Case of the Month: Stump of Left Below Knee Amputation

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 05, and is an invasive squamous cell carcinoma, well differentiated.

Sections show a broad epidermal proliferation with exo- and endophytic components; however, not all slides contain every feature described below. There is epidermal acanthosis with papillomatosis covered by hyperkeratosis and parakeratosis. Epidermal projections within the underlying dermis with a pushing border and composed of well-differentiated squamous cells with a bland appearance. For the most part the epidermal endophytic component appears contained within an intact basement membrane; however small foci of irregularly shaped squamous nests suggestive of frank invasion are noted. Based on the clinical and histological appearance a diagnosis of invasive squamous cell carcinoma, well differentiated with features of verrucous carcinoma, arising in an amputation stump is made.

Primary cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer in Caucasian population; however, it is relatively rare in African Americans. Cutaneous SCCs are common in older population, favor male gender, and tend to involve areas affected by chronic exposure to sun such as face, neck, arms, and hands. The most important etiological factor appears to be ultraviolet (UV) radiation, especially UV-B, supported by the presence of concomitant actinic keratoses seen in a significant proportion of cutaneous SCCs. The mechanism is complex, likely related to DNA damage in the epidermal cells and suppression of the cutaneous immune system induced by UV radiation. Human papillomavirus (HPV) also plays a role especially in genital SCC and in immunosuppressed patients. Less common etiologic factors for cutaneous SCC include arsenic exposure, smoking, radiation therapy, coal tar and treatment with BRAF inhibitor vemurafenib and other kinase inhibitors. SCC occurring in younger patients is rare and usually associated with genetic disorders such as xeroderma pigmentosum and epidermolysis bulosa. SCC tumors are also known to occur in areas of chronically inflamed, traumatized, burned or scarred skin. These are known by the eponym of Marjolin's ulcer and are relatively rare in developed countries. SCC arising in an amputation stump such as the presented case is rare; however, several have been reported in the literature and represent the same phenomenon as Marjolin's ulcers. A distinct variant of SCC is verrucous carcinoma (VC) which presents as a slow-growing exophytic and warty tumor. VC has been described in the mouth, genital area or on the plantar surface of the foot. Burrowing deep sinuses are often present in the lesions involving the foot giving the clinical picture of intercommunicating branching tunnels and clefts that resemble the burrows in a "rabbit warren" and have led to the designation of "epithelioma cuniculatum" for the tumors arising in this area (from the Latin cuniculatus meaning in the form of a channel or tube). Rarely VC may involve other parts of the skin surface and there are reports of SCC with features of VC developing in prior burn scars and areas of chronic inflammation akin to our case. Anogenital VC, also known as Buschke-Lőwenstein tumor has usually a more pronounced exophytic component and often arises in a preexistent condyloma acuminatum. A subject of controversy is whether these anogenital variants represent VC or giant condyloma acuminatum. There are also some recent claims that epithelioma cuniculatum in the classic description is a different entity than VC because it lacks a warty surface. Various HPV subtypes have been found in VC supporting a viral etiology. In addition, genital lesions often arise in association with a preexistent condyloma acuminatum and may show koilocytosis of the surface epithelium supporting again an HPV-related etiology. In other cases, VCs have been described to arise in areas of chronic inflammation, old scars, and chronic pressure ulcers suggesting a mechanism similar to Marjolin's ulcers.

The histology of SCC consists of nests, tongues, and sheets of squamous cells that tend to arise from the surface epidermis and extend into the dermis. Invasion into the dermis is usually represented by irregularly shaped islands of epithelial cells separated from the surface epidermis and surrounded by a desmoplastic stroma. The cells have dense eosinophilic cytoplasm and a variable degree of nuclear atypia and keratinization. SCCs are usually graded into categories of "well," "moderately," and "poorly" differentiated depending on the extent of atypia, keratinization, and resemblance with normal epidermis. As a rule, a tumor is classified according to its most poorly differentiated region. An alternative grading scheme is Broders; system which includes 4 grades defined by the percentage of tumor that is well differentiated (>75%, 50-75%, 25-50%, and <25% corresponding to grades 1, 2, 3, and 4, respectively). This system is somewhat complicated and subjective and is employed infrequently today. VC is a special form of well-differentiated SCC characterized by an exo-endophytic appearance with papillomatosis and bulbous epidermal down-growths extending into the deep dermis and even the subcutis. The individual keratinocytes have only low-grade atypia and decreased mitotic activity. Individual infiltrative foci of unequivocal dermal invasion, not connected to the overlying epidermis are difficult to find; however, the bulbous epidermal processes show a pushing margin, which is considered a form of dermal invasion. Draining sinuses with inflammation, burrows filled with parakeratin horns and a neutrophilic infiltrate are characteristically seen.

Most cutaneous SCCs are only locally aggressive and have low risk of metastasis, usually being cured by excision. Recurrences are more common for tumors that show deep invasion, poor differentiation, perineural invasion, and acantholytic features. The incidence of metastases depends on the clinical setting and morphologic parameters. For tumors arising on sun-exposed skin, the incidence is around 0.5% while the risk is 2-3% for lesions arising in skin not exposed to sun. There is an even higher risk of metastasis for SCC of the lip and ear in the range of 2-16%. SCCs arising in Marjolin's ulcers have an incidence of metastatic disease in the 18-60% range despite being histologically well differentiated while for vulval, perineal, and penile SCC the incidence is as high as 30-80%. The risk of metastasis correlates also with tumor size (>2.0 cm), depth of invasion, neurotropism, and an acatholytic pattern. One study found that tumor size (>4.0 cm), depth of invasion, and invasion beyond subcutaneous tissue correlates with a higher disease specific mortality. VC usually has a good prognosis with a low metastatic risk and mortality. The exceptions are anal and perianal lesions that have recurrence and mortality rates of 70% and 20-30%, respectively.

The most important differential diagnosis for SCC and VC is reactive pseudoepitheliomatous hyperplasia (PEH). PEH usually show a less complex architecture than SCC however, at times may show all the features of a squamous cell carcinoma. Compared to VC, PEH has usually more irregular and sharp epidermal projections. At times, correct histological diagnosis is difficult and interpretation must take into account the clinical picture. VC can resemble a verruca vulgaris (viral wart) due to the occasional presence of koilocytes and association with preexistent condylomata, especially if only a superficial biopsy is available. VCs are characterized by an endophytic component with involvement of the underlying tissues while warts have only exophytic growth patterns. Keratoacanthoma (KA) is a keratinocytic tumor presenting as a nodule with a central keratin-filled crater, usually involving the exposed surfaces of the body. KAs are characterized by rapid growth (over 1-2 weeks) and spontaneous involution over the course of several months. Histology shows an exo-endophytic crateriform squamous lesion with a keratin plug that may resemble VC. VC can be distinguished from KA by the clinical history including location and slow growth, lack of a crateriform architecture and deeper extension into the fat (as opposed to KAs which do not extend deeper than the eccrine sweat glands). Prurigo nodule is characterized by development of a lichenified and excoriated nodule in response to localized scratching and picking. Histology shows epidermal acanthosis with elongation of rete ridges and at times pseudoepitheliomatous hyperplasia raising the possibility of SCC. As opposed to SCC, prurigo nodules are induced by an exogenous stimulus (scratching) and usually resolve after that stimulus is removed.

1. Which one of the following statements regarding Marjolin’s ulcer is true?
   
   1. Marjolin's ulcer is an eponym used for a squamous cell carcinoma arising in areas of chronically inflamed or scarred skin.
   2. Marjolin's ulcer is an eponym used for a squamous cell carcinoma arising in association with condyloma acuminatum.
   3. Marjolin's ulcer is an eponym used for a verrucous carcinoma involving the plantar foot.
   4. Marjolin's ulcer is an eponym used for a verrucous carcinoma involving the anogenital area.
   5. Marjolin's ulcers have a better prognosis than cutaneous squamous cell carcinomas arising on sun-exposed skin.
2. Which one of the following primary sites of involvement correlates with a more aggressive prognosis for cutaneous squamous cell carcinoma?
   
   1. Back
   2. Lip
   3. Lower extremities
   4. Trunk
   5. Upper extremities
3. One of the characteristic histological features seen in verrucous carcinoma is the presence of sinus tracts.
   
   1. True
   2. False

1. Bauer T, David T, Rimareix F, Lortat-Jacob A. Marjolin's ulcer in chronic osteomyelitis: seven cases and a review of the literature. Rev Chir Orthop Reparatrice Appar Mot. 2007;93(1):63-71.
2. Bloemsma GC, Lapid O. Marjolin's ulcer in an amputation stump. J Burn Care Res. 2008;29(6):1001-1003.
3. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23(4):759-765.
4. del Pino M, Bleeker MCG, Quint WG, et al. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma. Mod Pathol. 2012;25(10):1354-1363.
5. Huang CY, Feng CH, Hsiao YC, et al. Burn scar carcinoma. J Dermatolog Treat. 2010;21(6):350-356.
6. Jungmann J, Vogt T, Müller CS. Giant verrucous carcinoma of the lower extremity in women with dementia. BMJ Case Rep. 2012.
7. Kubik MJ, Rhatigan RM. Carcinoma cuniculatum: not a verrucous carcinoma. J Cutan Pathol. 2012. 39(12):1083-1087.
8. McKee PH, Calonje E, Granter S. Pathology of the Skin. 4th ed. Philadelphia, PA: Elsevier Saunders; 2012.
9. Uchida K, Miyazaki T, Nakajima H, et al., Cutaneous squamous cell carcinoma (SCC) arising in stump of amputated finger in a patient with resected glossal SCC. BMC Res Notes. 2012;5:595.
10. Weedon D. Tumors of the epidermis. In: Weedon D, ed.Weedon's Skin Pathology, Philadelphia, PA: Churchill Livingstone; 2010:668-703.

2014
Aleodor A. Andea, MD, MBA
Surgical Pathology Committee
University of Michigan
Ann Arbor, MI

1. Marjolin's ulcer is an eponym used for a squamous cell carcinoma arising in areas of chronically inflamed or scarred skin. (a). 
2. Lip (b). 
3. True (a).