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Coincidental consort clear cell cutaneous carcinoma: facial squamous cell carcinoma in situ containing human papillomavirus and cancer cells with clear cytoplasm in an octogenarian couple.

Abstract: Clear cell squamous cell carcinoma in situ, also referred to as pagetoid or clear cell Bowen disease, is a rare pathologic variant of this neoplasm. It is characterized by neoplastic cells with clear or pale cytoplasm. An octogenarian husband and wife concurrently developed new facial skin lesions which demonstrated squamous cell carcinoma in situ consisting of cancer cells with clear cytoplasm. Cutaneous human papillomavirus (HPV) typing detected HPV Type 5 and HPV Type 21 in the tumors of the husband and wife, respectively. HPV is a potential etiologic factor in the oncogenesis of nonmelanoma skin cancer, and HPV DNA has been demonstrated in extragenital squamous cell carcinoma in situ. The detection of DNA from different HPV types in the tumors of our patients suggests that the concurrent occurrence of their skin cancers may have been coincidental. However, the presence of HPV DNA in their tumors introduces the possibility of a viral-associated oncogenesis for clear cell squamous cell carcinoma in situ.

Key Words: cancer, carcinoma, cell, clear, consort, cutaneous, cytoplasm, human, face, facial, in situ, malignancy, neoplasm, octogenarian, papillomavirus, skin, squamous

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Clear cell squamous cell carcinoma (SCC) in situ is an uncommon pathologic variant of SCC in situ. (1-17) An octogenarian husband and wife concurrently developed a new facial skin lesion which demonstrated SCC in situ consisting of cancer cells with clear cytoplasm. The simultaneous occurrence of this infrequently observed histologic form of in situ carcinoma involving an exposed area of potential contact in each spouse raised the possibility that the onset of their malignancy was not merely due to coincidence, but possibly secondary to a viral-induced etiology.

Case Reports

Patient 1

A healthy 82-year-old Caucasian female presented for evaluation of a new skin lesion on her face. She did not have epidermodysplasia verruciformis, psoriasis, or a history of treatment with psoralen and ultraviolet A (PUVA). Examination showed a 1.0 X 1.3 cm erythematous hyperkeratotic plaque (Fig. 1). The clinical differential diagnoses included an inflamed seborrheic keratosis and SCC in situ.

Microscopic examination of the lesional biopsy specimen revealed acanthosis with atypical keratinocytes present throughout all layers of the epidermis. Many of the atypical keratinocytes had clear cytoplasm. The pathologic features established a diagnosis of clear cell SCC in situ (Fig. 2).

DNA extraction was performed from the paraffin-embedded tissue specimen of the skin lesion using an EX-WAX DNA extraction kit (Chemicon Int. Inc., Te-mecula, CA). The amplifiable quality of DNA samples was assessed by [beta]-globin reference gene polymerase chain reaction (PCR) of the DNA extracted from the sample. Consensus HPV primer sets designed for detection of cutaneous HPVs were utilized in nested PCR and the presence of putative HPV DNA fragment was obtained (Fig. 3). (18) The fragment was subjected to cloning, sequencing and typing, as described earlier. (19) HPV Type 21 DNA was identified in the sample.

The residual in situ carcinoma was excised with microscopic evaluation of the peripheral margins. The tumor was cleared after the first stage of Mohs surgery; the postoperative defect extended to adipose and measured 2.1 X 1.6 cm (Fig. 4). The surgical wound was repaired with a cheek advancement flap (Fig. 5).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Patient 2

A healthy 83-year-old Caucasian male presented for evaluation of a new skin lesion on his face. He did not have epidermodysplasia verruciformis, psoriasis, or a history of treatment with PUVA. Examination showed a 1.0 X 1.0 cm erythematous hyperkeratotic plaque (Fig. 6). The clinical differential diagnoses included an actinic keratosis and SCC in situ. A shave biopsy of the lesion was performed; subsequently, the lesional site was thrice electrodesiccated and curetted.

Microscopic examination of the lesional biopsy specimen showed acanthosis with atypical keratinocytes present throughout all layers of the epidermis (Fig. 7). Most of the tumor cells had typical basophilic cytoplasm; however, there were several areas within the tumor in which some of the atypical keratinocytes had clear cytoplasm. The pathologic features were consistent with a diagnosis of clear cell SCC in situ.

DNA extraction, reference gene PCR, and HPV PCR were performed from the paraffin-embedded tissue specimen of the skin lesion as mentioned above (Fig. 3). An HPV Type 5 variant (P5-55/P5-60) was detected in the patient's tumor sample.

The lesional site continues to be monitored clinically. The area has completely healed since biopsy and treatment. To date, there is no evidence of recurrence.

Discussion

Squamous cell carcinoma in situ is typically a slow-growing tumor that presents as a discretely demarcated, red, scaly plaque, frequently with crusting, fissuring, and hyperkeratosis, which arises in the sun-damaged skin of elderly individuals. (1-3) Microscopic examination usually shows acanthosis of the epidermis with atypical keratinocytes present throughout all levels of the epidermis. (4) The presence of neoplastic cells with clear or pale cytoplasm is a rare pathologic variant of SCC in situ (2); indeed, the tumor cells morphologically resemble those of Paget disease. (5,6)

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Clear cell SCC in situ (1) has also been referred to as pagetoid (13-15) or clear cell (5,16) Bowen disease. Clear cell SCC (5,7-9) and signet-ring SCC (10-12) have also been described. Some investigators suggest that signet-ring SCC is a variant of clear cell SCC, (10,12) whereas other researchers consider signet-ring SCC to represent a distinct pathologic subtype of SCC which can also have neoplastic cells with abundant clear cytoplasm. (2,3,11)

Initially, the clear cell changes of SCC in situ and SCC were considered to be degenerative. (8,9) However, subsequent studies also show that the atypical keratinocytes in these tumors stained positive with periodic acid-Schiff, and that the positivity was removed after diastase digestion; this was consistent with the neoplastic cells containing glycogen and no neutral mucopolysaccharides. (5,7,12,17) Hence, the clear cell change is sometimes due to cytoplasmic glycogen and sometimes due to degenerative changes or possibly lipid accumulation.

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Immunoperoxidase stains of clear cell SCCs and clear cell SCCs in situ demonstrate positive immunoreactivity for keratin. Immunoreactivity for carcinoembryonic antigen (CEA), gross cystic disease fluid protein (GCDFP)-15, S-100 protein (S-100), and HMB-45 is absent. (6,17) Positive immunoperoxidase staining for epithelial membrane antigen (EMA) may be present in some of these tumors. (5,13,14,20)

Extramammary Paget disease and mammary Paget disease are the conditions whose pathologic features most closely mimic those of clear cell SCC in situ. However, other benign and malignant tumors which can be characterized by intraepidermal pagetoid cells are also in the pathologic differential diagnosis of clear cell SCC in situ (Table 1). (14,17) In addition, the pathologic differential diagnosis of clear cell SCC in situ also includes other clear cell neoplasms of the skin (Table 2). (5,21)

HPV may be an etiologic factor in the cutaneous oncogenesis of nonmelanoma skin cancer. (22) For example, there is clearly an association between verrucae and SCC in patients with epidermodysplasia verruciformis in which HPV types, predominantly HPV 5 and occasionally HPV 8, 14, 17, 20, or 47, are found in over 90% of the tumors on sun-exposed areas. (22) The role of HPV infection in the development of nonmelanoma skin cancer in other immunosuppressed individuals, such as organ transplant recipients, has also been suggested. (23)

[FIGURE 7 OMITTED]

Recently, HPV types have been identified in SCCs of immunocompetent individuals. (24,25) In one study, HPV DNA (HPV 6/11, 16/18, and/or 31/33) was detected in 56% of 34 samples from 30 immunocompetent patients with extragenital SCC in situ. (26) Another study demonstrated that positive serologic findings for HPV Type 8 was associated with SCC occurrence in immunocompetent individuals; the investigators speculated that along with genetic predisposition, solar radiation and other environmental exposures, infection with HPV could act as a cofactor in the development of SCC. (27)

Digital SCC has been associated with HPV in at least 73 individuals. (28,29) The predominant subtype of HPV in nearly 90% of these patients was HPV 16; the other HPV types were 26, 31, and 35. (28,29) An antecedent genital dysplasia or carcinoma containing the same HPV subtype as the digital SCC was observed in 10% of the patients, which introduces the possibility of genital-digital spread as a mechanism of tumor genesis in these individuals. (28,29)

The morphology of our patient's tumor cells, with their clear cytoplasm and often eccentric nuclei, was reminiscent of the koilocytic changes that can be observed secondary to HPV infection. Also, the concurrent occurrence of this uncommon clear cell pathologic variant of SCC in situ on exposed areas of potential skin-to-skin contact raised the possibility that the neoplasm may have been viral-associated. This prompted us to evaluate the lesions for HPV DNA.

We were able to detect HPV Type 5 DNA and HPV Type 21 DNA from the paraffin-embedded tissue biopsies of the clear cell SCCs in situ from the husband and wife, respectively, by a nested PCR system designed for detection of cutaneous HPV DNA. (18) This PCR system is more sensitive than other PCR methods, and is capable of amplifying a broad spectrum of HPV types from skin tumors. (18,30-35)

Similar to our patient, HPV Types 5 and 21 have previously been observed in tumors of the skin from either immunosuppressed or immunocompetent individuals. Forslund et al (36) identified HPV Types 5 and 21 in keratoacanthomas from immunosuppressed organ transplant recipients. In addition, Harwood et al (37) detected both of these HPV types in PUVA-associated nonmelanoma skin cancers from immunocompetent patients treated for psoriasis. Also, HPV Type 5 has been demonstrated in psoriatic lesions from patients without skin cancer. (38)

Conjugal transmission of HPV-associated SCC has been documented in at least one set of monogamous sexual partners (29) and speculated in another 3 couples. (28) High et al (29) described a 36-year-old HIV seropositive man who developed proximal nail fold SCC which was infected with HPV 26; his monogamous sexual partner had a condyloma which revealed the same viral genotype. (29) Alam et al (28) reported a series of 23 patients with digital SCC associated with HPV; 3 of the men with SCC on either their right middle finger (HPV 16), right index finger (positive for HPV, genotype unknown), or left index finger (HPV 16) had wives who either had SCC of the cervix leading to hysterectomy, had a hysterectomy, or had Pap smear dysplasia, respectively. (28)

The observation of an unusual pathologic variant of SCC in situ which contained tumor cells with clear cytoplasm on the faces of both husband and wife prompted us to suspect that their tumors may have been causally related, and perhaps associated with an infectious etiology. The detection of different types of HPV DNA in our patients' cutaneous cancers did not allow us to confirm our hypothesis of skin-to-skin transmission of a single tumor-associated etiologic virus from one spouse to the other. However, the possibility that the simultaneous occurrence of these tumors could be due to patient-to-patient transmission of oncogenic HPV strains cannot be completely ruled out.

There are several possible explanations that could potentially account for finding different HPV subtypes in our patients, such as selective eradication of the other viral type by the patient's immune system, different factors favoring overgrowth of one subtype in each patient, and/or technical artifact with the DNA or primer degradation of the PCR reaction. Since our reference gene amplification was good, this latter possibility is unlikely. Hence, although we were not able to establish transmission of the oncogenic HPV species from one patient to the other, the presence of HPV in their neoplasm raises the possibility that HPV infection may play a role in the oncogenic pathogenesis of their tumors.

Conclusion

Clear cell SCC in situ is rare. Several conditions, including tumors with intraepidermal pagetoid cells, mimic the pathologic appearance of clear cell SCC in situ. HPV is a potential etiologic factor in the oncogenesis of nonmelanoma skin cancer, including SCC in situ. Not only has HPV DNA been demonstrated in extragenital SCC in situ and SCC, but conjugal transmission of HPV-associated SCC has been documented.

The detection of DNA from different HPV types in the tumors of our patients suggests that the concurrent occurrence of their skin cancers may have been coincidental. However, the presence of HPV DNA in their tumors introduces the possibility of a viral-associated oncogenesis for clear cell squamous cell carcinoma in situ.

References

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30. Sra KK, Torres G, Rady P, et al. Molecular diagnosis of infectious diseases in dermatology. J Am Acad Dermatol 2005;53:749-765.

31. Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification to genital human papillomaviruses. J Clin Microbiol 2000;38:357-361.

32. van den Brule AJ, Pol R, Fransen-Daalmeijer N, et al. GP5+/6+ PCR followed by reverse line blot analysis enables rapid and high-throughput identification of human papillomavirus genotypes. J Clin Microbiol 2002;40:779-787.

33. Berkhout RJ, Tieben LM, Smits HL, et al. Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J Clin Microbiol 1995;33:690-695.

34. Meyer T, Arndt R, Christophers E, et al. Frequency and spectrum of HPV types detected in cutaneous squamous-cell carcinomas depend on the HPV detection system: a comparison of four PCR assays. Dermatology 2000;201:204-211.

35. Fuessel Haws AL, He Q, Rady PL, et al. Nested PCR with the PGMY09/11 and GP5+/6+ primer sets improves detection of HPV DNA in cervical samples. J Virol Methods 2004;122:87-93.

36. Forslund O, DeAngelis PM, Beigi M, et al. Identification of human papillomavirus in keratoacanthomas. J Cutan Pathol 2003;30:423-429.

37. Harwood CA, Spink PJ, Surentheran T, et al. Detection of human papillomavirus DNA in PUVA-associated non-melanoma skin cancers. J Invest Dermatol 1998;111:123-127.

38. Mahe E, Bodemer C, Descamps V, et al. High frequency of detection of human papillomaviruses associated with epidermodysplasia verruciformis in children with psoriasis. Br J Dermatol 2003;149:819-825.

Philip R. Cohen, MD, Keith E. Schulze, MD, Peter L. Rady, MD, PhD, Stephen K. Tyring, MD, PhD, MBA, Qin He, MD, Paul T. Martinelli, MD, and Bruce R. Nelson, MD

From the Dermatologic Surgery Center of Houston, Houston, Texas; the Department of Dermatology, University of Texas-Houston Medical School, Houston, Texas; and the Department of Dermatology, Center for Clinical Research, Houston, TX.

Reprint requests to Dr. Bruce R. Nelson, Dermatologic Surgery Center of Houston, PA, 6655 Travis, Suite 840, Houston, TX 77030. Correspondence to Dr. Philip R. Cohen, 805 Anderson Street, Bellaire, TX 77401-2806. Email: mitehead@aol.com

Accepted October 16, 2006.

RELATED ARTICLE: Key Points

* Clear cell squamous cell carcinoma in situ, characterized by neoplastic cells with clear or pale cytoplasm, is a rare pathologic variant of this neoplasm.

* The pathologic differential diagnosis of clear cell squamous cell carcinoma in situ includes extramammary Paget disease, mammary Paget disease, benign and malignant tumors characterized by intraepidermal pagetoid cells, and other clear cell neoplasms of the skin.

* Human papillomavirus is a potential etiologic factor in the oncogenesis of nonmelanoma skin cancer.

* Human papillomavirus DNA has been demonstrated in extragenital squamous cell carcinoma in situ.

* The detection of HPV DNA in our patients' clear cell squamous cell carcinomas in situ introduces the possibility that a viral-associated oncogenesis may contribute to the development of this pathologic variant of skin cancer.
Table 1. Pathologic differential diagnosis of clear cell squamous cell
carcinoma in situ: conditions with intraepidermal Pagetoid cells

Clear cell papulosis
Clear cell squamous cell carcinoma in situ
Clear cells of Toker (of the nipple epidermis)
Extramammary Paget disease
Cutaneous T-cell lymphoma
Eccrine porocarcinoma
Histiocytosis X (Langerhans cell histiocytosis)
Langerhans cell microabscess (in cutaneous delayed hypersensitivity
 reactions)
Malignant melanoma in situ (superficial spreading)
Merkel cell carcinoma (with pagetoid intraepidermal spread)
Metastasis (epidermotropic)
Pagetoid dyskeratosis
Paget disease (extramammary and mammary)
Sebaceous carcinoma
Spitz nevus (pagetoid)

Table 2. Pathologic differential diagnosis of clear cell squamous cell
carcinoma in situ: clear cell neoplasms of the skin

Clear cell acanthoma
Clear cell basal cell carcinoma
Clear cell eccrine carcinoma
Clear cell hidradenoma
Clear cell myoepithelioma/myoepithelial carcinoma
Clear cell squamous cell carcinoma in situ/squamous cell carcinoma
Clear cell syringoma
Clear cells of Toker of the nipple epidermis
Malignant melanoma--balloon cell variant
Malignant melanoma in situ
Metastatic neoplasms (breast carcinoma, renal cell carcinoma, and
 others)
Paget disease (extramammary and mammary)
Sebaceous adenoma/epithelioma/carcinoma
Tricholemmoma/trichilemmal carcinoma
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Article Details
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Title Annotation:Case Report
Author:Nelson, Bruce R.
Publication:Southern Medical Journal
Article Type:Disease/Disorder overview
Date:May 1, 2007
Words:3405
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