the past 2 years. On physical examination, there was a macerated plaque with areas of thick filiform hyperkeratosis on the plantar surface of the left foot (Figures 1 and 2). What is your diagnosis? Scroll Down

        

 

 

 

 

 

DIAGNOSIS:

Verruca plantaris are caused by infection of the epidermis with human papillomavirus (HPV). HPV is a circular double-stranded DNA virus that belongs to the family Papillomaviridae. There are more than 120 types of HPV. The virus is introduced in the skin and mucosal epithelia at specific sites after minimal trauma and can persist asymptomatically or cause benign and malignant warts (papillomas).1,2 A large population-based study of skin pathology in the United States found the prevalence of nongenital warts to be 0.85%. The prevalence rate (15.5) was greatest among individuals aged 12 to 17 years followed by 13.1 among children aged 6 to 11 years and 12.4 among adults aged 18 to 24 years.3,4

Clinical Presentation
Verruca plantaris are epidermal proliferations of the skin due to infection with HPV manifesting as thick hyperkeratotic plaques. Lesions may be single or multiple and are located on the soles of the feet, often at pressure points such as the heel or underneath the metatarsal heads. These lesions are highly vascularized and rough to the touch.5,6 HPV-1, HPV-2, and HPV-4 are most commonly associated with verruca plantaris (Table).

The virus is transmitted through direct skin-to-skin contact or indirectly through contact with contaminated surfaces or objects. Transmission is facilitated by breaks in the skin and from activities that cause maceration of the skin such as swimming.7 In many cases, verruca plantaris resolve spontaneously in about 1 to 2 years, but infections may persist in immunocompromised individuals.1 Immunosuppressed patients, such as transplant patients are also at an increased risk for the development of multiple verruca.8 Patients typically seek treatment for cosmetic purposes or because of pain with weight bearing or pressure.

Diagnosis of verruca plantaris is typically based on clinical examination.3 Myrmecia are deep palmoplantar warts commonly associated with HPV-1 and characterized by a central keratotic plug surrounded by a harder rim of keratin.9 These lesions are painful upon application of lateral pressure and bleed when pared down to expose tiny red-black puncta representative of thrombosed capillaries.7 Superficial mosaic verruca are associated with HPV-2 and HPV-4, typically present as multiple and confluent lesions that form a thick layer, and are painless.9

Differential Diagnosis
The differential diagnosis for verruca plantaris includes plantar corns and calluses. Dermoscopically, verruca plantaris appear as a verrucous and yellow tinged area composed of a variable number of irregularly distributed red-black dots or streaks.10 Corns typically have a translucent central core, whereas calluses appear as a homogenous opacity under the dermatoscope.11

Histology
Histologic analysis of verruca plantaris demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies. Myrmecia demonstrate a unique histologic appearance characterized by endophytic growth, hyperacanthosis, and papillomatosis. The cornified layer is thick and compact with some red blood cells. There is abundant parakeratosis and intracytoplasmic eosinophilic inclusion bodies of HPV-1 viral particles.9 Superficial mosaic verruca are characterized by exophytic growth and hyperacanthosis with papillomatosis. The stratum granulosum is composed of vacuolated cells and intracytoplasmic basophilic keratohyalin granules.9,12

Verruca Plantaris and Verrucous Carcinoma
Verrucous carcinoma was first described in 1948 by Ackerman as an indolent and well-differentiated squamous cell carcinoma that rarely metastasizes.13 First described in the oral cavity, there are 3 main clinicopathologic types of  verrucous carcinoma named according to anatomic location and involving the oral mucosa (oral papillomatosis), anogenital region (giant condyloma acuminatum of Buschke and Lowenstein), and the plantar surface (epithelioma cuniculatum [EC]).14,15 While the pathogenesis of verrucous carcinoma is largely unknown, HPV infection is thought to contribute to the development of all types. Exposure to tobacco products has been associated with verrucous carcinoma involving the oral cavity.15

EC was first described by Aird and colleagues16 in 1954; the incidence is unknown. Males are predominantly affected (79%-89%) and tumors typically occur in the fifth decade of life.15 HPV-6, HPV-11, HPV-16, and HPV-18 have been associated with tumor development (Table). Other etiological factors include trauma, radiation exposure, chronic irritation, arsenic ingestion, and immunosuppression.17,18 It is well known that immunosuppressed organ transplant patients are at an increased risk for the development of skin cancer and verrucae.18-21 There are a number of cases describing EC in transplant patients on immunosuppressive therapy and in other immunosuppressed individuals.22,23

EC classically presents as a fungating, exophytic mass in a patient with a history of recalcitrant plantar warts. The disease follows a chronic course, often evolving from a discrete focal lesion.23 Diagnosis is often delayed as lesions develop slowly and may initially be misdiagnosed as plantar verrucae. A clue to diagnosis is that these lesions typically fail to respond to the standard therapeutic modalities for plantar verrucae.24 Tissue biopsy of the lesion may then aid in reaching the correct diagnosis. EC is characterized histologically by well-differentiated squamous epithelia, minimal cellular atypia, and blunt epidermal projections surrounded by edematous stroma.14,25 There is hyperkeratosis and parakeratosis as well as multiple keratin filled cysts and crypts.17,23,26

Characteristic clinical findings may also be useful. EC lesions have multiple sinuses and keratin-filled crypts that drain a malodorous fluid and occur on the soles of the feet at weight-bearing areas. The tumor has a tendency to invade locally, involving deeper structures such as plantar fascia, tendon, and bone.22 Although mortality is low, morbidity is significant due to skin and soft tissue destruction as well as involvement of muscle and bone.

Management of Verruca Plantaris
There are a number of different therapeutic options for patients with plantar verrucae including pharmacologic agents that are destructive, antimitotic, or via immunotherapeutic effect. First-line therapy is with destructive agents including salicylic acid, an organic acid that destroys HPV-infected epidermal cells.6 Treatment with salicylic acid is optimized when patients first soak the lesion in warm water and pare the lesion down. Cantharidin, a vesicant no longer marketed in the United States, is an effective destructive agent that causes mitochondrial cell death, acantholysis, and blistering 24 to 48 hours after application. Second-line therapy is with liquid nitrogen cryotherapy. Intralesional or topical application of the antimitotic agent bleomycin is used in the treatment of recalcitrant cutaneous warts.5,27 Bleomycin creates double strand breaks in DNA causing apoptosis. Immunotherapy involves intradermal injection of Candida antigens directly into the lesion to stimulate the host’s natural cell-mediated immune response and lead to clearance of HPV. Imiquimod 5% cream is another immunotherapeutic agent that inhibits HPV replication through upregulation of host factors such as tumor necrosis factor.28 Immunotherapy is a first-line treatment option in immunocompromised patients and a second-line therapy in patients who have failed cryotherapy.27

Topical therapies typically fail in the management of EC. It is common for EC to initially be misdiagnosed as verruca plantaris, and in these patients, lesions continue to evolve with use of topical agents. In such cases, biopsy is necessary to establish an accurate diagnosis and recommend an appropriate management plan. Treatment of EC involves wide local excision. Amputation may sometimes be necessary if the EC has significantly involved deep structures. Radiation is contraindicated due to high potential for recurrence.18

Our Patient
Our patient, who presented with a large lesion on the plantar surface of the left foot (Figures 1 and 2), had a past medical history significant for hepatocellular carcinoma followed by liver transplant and was on antirejection medication, tacrolimus at a dose of 6 mg daily. An initial punch biopsy showed classical features of verruca plantaris 2 years prior to his presentation to our clinic for follow up.

He was treated with epsom salt soaks, gentian violet, and imiquimod 5% cream 3 times a week while waiting for an appointment at the podiatric medicine department for therapeutic debridements and further evaluation. Minimal improvement was seen at a 1-year follow-up visit, and the left plantar foot had developed a macerated verrucous plaque with areas of thick filiform hyperkeratosis. Deep excisional biopsy was performed to rule out verrucous carcinoma. The patient’s history of organ transplantation on immunosuppressive therapy and history of recalcitrant plantar wart with malodorous exudate was concerning for possible EC. An incisional biopsy revealed verruca vulgaris and the patient was advised to keep regular follow-up appointments with the podiatric medicine department for debridements to be followed by use of imiquimod 5% cream. Vinegar soaks twice a day followed by sandpaper to thickened areas was also recommended. The malodorous drainage was attributed to infection and the patient was given metronidazole cream to apply to the affected area. Appropriate antibiotic coverage use per culture results was also recommended. The patient continues to be followed mutually by the dermatology and podiatric medicine clinics.

Conclusion
Plantar verrucae are commonly caused by HPV-1, HPV-2, and HPV-4. Lesions typically develop at pressure points on the heel or underneath the metatarsal heads and are painful with application of lateral pressure. Histologic analysis demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies (Figures 3 and 4). Infection with certain HPV types predisposes individuals to the development of EC. There is also a large body of evidence supporting an increased risk for the development of EC, verrucae, and other types of skin disease in organ transplant patients on immunosuppressive therapy. Treatment of plantar verrucae is with destructive agents such as salicylic acid, although newer approaches involving immunotherapeutic agents such as imiquimod 5% cream may also be effective. Management of EC involves wide local excision and/or amputation as conservative measures typically fail.

Stephanie Chapman is an MD Candidate 2017 at Michigan State University, College of Human Medicine in East Lansing, MI.
Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Disclosure: The authors report no relevant financial relationships.   

Acknowledgement: We thank Celine Mestel, MD, PhD, and Stephanie Gallitano, MD, for helping with the preparation of this manuscript and taking histology pictures.

References
1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.     
2. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70-79.    
3. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.
4. Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1-74 years. United States, 1971-1974. Vital Health Stat 11. 1978;(212):i-v, 1-72.
5. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014;348:g3339.
6. Micali G, Dall’Oglio F, Nasca M, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am J Clin Dermatol. 2004;5(5):311-317.
7. Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445(1-2):21-34.
8. Marks JG Jr, Miller JJ. Lookingbill & Marks’ Principles of Dermatology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
9. Laurent R, Kienzler JL, Croissant O, Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type 1 (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101-111.
10. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216(1):14-23.
11. Bae JM, Kang H, Kim HO, Park YM. Differential diagnosis of plantar wart from corn, callus, and healed wart with the aid of dermoscopy. Br J Dermatol. 2009;160(1):220-222.
12. Gross G, Pfister H, Hagedorn M, Gissmann L. Correlation between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol. 1982;78(2):160-164.
13. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23(4):670-678.

 

 

A 65-year-old African American man with a past medical history significant for hepatocellular carcinoma and liver transplant on 6 mg tacrolimus daily was seen for follow-up of a large lesion on the plantar surface of the left foot that had been present for the past 2 years. On physical examination, there was a macerated plaque with areas of thick filiform hyperkeratosis on the plantar surface of the left foot (Figures 1 and 2).

        

 

 

 

What is your diagnosis? 

DIAGNOSIS:

Verruca plantaris are caused by infection of the epidermis with human papillomavirus (HPV). HPV is a circular double-stranded DNA virus that belongs to the family Papillomaviridae. There are more than 120 types of HPV. The virus is introduced in the skin and mucosal epithelia at specific sites after minimal trauma and can persist asymptomatically or cause benign and malignant warts (papillomas).1,2 A large population-based study of skin pathology in the United States found the prevalence of nongenital warts to be 0.85%. The prevalence rate (15.5) was greatest among individuals aged 12 to 17 years followed by 13.1 among children aged 6 to 11 years and 12.4 among adults aged 18 to 24 years.3,4

Clinical Presentation
Verruca plantaris are epidermal proliferations of the skin due to infection with HPV manifesting as thick hyperkeratotic plaques. Lesions may be single or multiple and are located on the soles of the feet, often at pressure points such as the heel or underneath the metatarsal heads. These lesions are highly vascularized and rough to the touch.5,6 HPV-1, HPV-2, and HPV-4 are most commonly associated with verruca plantaris (Table).

The virus is transmitted through direct skin-to-skin contact or indirectly through contact with contaminated surfaces or objects. Transmission is facilitated by breaks in the skin and from activities that cause maceration of the skin such as swimming.7 In many cases, verruca plantaris resolve spontaneously in about 1 to 2 years, but infections may persist in immunocompromised individuals.1 Immunosuppressed patients, such as transplant patients are also at an increased risk for the development of multiple verruca.8 Patients typically seek treatment for cosmetic purposes or because of pain with weight bearing or pressure.

Diagnosis of verruca plantaris is typically based on clinical examination.3 Myrmecia are deep palmoplantar warts commonly associated with HPV-1 and characterized by a central keratotic plug surrounded by a harder rim of keratin.9 These lesions are painful upon application of lateral pressure and bleed when pared down to expose tiny red-black puncta representative of thrombosed capillaries.7 Superficial mosaic verruca are associated with HPV-2 and HPV-4, typically present as multiple and confluent lesions that form a thick layer, and are painless.9

Differential Diagnosis
The differential diagnosis for verruca plantaris includes plantar corns and calluses. Dermoscopically, verruca plantaris appear as a verrucous and yellow tinged area composed of a variable number of irregularly distributed red-black dots or streaks.10 Corns typically have a translucent central core, whereas calluses appear as a homogenous opacity under the dermatoscope.11

Histology
Histologic analysis of verruca plantaris demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies. Myrmecia demonstrate a unique histologic appearance characterized by endophytic growth, hyperacanthosis, and papillomatosis. The cornified layer is thick and compact with some red blood cells. There is abundant parakeratosis and intracytoplasmic eosinophilic inclusion bodies of HPV-1 viral particles.9 Superficial mosaic verruca are characterized by exophytic growth and hyperacanthosis with papillomatosis. The stratum granulosum is composed of vacuolated cells and intracytoplasmic basophilic keratohyalin granules.9,12

Verruca Plantaris and Verrucous Carcinoma
Verrucous carcinoma was first described in 1948 by Ackerman as an indolent and well-differentiated squamous cell carcinoma that rarely metastasizes.13 First described in the oral cavity, there are 3 main clinicopathologic types of  verrucous carcinoma named according to anatomic location and involving the oral mucosa (oral papillomatosis), anogenital region (giant condyloma acuminatum of Buschke and Lowenstein), and the plantar surface (epithelioma cuniculatum [EC]).14,15 While the pathogenesis of verrucous carcinoma is largely unknown, HPV infection is thought to contribute to the development of all types. Exposure to tobacco products has been associated with verrucous carcinoma involving the oral cavity.15

EC was first described by Aird and colleagues16 in 1954; the incidence is unknown. Males are predominantly affected (79%-89%) and tumors typically occur in the fifth decade of life.15 HPV-6, HPV-11, HPV-16, and HPV-18 have been associated with tumor development (Table). Other etiological factors include trauma, radiation exposure, chronic irritation, arsenic ingestion, and immunosuppression.17,18 It is well known that immunosuppressed organ transplant patients are at an increased risk for the development of skin cancer and verrucae.18-21 There are a number of cases describing EC in transplant patients on immunosuppressive therapy and in other immunosuppressed individuals.22,23

EC classically presents as a fungating, exophytic mass in a patient with a history of recalcitrant plantar warts. The disease follows a chronic course, often evolving from a discrete focal lesion.23 Diagnosis is often delayed as lesions develop slowly and may initially be misdiagnosed as plantar verrucae. A clue to diagnosis is that these lesions typically fail to respond to the standard therapeutic modalities for plantar verrucae.24 Tissue biopsy of the lesion may then aid in reaching the correct diagnosis. EC is characterized histologically by well-differentiated squamous epithelia, minimal cellular atypia, and blunt epidermal projections surrounded by edematous stroma.14,25 There is hyperkeratosis and parakeratosis as well as multiple keratin filled cysts and crypts.17,23,26

Characteristic clinical findings may also be useful. EC lesions have multiple sinuses and keratin-filled crypts that drain a malodorous fluid and occur on the soles of the feet at weight-bearing areas. The tumor has a tendency to invade locally, involving deeper structures such as plantar fascia, tendon, and bone.22 Although mortality is low, morbidity is significant due to skin and soft tissue destruction as well as involvement of muscle and bone.

Management of Verruca Plantaris
There are a number of different therapeutic options for patients with plantar verrucae including pharmacologic agents that are destructive, antimitotic, or via immunotherapeutic effect. First-line therapy is with destructive agents including salicylic acid, an organic acid that destroys HPV-infected epidermal cells.6 Treatment with salicylic acid is optimized when patients first soak the lesion in warm water and pare the lesion down. Cantharidin, a vesicant no longer marketed in the United States, is an effective destructive agent that causes mitochondrial cell death, acantholysis, and blistering 24 to 48 hours after application. Second-line therapy is with liquid nitrogen cryotherapy. Intralesional or topical application of the antimitotic agent bleomycin is used in the treatment of recalcitrant cutaneous warts.5,27 Bleomycin creates double strand breaks in DNA causing apoptosis. Immunotherapy involves intradermal injection of Candida antigens directly into the lesion to stimulate the host’s natural cell-mediated immune response and lead to clearance of HPV. Imiquimod 5% cream is another immunotherapeutic agent that inhibits HPV replication through upregulation of host factors such as tumor necrosis factor.28 Immunotherapy is a first-line treatment option in immunocompromised patients and a second-line therapy in patients who have failed cryotherapy.27

Topical therapies typically fail in the management of EC. It is common for EC to initially be misdiagnosed as verruca plantaris, and in these patients, lesions continue to evolve with use of topical agents. In such cases, biopsy is necessary to establish an accurate diagnosis and recommend an appropriate management plan. Treatment of EC involves wide local excision. Amputation may sometimes be necessary if the EC has significantly involved deep structures. Radiation is contraindicated due to high potential for recurrence.18

Our Patient
Our patient, who presented with a large lesion on the plantar surface of the left foot (Figures 1 and 2), had a past medical history significant for hepatocellular carcinoma followed by liver transplant and was on antirejection medication, tacrolimus at a dose of 6 mg daily. An initial punch biopsy showed classical features of verruca plantaris 2 years prior to his presentation to our clinic for follow up.

He was treated with epsom salt soaks, gentian violet, and imiquimod 5% cream 3 times a week while waiting for an appointment at the podiatric medicine department for therapeutic debridements and further evaluation. Minimal improvement was seen at a 1-year follow-up visit, and the left plantar foot had developed a macerated verrucous plaque with areas of thick filiform hyperkeratosis. Deep excisional biopsy was performed to rule out verrucous carcinoma. The patient’s history of organ transplantation on immunosuppressive therapy and history of recalcitrant plantar wart with malodorous exudate was concerning for possible EC. An incisional biopsy revealed verruca vulgaris and the patient was advised to keep regular follow-up appointments with the podiatric medicine department for debridements to be followed by use of imiquimod 5% cream. Vinegar soaks twice a day followed by sandpaper to thickened areas was also recommended. The malodorous drainage was attributed to infection and the patient was given metronidazole cream to apply to the affected area. Appropriate antibiotic coverage use per culture results was also recommended. The patient continues to be followed mutually by the dermatology and podiatric medicine clinics.

Conclusion
Plantar verrucae are commonly caused by HPV-1, HPV-2, and HPV-4. Lesions typically develop at pressure points on the heel or underneath the metatarsal heads and are painful with application of lateral pressure. Histologic analysis demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies (Figures 3 and 4). Infection with certain HPV types predisposes individuals to the development of EC. There is also a large body of evidence supporting an increased risk for the development of EC, verrucae, and other types of skin disease in organ transplant patients on immunosuppressive therapy. Treatment of plantar verrucae is with destructive agents such as salicylic acid, although newer approaches involving immunotherapeutic agents such as imiquimod 5% cream may also be effective. Management of EC involves wide local excision and/or amputation as conservative measures typically fail.

Stephanie Chapman is an MD Candidate 2017 at Michigan State University, College of Human Medicine in East Lansing, MI.
Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Disclosure: The authors report no relevant financial relationships.   

Acknowledgement: We thank Celine Mestel, MD, PhD, and Stephanie Gallitano, MD, for helping with the preparation of this manuscript and taking histology pictures.

References
1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.     
2. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70-79.    
3. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.
4. Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1-74 years. United States, 1971-1974. Vital Health Stat 11. 1978;(212):i-v, 1-72.
5. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014;348:g3339.
6. Micali G, Dall’Oglio F, Nasca M, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am J Clin Dermatol. 2004;5(5):311-317.
7. Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445(1-2):21-34.
8. Marks JG Jr, Miller JJ. Lookingbill & Marks’ Principles of Dermatology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
9. Laurent R, Kienzler JL, Croissant O, Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type 1 (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101-111.
10. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216(1):14-23.
11. Bae JM, Kang H, Kim HO, Park YM. Differential diagnosis of plantar wart from corn, callus, and healed wart with the aid of dermoscopy. Br J Dermatol. 2009;160(1):220-222.
12. Gross G, Pfister H, Hagedorn M, Gissmann L. Correlation between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol. 1982;78(2):160-164.
13. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23(4):670-678.

DIAGNOSIS:

Verruca plantaris are caused by infection of the epidermis with human papillomavirus (HPV). HPV is a circular double-stranded DNA virus that belongs to the family Papillomaviridae. There are more than 120 types of HPV. The virus is introduced in the skin and mucosal epithelia at specific sites after minimal trauma and can persist asymptomatically or cause benign and malignant warts (papillomas).1,2 A large population-based study of skin pathology in the United States found the prevalence of nongenital warts to be 0.85%. The prevalence rate (15.5) was greatest among individuals aged 12 to 17 years followed by 13.1 among children aged 6 to 11 years and 12.4 among adults aged 18 to 24 years.3,4

Clinical Presentation
Verruca plantaris are epidermal proliferations of the skin due to infection with HPV manifesting as thick hyperkeratotic plaques. Lesions may be single or multiple and are located on the soles of the feet, often at pressure points such as the heel or underneath the metatarsal heads. These lesions are highly vascularized and rough to the touch.5,6 HPV-1, HPV-2, and HPV-4 are most commonly associated with verruca plantaris (Table).

The virus is transmitted through direct skin-to-skin contact or indirectly through contact with contaminated surfaces or objects. Transmission is facilitated by breaks in the skin and from activities that cause maceration of the skin such as swimming.7 In many cases, verruca plantaris resolve spontaneously in about 1 to 2 years, but infections may persist in immunocompromised individuals.1 Immunosuppressed patients, such as transplant patients are also at an increased risk for the development of multiple verruca.8 Patients typically seek treatment for cosmetic purposes or because of pain with weight bearing or pressure.

Diagnosis of verruca plantaris is typically based on clinical examination.3 Myrmecia are deep palmoplantar warts commonly associated with HPV-1 and characterized by a central keratotic plug surrounded by a harder rim of keratin.9 These lesions are painful upon application of lateral pressure and bleed when pared down to expose tiny red-black puncta representative of thrombosed capillaries.7 Superficial mosaic verruca are associated with HPV-2 and HPV-4, typically present as multiple and confluent lesions that form a thick layer, and are painless.9

Differential Diagnosis
The differential diagnosis for verruca plantaris includes plantar corns and calluses. Dermoscopically, verruca plantaris appear as a verrucous and yellow tinged area composed of a variable number of irregularly distributed red-black dots or streaks.10 Corns typically have a translucent central core, whereas calluses appear as a homogenous opacity under the dermatoscope.11

Histology
Histologic analysis of verruca plantaris demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies. Myrmecia demonstrate a unique histologic appearance characterized by endophytic growth, hyperacanthosis, and papillomatosis. The cornified layer is thick and compact with some red blood cells. There is abundant parakeratosis and intracytoplasmic eosinophilic inclusion bodies of HPV-1 viral particles.9 Superficial mosaic verruca are characterized by exophytic growth and hyperacanthosis with papillomatosis. The stratum granulosum is composed of vacuolated cells and intracytoplasmic basophilic keratohyalin granules.9,12

Verruca Plantaris and Verrucous Carcinoma
Verrucous carcinoma was first described in 1948 by Ackerman as an indolent and well-differentiated squamous cell carcinoma that rarely metastasizes.13 First described in the oral cavity, there are 3 main clinicopathologic types of  verrucous carcinoma named according to anatomic location and involving the oral mucosa (oral papillomatosis), anogenital region (giant condyloma acuminatum of Buschke and Lowenstein), and the plantar surface (epithelioma cuniculatum [EC]).14,15 While the pathogenesis of verrucous carcinoma is largely unknown, HPV infection is thought to contribute to the development of all types. Exposure to tobacco products has been associated with verrucous carcinoma involving the oral cavity.15

EC was first described by Aird and colleagues16 in 1954; the incidence is unknown. Males are predominantly affected (79%-89%) and tumors typically occur in the fifth decade of life.15 HPV-6, HPV-11, HPV-16, and HPV-18 have been associated with tumor development (Table). Other etiological factors include trauma, radiation exposure, chronic irritation, arsenic ingestion, and immunosuppression.17,18 It is well known that immunosuppressed organ transplant patients are at an increased risk for the development of skin cancer and verrucae.18-21 There are a number of cases describing EC in transplant patients on immunosuppressive therapy and in other immunosuppressed individuals.22,23

EC classically presents as a fungating, exophytic mass in a patient with a history of recalcitrant plantar warts. The disease follows a chronic course, often evolving from a discrete focal lesion.23 Diagnosis is often delayed as lesions develop slowly and may initially be misdiagnosed as plantar verrucae. A clue to diagnosis is that these lesions typically fail to respond to the standard therapeutic modalities for plantar verrucae.24 Tissue biopsy of the lesion may then aid in reaching the correct diagnosis. EC is characterized histologically by well-differentiated squamous epithelia, minimal cellular atypia, and blunt epidermal projections surrounded by edematous stroma.14,25 There is hyperkeratosis and parakeratosis as well as multiple keratin filled cysts and crypts.17,23,26

Characteristic clinical findings may also be useful. EC lesions have multiple sinuses and keratin-filled crypts that drain a malodorous fluid and occur on the soles of the feet at weight-bearing areas. The tumor has a tendency to invade locally, involving deeper structures such as plantar fascia, tendon, and bone.22 Although mortality is low, morbidity is significant due to skin and soft tissue destruction as well as involvement of muscle and bone.

Management of Verruca Plantaris
There are a number of different therapeutic options for patients with plantar verrucae including pharmacologic agents that are destructive, antimitotic, or via immunotherapeutic effect. First-line therapy is with destructive agents including salicylic acid, an organic acid that destroys HPV-infected epidermal cells.6 Treatment with salicylic acid is optimized when patients first soak the lesion in warm water and pare the lesion down. Cantharidin, a vesicant no longer marketed in the United States, is an effective destructive agent that causes mitochondrial cell death, acantholysis, and blistering 24 to 48 hours after application. Second-line therapy is with liquid nitrogen cryotherapy. Intralesional or topical application of the antimitotic agent bleomycin is used in the treatment of recalcitrant cutaneous warts.5,27 Bleomycin creates double strand breaks in DNA causing apoptosis. Immunotherapy involves intradermal injection of Candida antigens directly into the lesion to stimulate the host’s natural cell-mediated immune response and lead to clearance of HPV. Imiquimod 5% cream is another immunotherapeutic agent that inhibits HPV replication through upregulation of host factors such as tumor necrosis factor.28 Immunotherapy is a first-line treatment option in immunocompromised patients and a second-line therapy in patients who have failed cryotherapy.27

Topical therapies typically fail in the management of EC. It is common for EC to initially be misdiagnosed as verruca plantaris, and in these patients, lesions continue to evolve with use of topical agents. In such cases, biopsy is necessary to establish an accurate diagnosis and recommend an appropriate management plan. Treatment of EC involves wide local excision. Amputation may sometimes be necessary if the EC has significantly involved deep structures. Radiation is contraindicated due to high potential for recurrence.18

Our Patient
Our patient, who presented with a large lesion on the plantar surface of the left foot (Figures 1 and 2), had a past medical history significant for hepatocellular carcinoma followed by liver transplant and was on antirejection medication, tacrolimus at a dose of 6 mg daily. An initial punch biopsy showed classical features of verruca plantaris 2 years prior to his presentation to our clinic for follow up.

He was treated with epsom salt soaks, gentian violet, and imiquimod 5% cream 3 times a week while waiting for an appointment at the podiatric medicine department for therapeutic debridements and further evaluation. Minimal improvement was seen at a 1-year follow-up visit, and the left plantar foot had developed a macerated verrucous plaque with areas of thick filiform hyperkeratosis. Deep excisional biopsy was performed to rule out verrucous carcinoma. The patient’s history of organ transplantation on immunosuppressive therapy and history of recalcitrant plantar wart with malodorous exudate was concerning for possible EC. An incisional biopsy revealed verruca vulgaris and the patient was advised to keep regular follow-up appointments with the podiatric medicine department for debridements to be followed by use of imiquimod 5% cream. Vinegar soaks twice a day followed by sandpaper to thickened areas was also recommended. The malodorous drainage was attributed to infection and the patient was given metronidazole cream to apply to the affected area. Appropriate antibiotic coverage use per culture results was also recommended. The patient continues to be followed mutually by the dermatology and podiatric medicine clinics.

Conclusion
Plantar verrucae are commonly caused by HPV-1, HPV-2, and HPV-4. Lesions typically develop at pressure points on the heel or underneath the metatarsal heads and are painful with application of lateral pressure. Histologic analysis demonstrates cellular vacuolation in and below the granular layer, and intracytoplasmic basophilic and eosinophilic inclusion bodies (Figures 3 and 4). Infection with certain HPV types predisposes individuals to the development of EC. There is also a large body of evidence supporting an increased risk for the development of EC, verrucae, and other types of skin disease in organ transplant patients on immunosuppressive therapy. Treatment of plantar verrucae is with destructive agents such as salicylic acid, although newer approaches involving immunotherapeutic agents such as imiquimod 5% cream may also be effective. Management of EC involves wide local excision and/or amputation as conservative measures typically fail.

Stephanie Chapman is an MD Candidate 2017 at Michigan State University, College of Human Medicine in East Lansing, MI.
Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Disclosure: The authors report no relevant financial relationships.   

Acknowledgement: We thank Celine Mestel, MD, PhD, and Stephanie Gallitano, MD, for helping with the preparation of this manuscript and taking histology pictures.

References
1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324(1):17-27.     
2. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70-79.    
3. Sterling JC, Handfield-Jones S, Hudson PM; British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol. 2001;144(1):4-11.
4. Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1-74 years. United States, 1971-1974. Vital Health Stat 11. 1978;(212):i-v, 1-72.
5. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014;348:g3339.
6. Micali G, Dall’Oglio F, Nasca M, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am J Clin Dermatol. 2004;5(5):311-317.
7. Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013;445(1-2):21-34.
8. Marks JG Jr, Miller JJ. Lookingbill & Marks’ Principles of Dermatology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
9. Laurent R, Kienzler JL, Croissant O, Orth G. Two anatomoclinical types of warts with plantar localization: specific cytopathogenic effects of papillomavirus. Type 1 (HPV-1) and type 2 (HPV-2). Arch Dermatol Res. 1982;274(1-2):101-111.
10. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216(1):14-23.
11. Bae JM, Kang H, Kim HO, Park YM. Differential diagnosis of plantar wart from corn, callus, and healed wart with the aid of dermoscopy. Br J Dermatol. 2009;160(1):220-222.
12. Gross G, Pfister H, Hagedorn M, Gissmann L. Correlation between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol. 1982;78(2):160-164.
13. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23(4):670-678.

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