Verrucous Lesions: When To Biopsy, When Not to Biopsy

Given that warts can mimic the clinical appearance of carcinomas and melanoma, accurate diagnosis is crucial. These authors review key considerations and provide a guide to when a biopsy can clarify the clinical picture.

Viral warts may present with a variety of dermatologic appearances.¹ There are many verrucous lesions that can mimic those infected with human papillomavirus (HPV). Cutaneous warts reportedly affect 7 to 10 percent of the population with the highest incidence in individuals 12 to 16 years of age.² This viral infection does not have a sex predilection and more commonly affects immunocompromised individuals in the adult population.³

Clinically, viral warts present with characteristic features: pinpoint bleeding appearing as small black dots upon debridement, interruption of normal skin lines and lateral compression eliciting pain. Via the portal of entry, viral particles infect keratinocytes, leading to abnormal histologic growth, including hyperkeratosis, papillomatosis and acanthosis at the microscopic level.³

Various treatments exist for cutaneous warts. Physicians have used topical applications of medications such as salicylic acid, 5-fluorouracil (5-FU) and/or imiquimod with differing reports as to the efficacy.⁴ Others may employ modalities like cryotherapy, thermocautery or different types of laser treatment to physically destroy viral lesions. Surgical excision is another means of attempting to eradicate the viral infection.⁴ The fact that there are many more treatments available elucidates the difficulty in treatment, persistence of the lesion and likely recurrent nature of this infection. There is some controversy in treatment protocol as warts occasionally resolve spontaneously.⁵

Referral to a specialist for a cutaneous wart is recommended for immunocompromised patients, when diagnosis of the lesion is uncertain and when the lesion is particularly large, or has failed three or more months of treatment.⁵ These circumstances may warrant performing a biopsy for evaluation of a possible misdiagnosis.

What Can Mimic Verruca?

The differential could include a myriad of diagnoses that are growths of the skin. It is important not to rule out any variants of the disorder until obtaining a biopsy and pathological impression.

The differential diagnosis of cutaneous warts should include:

• corns/calluses/hyperkeratosis
• ectopic nail
• cutaneous horn
• mycosis fungoides
• angiokeratoma
• eccrine syringofibroadenoma
• squamous cell carcinoma
• carcinoma cuniculatum
• Verrucous carcinoma
• Acral lentiginous melanoma (melanotic/amelanotic variants)
• Kaposi’s sarcoma

Hyperkeratotic lesions (corns and calluses) are quite obvious as one can mistake the more common diagnosis as verruca plantaris.^5,6 Ectopic nails are rare but in a case by Bilenchi and coworkers in 2012, a recalcitrant mass treated as a wart for two years ended up being an ectopic nail.⁷ This reminds us we cannot rule out random genetic occurrences.

Physicians often diagnose cutaneous horns as warts but there may be some coincidental basis for this whereas some horns have a verrucous base. It is important to keep in mind that cutaneous horns can have malignant potential (which we’ll discuss below).⁸

Schlichte and colleagues provided insight into the various fungal infections that could be confounding the diagnosis of the common wart.⁹ The authors report three cases of verruca-simulating lesions that were mycosis fungoides upon further examination.

A case describing an angiokeratoma mimicking a plantar verruca can present a challenge to diagnosticians whereas angiokeratomas are vascular lesions that could potentially present as a hyperkeratotic buildup that has the stereotypical vasculature of a basic verruca.¹⁰

Syringofibroadenoma, a rare benign neoplasm thought to be of eccrine origin, can also mimic verrucous lesions.¹¹ One should definitively distinguish between the two using a polymerase chain reaction (PCR) technique for HPV typing.

The most ominous differentials that come to mind when dealing with verrucous lesions generally tend to be cancers. It is important to remember that clinicians have reported squamous cell carcinoma (rare variants including verrucous carcinoma and carcinoma cuniculatum), amelanotic acral lentiginous melanoma and Kaposi’s sarcoma as final diagnoses of lesions mimicking verruca at initial presentation.^5,12-15 Watch suspicious lesions carefully and inspect them for morphological changes (size, shape and pattern) indicating that it may be more than verruca.

Diagnostic Insights On Cutaneous Horns

Although rare, cutaneous horns warrant clinical attention. Cutaneous horns are large projections of hyperkeratotic tissue that commonly present in light-skinned individuals in their fifth decade or later.¹⁶ More than 30 percent of these lesions present with a malignant base.^8,16 This lesion can present with a wide array of pathology at the base, ranging from verruca vulgaris (benign) to actinic keratosis (premalignant) to squamous cell carcinoma (malignant), just to name a few mentioned in the literature.^8,16

Pyne and coworkers found that squamous cell carcinoma was the most common malignant entity present at the horn base.¹⁷ Of the malignancies present at the horn base, squamous cell carcinoma reportedly arises at a rate of 94 percent.¹⁸ There are certain clinical features in bases associated with squamous cell carcinoma. These features include an erythematous base, tenderness and a large base-to-height ratio.¹⁷ Risk factors are sun-exposed areas, personal and/or family history of skin cancer or actinic keratosis, and age.^8,16 Due to the malignant potential of these lesions, patients at risk presenting with cutaneous horns should have an excisional biopsy with the clinician taking special care to excise the base and send for pathology.¹⁹

The left photo above shows a filamentous cutaneous horn on the plantar aspect of the right foot of uncertain but long-term duration. The lesion was “painless but often irritated,” and the middle-aged male patient admitted to tugging at it continually with his fingernails, sometimes to the point of bleeding. He stated that the lesion occasionally “fell off” but quickly grew back again. The senior author performed a punch biopsy (see right photo below), totally encompassing the lesion for the purposes of removing the irritated lesion and ruling out malignant changes at the base of the horn. The pathologic diagnosis of lichen simplex chronicus was consistent with the patient history. The biopsy resulted in complete resolution of the lesion.

What You Should Know About Nail Unit Tumors

Physicians often misdiagnose many tumors of the nail apparatus. The nail plate may obscure dermal abnormalities, especially if it is thickened or discolored. Dominguez-Cherit and colleagues report that common benign tumors include but are not limited to myxoid pseudocyst, pyogenic granuloma, glomus tumor, enchondroma, neurofibroma, eccrine poroma, and fibrous tumor.²⁰ Benign fibrous tumors, including periungual fibroma, acquired digital fibrokeratoma, angiofibroma and neurofibroma, frequently cause the affected nail plate to experience longitudinal depressions and grooves, which may lead to increased tenderness along the nail folds. Malignant tumors of the nail unit include melanoma, squamous and basal cell carcinomas. Invasion of the nail unit due to metastasis from the lung, breast, colon and kidney is also possible.

In the left photos, one can see nail plate alteration and subungual keratotic growth involving the lateral nail plate in a 58-year-old male. The patient received fluconazole seven years prior for onychomycosis. The patient had a biopsy based on atypical appearance for onychomycosis and it revealed malignancy.

Is It Cancer?

Physicians often miss squamous cell carcinoma of the nail unit on initial presentation since it can masquerade other ungual pathologies, such as onychomycosis, verruca and paronychia.

Tang and colleagues report that 54.7 percent of individuals with nail unit squamous cell carcinoma had it for two years or longer before getting a correct diagnosis.²¹ It is a rare malignancy reported with a higher incidence in the male adult population and can be subungually or periungually localized. Risk factors for this malignant lesion are tobacco use, exposure to toxins and radiation, trauma and immunosuppressed states. Overall, these tumors have a slow rate of growth and a low rate of metastasis in comparison to other malignancies affecting the nail apparatus.

Verrucous carcinoma is a rare subtype of squamous cell carcinoma that may present on the digit and there are only 13 reported cases in the literature.²² This condition most commonly affects the hallux in the lower extremity of males. Histologically, epithelial proliferation compresses neighboring connective tissue, thereby inducing tenderness that one can detect clinically. Hyperkeratosis and viral changes consistent with verruca vulgaris may accompany hyperplastic and infiltrative changes suggestive of verrucous carcinoma.²³ Enlarged lymph nodes should raise clinical concern.

Aside from biopsy, HPV typing via PCR or DNA dot blot hybridization is another diagnostic test. These tests assess for certain HPV types underlying the lesion. Human papillomavirus types 6, 11, 16 and 18 are variants highly associated with verrucous carcinoma and may be responsible for malignant transformation.^24,25

The photo at right shows lysis of the right great toenail of a 58-year-old male with a multi–year history of multiple soccer injuries that all healed uneventfully. Over the two years prior to presentation (October 2015), he noticed progressive discoloration of the nail plate. He had nail avulsion in his home country of Grenada. Granulation of the nail bed persisted and on presentation to the senior author, biopsy of the nail bed revealed invasive squamous cell carcinoma. A positron emission tomography (PET) scan revealed a reactive right inguinal lymph node. He declined Mohs surgery for the lesion site, underwent 33 radiation treatments and had an ultrasound-guided right groin node biopsy.

When A Biopsy Reveals Carcinoma

The severity of risk of non-melanoma cutaneous lesions determines the extent of excision. According to guidelines provided by the National Comprehensive Cancer Network, one should treat low-risk tumors with 4 mm peripheral margins for standard excision.²⁶ High-risk cutaneous squamous cell carcinoma, which does not commonly affect the lower extremity, requires greater margins of excision (>6 mm). Guidelines for deep margins are not available.

Nahhas and coworkers demonstrate the inconsistent nature across international guidelines, pointing out that a global consensus on surgical margin guidelines for non-melanoma lesions is yet to be established.²⁷ These authors therefore stress the importance of creating a unified set of standards in order to treat patients most precisely and safely.

Standard excision and wide local excision are surgical options, but Mohs micrographic surgery is the gold standard and the primary indication for this procedure is non-melanoma skin cancer.²⁸ This surgery was primarily reserved for the treatment of basal and squamous cell carcinomas when it was introduced some 70 years ago. However, it has now been implemented for cancers such as melanoma in situ, microcystic adnexal carcinoma and dermatofibrosarcoma protuberans, to name a few. Pugliano-Muaro and Goldman evaluated the use of Mohs surgery in the treatment of 215 patients with 260 high-risk cutaneous squamous cell carcinoma lesions.²⁹ According to this study, there was a low recurrence rate (three recurred after Mohs surgery) and low mortality rate (six lesions metastasized with one fatality).

The study authors recommend Mohs surgery as an alternative procedure due to its association with a lower recurrence rate, minimal scar formation and remainder of healthy skin in comparison to other methods.²⁸

When Should You Biopsy?

Due to lesion morphology, it is often a challenge to properly diagnose and treat verrucous-appearing lesions in a timely manner. One should consider suspect lesions for biopsy when there is a personal or family history of cancer, diagnostic uncertainty, recalcitrant lesions, extensive verrucous lesions or an immunocompromised state. Approach lesions with said findings with a high index of suspicion and biopsy them as soon as possible to avoid an unfavorable outcome and/or pedal deformity.

Biopsy technique is important and should include deep dermis and subcutaneous tissue.³⁰ Superficial margins of a verrucous carcinoma will resemble verruca (acanthosis, papillomatosis and hyperkeratosis) while deep margins may reveal invasion of the tumor mass. Consider the age of the patient. Squamous cell carcinoma is common in the fifth or sixth decade while common warts are more likely associated with younger populations. As a result, carefully examine verrucous-appearing lesions and biopsy them in the older patient population.³¹ With respect to the aforementioned criteria, consider early intervention via biopsy to exclude pre-malignant or malignant lesions.^4,5

Ms. Black is a fourth-year student at the New York College of Podiatric Medicine.  

Mr. Saccomanno is a fourth-year student at the New York College of Podiatric Medicine.  

Mr. Stowers is a fourth-year student at the New York College of Podiatric Medicine.     

Dr. Markinson is an Associate Professor at the Icahn School of Medicine at Mount Sinai in New York City.

References

1.     Cubie HA. Diseases associated with human papillomavirus infection. Virology. 2013; 445(1):21-34.
2.     Ural A, Arslan S, Ersoz S, Deger B. Verruca vulgaris of the tongue: a case report with literature review. Bosnian J Basic Med Sci. 2014; 14(3):136.
3.     Cardoso JC, Calonje E. Cutaneous manifestations of human papillomaviruses: a review. Acta Dermatovenerologica Alp Pannonica Adriatica. 2011; 20(3):145-154.
4.     Leung L. Recalcitrant nongenital warts. Australian Fam Phys. 2011; 40(1/2):40.
5.     Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014; 348:g3339.
6.     Lio P. Warts, molluscum and things that go bump on the skin: a practical guide. Arch Dis Child Educ Pract Ed. 2007; 92(4):ep119-ep124.
7.     Bilenchi R, Poggiali S, DePaola M, et al. Keratotic horn on left fifth fingertip: congenital ectopic nail misdiagnosed as a common wart. Pediatr Dermatol. 2013; 30(2):267-269.
8.     Sathyanarayana SA, Deutsch GB, Edelman M, Cohen-Kashi KJ, et al. Cutaneous horn: a malignant lesion? A brief review of the literature. Dermatol Surg. 2012; 38(2 Part 1):285-287.
9.     Schlichte MJ, Talpur R, Venkatarajan S, et al. Verrucous presentation in patients with mycosis fungoides. Int J Dermatol. 2016; 55(3):e126-e129.
10.     Dunnihoo ME, Kitterman RT, Tran D. Angiokeratoma presenting as plantar verruca: a case study. J Am Podiatr Med Assoc. 2010; 100(6):502-504.
11.     Xu XL, Zhang W, Liu WD, Sun JF. A case of multiple eccrine syringofibroadenoma mimicking verruca vulgaris. J Dermatol. 2013; 40(8):665-666.
12.     Ferreira CP, Miranda A, da Costa Nery JA. Kaposi’s sarcoma simulating verrucous syndrome. Brazil J Infect Dis. 2015; 19(4):444-445.
13.     Scarfì F, Galeone M, Bassi A, et al. Melanoma manifesting as a verrucous lesion in the interdigital toe space. Int J Dermatol. 2014; 53(9):1125-1126.
14.     Guarneri C, Valenti G. More than a plantar wart. J Hosp Med. 2010; 5(4):E28-E28.
15.     Girisha BS, Noronha TM, Permi HS, et al. Verrucous plaque on the sole of the foot: a case of missed diagnosis. Indian J Dermatol. 2016; 61(2):236.
16.     Fernandes NF, Sinha S, Lambert WC, Schwartz RA. Cutaneous horn: a potentially malignant entity. Acta Dermatovenerol Alp Panonica Adriat. 2009; 18(4):189-193.
17.     Pyne J, Sapkota D, Cheng Wong J. Cutaneous horns: clues to invasive squamous cell carcinoma being present in the horn base. Dermatol Practical Conceptual. 2013; 3(2):3.
18.     Mantese SA, Diogo PM, Rocha A, et al. Cutaneous horn: a retrospective histopathological study of 222 cases. An Bras Dermatol. 2010; 85(2):157-163.
19.     Haddad CJ, Haddad-Lacle JE. Cutaneous horn: get to the bottom of it. BMJ Case Rep. 2014; bcr2014204447.
20.     Domínguez‐Cherit J, Chanussot-Deprez C, Maria-Sarti H, et al. Nail unit tumors: a study of 234 patients in the dermatology department of the “Dr Manuel Gea González” General Hospital in Mexico City. Dermatol Surg. 2008; 34(10):1363-1371.
21.     Tang N, Maloney ME, Clark AH, Jellinek NJ. A retrospective study of nail squamous cell carcinoma at 2 institutions. Dermatol Surg. 2016; 42(Suppl1):S8-S17.
22.     Matoso A, Jellinek N, Telang GH. Verrucous carcinoma of the nail unit. Am J Dermatopathol. 2012; 34(8):e106-e110.
23.     Gordon DK, Ponder EN, Berrey BH, et al. Verrucous carcinoma of the foot, not your typical plantar wart: A case study. Foot. 2014; 24(2):94-98.
24.     Penera KE, Manji KA, Craig AB, et al. Atypical presentation of verrucous carcinoma a case study and review of the literature. Foot Ankle Spec. 2013; 6(4):318-322.
25.     Ray R, Bhagat A, Vasudevan B, et al. A rare case of plantar epithelioma cuniculatum arising from a wart. Indian J Dermatol. 2015; 60(5):485.
26.     National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology; squamous cell skin cancer. Available at https://www.nccn.org . Accessed on June 6, 2017].
27.     Nahhas AF, Scarbrough CA, Trotter S. A review of the global guidelines on surgical margins for nonmelanoma skin cancers. J Clin Aesthet Dermatol. 2017; 10(4):37.
28.     Alcalay J. The value of Mohs surgery for the treatment of nonmelanoma skin cancers. J Cutan Aesthet Surg. 2012; 5(1):1.
29.     Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high‐risk cutaneous squamous cell carcinoma. Dermatol Surg. 2010; 36(10):1544-1553.
30.     Vlahovic TC, Klimaz TL, Piemontese MK, Zinszer KM. Plantar verrucous carcinoma: an unusual case of bone invasion and osteomyelitis. Adv Skin Wound Care. 2009; 22(12):554-556.
31.     Kovich OI, Soldano AC. Clinical pathologic correlations for diagnosis and treatment of nail disorders. Dermatol Ther. 2007; 20(1):11-16.