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Invasive squamous cell carcinoma arising from verrucous carcinoma

European Journal of Dermatology. Volume 16, Number 4, 439-42, July-August 2006, Clinical report

Summary

Author(s) : A Shimizu, A Tamura, O Ishikawa , Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.

Summary : In 1948, Ackerman first coined the term “verrucous carcinoma” to describe a variant of well-differentiated squamous cell carcinomas of the oral cavity. Similar lesions of the skin, other mucosa or mucocutaneous regions were subsequently reported. To date, verrucous carcinoma has been considered to be a variant of well-differentiated squamous cell carcinoma, which sometimes shows invasive changes but rarely metastasizes. In this study, findings for 3 patients with verrucous carcinomas in which foci of invasive squamous cell carcinoma existed are presented. Furthermore, the clinical features of 9 patients with verrucous carcinoma of the skin observed in our hospital between 1990 and 2004 are summarized. Lesions were located on the face, trunk or extremities. Foci of invasive squamous cell carcinoma were found in 30% of verrucous carcinomas, almost equal to the reported rate of verrucous carcinoma in oral or penile regions. Verrucous carcinoma of the skin should be recognized as a unique subtype of in situ carcinomas, which show exophytic nodular growth and are potentially malignant.

Keywords : in situ carcinoma, squamous cell carcinoma, verrucous carcinoma

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Auteur(s) : A Shimizu, A Tamura, O Ishikawa

Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan

accepté le 6 Avril 2006

Verrucous carcinoma (VC) that arises on sun-exposed and sun-unexposed skin or mucosa [1] is thought to be highly differentiated squamous cell carcinoma, showing little or no invasion into underlying tissue. The clinicopathological concept of VC was first established by Ackerman, who reported 31 patients with ‘VC’ of the oral cavity [2]. A large number of similar lesions developing on other mucosa or skin have since been reported. Currently, the designation of VC has gradually expanded to cutaneous tumors. Verrucous carcinoma can be classified into four types according to anatomical localization: (a) verrucous carcinoma of the oral cavity (oral florid papillomatosis); (b) verrucous carcinoma of the genitoanal region (giant condyloma of Buschke and Löwenstein); (c) verrucous carcinoma of the plantar region (epithelioma cuniculatum); and (d) verrucous carcinoma occurring in other areas of the skin (cutaneous verrucous carcinoma) [1, 3]. Although most reported cases of VC follow a benign course, transformation into invasive squamous cell carcinoma has sometimes been described [4-7]. Most often the term “VC” is restricted to non-invasive tumors [8], however whether cutaneous “invasive” VCs actually exist remains controversial.In this study, 3 patients with VC in which invasive squamous cell carcinoma arose were examined. Reviewing 9 cases of VC on the skin experienced in our hospital, it is our contention that VC on the skin should be recognized as a unique subtype of in situ carcinoma, showing exophytic nodular growth of a potentially malignant nature.

Case reports

Patient 1

A 56-year-old man presented with a 1-month history of a growing verruciform lesion on the back. He had received PUVA therapy against mycosis fungoides for 6 years. On physical examination, a 32 × 22 mm verruciform nodule was present on his right back. Erythematous lesions of mycosis fungoides were observed around the tumor ( (figure 1A) ). Clinically, verruca vulgaris was suspected and surgical excision of the nodule was performed. Histological examination of the resected specimen indicated that most of the lesion showed an exophytic growth of keratinocytes ( (figure 1B) ). Hyperkeratosis and acanthosis were accompanied by marked upward elongation of dermal papillae. Thickened epidermis was composed of well-differentiated squamous cells ( (figure 1C) ). These findings were consistent with typical features of VC. In one part, squamous cells displaying nuclear atypia and loss of polarity invaded the mid-dermis down to Clark’s level IV ( (figure 1D) ). Neither perineural invasion, keratinocytes with clear cytoplasm, nor intratumoral collection of neutrophils were observed. There was dense mononuclear cell infiltration within the stroma. Although immunohistochemical staining for human papillomavirus (HPV) was performed, no positive cells were detected. Mitotic activity was also assessed using proliferating cell nuclear antigen (PCNA) stain. In foci of invasive lesions, most tumor cells were PCNA-positive. However, PCNA-positive cells of a non-invasive lesion showing features of ordinary VC were limited to within 2 or 3 layers from basal cells. The tumor was diagnosed as squamous cell carcinoma arising from verrucous carcinoma. Thereafter, rapidly growing mass lesions reaching the size of a hen’s egg developed in the right axilla and the patient was diagnosed with lymph node metastasis from squamous cell carcinoma using computed tomographic examination. Despite radiation therapy and chemotherapy, the metastatic lesions could not be controlled and the patient died of lung metastasis 1 year after the operation. An autopsy was not performed.

Patient 2

A 29-year-old man presented with a verrucous lesion on the chin. The lesion was present at birth, but began to grow over the last 4 years. The flat lesion had previously been unsuccessfully treated with a carbon dioxide laser. Physical examination revealed an 85 × 80 mm verruciform nodule with a foul smell on the chin ( (figure 2A) ). A biopsy was performed and the tumor was diagnosed as squamous cell carcinoma arising from verrucous carcinoma. There were no clinical findings suggestive of metastasis. Surgical resection and full-thickness skin grafting were performed. Histological examination indicated that the tumor branched out to form several lobules connected to each other via the thin stroma ( (figure 2B) ). At high-power magnification, most of the lesion consisted of large bulbous downward proliferation of well-differentiated squamous cells, representing typical features of verrucous carcinoma ( (figure 2C) ). In some areas, foci of infiltrating atypical keratinocytes were observed ( (figure 2D) ). The depth of invasion corresponded to Clark’s level IV. There was dense mononuclear cell infiltration within the stroma. Immunohistochemical staining for HPV revealed no positive reaction in the tumor cells. Neither perineural invasion, keratinocytes with clear cytoplasm or intratumoral collection of neutrophils were observed. Most of the invasive tumor cells were PCNA-positive, however the typical verrucous carcinoma lesion showed positive reaction only in a few layers from the basal cells. During 1 year of follow up, neither recurrence nor metastasis has been detected.

Patient 3

An 88-year-old man presented with a 50-year history of a growing lesion on the left heel. On physical examination, a 40 × 33 mm verrucous nodule with crust was present on the left heel. Surgical resection and reconstruction with a medial plantar fasciocutaneous flap was performed under general anesthesia. Histopathological examination of the resected specimen showed hyperkeratosis and downward proliferation of the epidermal rete ridge with elongation of dermal papillae. Squamous cells that compose the large bulbous epidermal rete ridge showed minimal nuclear atypia, compatible with verrucous carcinoma. Atypical keratinocytes invaded into the mid-dermis in one part of the lesion, showing transformation to squamous cell carcinoma. The depth of tumor invasion corresponded to Clark’s level IV. Neither perineural invasion, keratinocytes with clear cytoplasm, or intratumoral collection of neutrophils were observed. There was also dense mononuclear cell infiltration within the stroma. HPV-positive cells were not detected using immunohistochemical staining. Most of the invasive tumor cells were PCNA-positive, in contrast to keratinocytes in the non-invasive lesions that showed a positive reaction to only the basal and suprabasal layers. The patient died of an unrelated myocardial infarction 2 months later.

Discussion

In 1948, Ackerman introduced the term verrucous carcinoma to describe a variant of squamous cell carcinoma of the oral cavity. He reported 31 patients and described the features of verrucous carcinoma. In that study, this type of lesion occurred predominantly in the elderly, and most commonly on the buccal mucosa and lower gingiva. Clinically, lesions slowly grew to form verrucous nodules. No distant metastases occurred in the reported group and local recurrences occurred in only 2 patients. Microscopically, club-shaped fingers of hyperplastic epithelium gradually pushed rather than infiltrated their way into deeper tissues. The epithelium was well differentiated and the basement membrane remained intact [2].

In some verrucous carcinomas in oral or anogenital regions, either a small foci of common squamous cell carcinoma adjacent to typical verrucous carcinoma or regional lymph node metastasis has been observed. Anaplastic transformation of verrucous carcinoma into squamous cell carcinoma usually occurs following radiation therapy [4], but there have been few reports describing this type of anaplastic transformation occurring naturally [5-7]. A condition where less-differentiated squamous cell carcinoma coexists within verrucous carcinoma was argued to be ‘hybrid verrucous-squamous carcinoma’ by Medina et al. [9], and similar cases have been reported by other authors [10-14]. They described that foci of invasive squamous cell carcinoma are observed in 20% of verrucous carcinomas of the oral cavity. Medina was also sure that anaplastic transformation could occur from not only irradiation, but also naturally. However, there have been few reports on natural progression of verrucous carcinoma to squamous cell carcinoma. A similar papillomatous oral lesion is known as focal epithelial hyperplasia (Heck’s disease), considered to be a benign condition which is caused by HPV infection. Malignant transformation of this condition demonstrating presence of HPV 24 DNA has also been reported [15], although the claim of differentiation from verrucous carcinoma remains controversial [16].

In 9 patients with verrucous carcinomas of the skin observed in our hospital between 1990 and 2004, 3 patients had partially progressed to squamous cell carcinoma (table 1)( Table 1 ). That is, foci of invasive squamous cell carcinoma were seen in about 30% of VCs developing on the skin. Ages of patients with squamous cell carcinoma arising from VC were younger than those with simple VC, with 1 patient only 29 years old. In patients with invasive squamous cell carcinoma, the preceding skin lesion, ultraviolet light-damaged skin, may have played some role in the anaplastic progression. Although immunohistochemical staining for HPV was performed, no positive cells were detected from samples from these 9 cases. A high rate of PCNA-positive cells in the invasive lesion suggested that PCNA staining may contribute to the detection of micro-invasions or as an indicator of malignant potential.

In conclusion, it may not be uncommon for VC to eventually transform into invasive squamous cell carcinoma, causing occasional metastasis. Therefore, VC of the skin should be treated as an in situ carcinoma and carefully followed up.
Table 1 Summary of clinical findings for 9 cutaneous verrucous carcinomas (1990-2004)

	Verrucous carcinoma with SCC (n = 3)	Simple verrucous carcinoma (n = 6)
Age (years)	29-64 (mean: 50)	59-79 (mean: 72)
Location (case)	Chin:	1	Arm:	3
Trunk:	1	Leg:	1
Sole:	1	Trunk:	1
		Forehead:	1
Preceding Lesion (case)	Mycosis fungoides:	1	Pressure ulcer:	1
(PUVA therapy)
Nevus sebaceous:	1

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