Malignant Epithelial Tumors with Clear Cell Features 3461 Clear Cell Carcinoma

Clear cell carcinomas of the penis are rare tumors of probably sweat gland origin characterized by the presence of neoplastic cells with intracytoplasmic prominent PAS-positive material.19 Tumors preferentially affect the foreskin inner mucosa and are consistently HPV positive, mainly genotype 16. Clear cell carcinomas are composed of solid proliferations of clear cells, sometimes with geographical areas of necrosis. Histology is of a high-grade tumor with evident nuclear atypias. Extensive vascular invasion and a high metastatic rate are common findings. This unusual variant of penile cancer should be distinguished from penile SCC showing clear-cell features, urothelial clear cell carcinomas, and sebaceous carcinomas. Caution should be taken for not confusing glycogenated clear cells with koilocytes and with true neoplastic clear cells. Glycogenated clear cells can be found in usual and other well-differentiated keratinizing SCC variants but changes are focal and usually not prominent. These cells exhibit squamous differentiation with uniform and pyknotic nuclei and tend to predominate in the superficial areas and central regions of tumor nests. Koilocytes are readily found in warty carcinomas and also show clear cell changes and squamous maturation but nuclei are characteristically wrinkled and hyperchro-matic and bi- and multinucleation are common.49 In keratinizing and warty carcinomas neoplastic cells exhibit a broad spectrum of squamous differentiation ranging from cubic basal cells to polygonal more mature cells while in clear cell carcinoma they tend to proliferate in solid sheets and uniformly show a high-grade histology. However, in problematic cases immunohistochemistry may help in the differential diagnosis since clear cell carcinomas are consistently positive for MUC-1 while this

Fig. 3.18 Extramammary Paget's disease. (a) Rounded and large atypical cells with clear cytoplasm, named "Paget cells" are found throughout the entire epithelium, although they are more prominent at bottom layers (Courtesy of Elsa Velazquez, M.D., Brigham and Women's Hospital, Harvard Medical School, Boston, MA). (b) Immunohistochemistry for carcinoembryonic antigen (CEA) showing intense positivity in Paget cells (Courtesy of Elsa Velazquez, M.D., Brigham and Women's Hospital, Harvard Medical School, Boston, MA)

Fig. 3.18 Extramammary Paget's disease. (a) Rounded and large atypical cells with clear cytoplasm, named "Paget cells" are found throughout the entire epithelium, although they are more prominent at bottom layers (Courtesy of Elsa Velazquez, M.D., Brigham and Women's Hospital, Harvard Medical School, Boston, MA). (b) Immunohistochemistry for carcinoembryonic antigen (CEA) showing intense positivity in Paget cells (Courtesy of Elsa Velazquez, M.D., Brigham and Women's Hospital, Harvard Medical School, Boston, MA)

marker is usually negative in penile SCC. Other markers of sweat gland tumors, such as CEA and EMA, can also be useful. Extension from a clear cell urothelial carcinoma can simulate a clear cell carcinoma. However, urothelial carcinomas usually present with a previous history of urothelial malignancy elsewhere, are centered on the urethra and perimeatal area and only secondarily affect the foreskin, and show areas of urothelial carcinoma in situ in most cases. Urothelial markers (uro-plakin III, thrombomodulin) may serve in problematic cases. Sebaceous carcinomas show neoplastic cells with clear cytoplasms but the nuclei are small, indented, and irregular and the clear aspect correspond to lipid vacuoles.70-72

3.4.6.2 Extramammary Paget's Disease

Extramammary Paget's disease (EMPD) shares many clinicopathological features with its mammary homologue but also presents remarkable differences regarding pathogenesis and association with underlying malignancies.73-75 EMPD has a predilection for the perianal region, perineum, groin, pubic area, scrotum, and penis, although it has been observed in other apocrine gland-rich areas (such as axilla and ear) in isolated cases.)3,76 An exclusively penile location is very rare as the penis is usually affected as part of a more disseminated disease extending throughout the scrotum, perineum, and penis. In most cases the lesion is limited to the epidermis (primary EMPD) but in 11% of patients an underlying malignancy is found (secondary EMPD), usually from the prostate or bladder but also from the testicles, ureter, or kidney.77 Primary EMPD is a form of intraepithelial adenocar-cinoma in which large round neoplastic cells with ample and clear cytoplasm (Paget cells) are found throughout the epithelium, although they are more abundant in the bottom layers (Fig. 3.18a).76 Paget cells frequently compress surrounding keratinocytes and in occasions form gland-like structures with a central lumen. Nuclei are large and vesicular and nucleoli are prominent. Mitoses may be numerous and it is not unusual to find melanin within the cytoplasm of these cells. The epithelium may be atrophic or, more frequently, hyperplastic, with orto- or parak-eratosis. Paget cells can also be found within the epithelial sheets of hair follicles, sweat gland excretory ducts, or secretory coils. It has been postulated that these cells originate in the intraepidermal portion of sweat glands, from pluripotent keratinocyte stem cells or from yet-uncharacterized Toker-like cells present in the genital area.73,76,78-80 In some occasions invasion of the underlying dermis is seen and this can progress to vascular invasion, regional and distant metastasis, and death.73,76,80,81

In secondary EMPD an underlying tumor is found, mainly from the genitourinary or lower gastrointestinal tract. Morphologically it is similar to primary EMPD and efforts should be aimed to identify, if present, the associated internal malignancy. Immunohistochemistry is crucial in achieving this. Paget cells in primary EMPD are usually positive for CK7, MUC-1, and MUC-5AC and negative for MUC-2, MUC-6, and CK20.737881 They are also positive for glandular markers such as CAM 5.2, EMA, CEA and GCDFP-15 (Fig. 3.18b).73 Conversely, Paget cells in secondary EMPD, which probably originates from the epidermo-tropic dissemination of the underlying tumor^3,78 are usually positive for specific tissue markers such as PSA (prostate), uroplakin-III (urothelium), and CDX-2 (colon-rectum). They are also positive for MUC-2 and negative for GCDFP-15.73,78 The differential diagnoses of EMPD include conditions in which clear cells are present within the epidermis (clear cell papulosis, pagetoid dis-keratosis, and benign mucinous metaplasia) and neoplasm with an intraepithe-lial pattern of growth (malignant melanoma, mycosis fungoides, and pagetoid Bowen's disease).

Clear cell papulosis is a rare clinicopathological entity which preferentially affects the pubic area of young Asian individuals.82-84 Clinically, multiple small white papules are seen along the milky line and lower abdomen. Histologically it is characterized by the presence of round cells with ample clear cytoplasm and bland cytology preferentially located in the bottom layers of the epithelium. The immunophenotype of these cells is similar to that presented by Paget cells but morphology is distinctive.82,84,85 Pagetoid dyskeratosis is frequently found in the inner foreskin of patients with phimosis.86-88 Histologically it is characterized by round pale cells interspersed between normal keratinocytes, predominantly located in the upper layers of the epithelium.88 Cytology remains bland and intercellular bridges are observed between the clear cells and the surrounding keratinocytes. Nuclei are centrally located and are small and pyknotic, occasionally pale, with a perinuclear halo. Clusters of cells can be found but no glandular structures are discernible. Mitotic activity is very low. Cells are negative for PAS, mucicarmine, Alcian-Blue, EMA, CK7, and CEA and positive for 34PE12 and CK22.86,87 Finally, in benign mucinous metaplasia, a condition preferentially found in the inner foreskin mucosa of elder patients,89-92 gobletlike cells are found in the upper portions of the stratified epithelium, replacing more than infiltrating it, with abundant clear cytoplasm and basally located nuclei. These cells are positive for PAS, Alcian Blue, CAM 5.2, CEA, and EMA. Association with chronic inflammatory conditions (nonspecific chronic posthitis, Zoon's balanitis) is common supporting the view that mucinous metaplasia is rather a reaction process than a distinctive entity. Malignant melanomas and mycosis fungoides can be very difficult to distinguish from EMPD based solely on the morphology. 24,76,93 Immunohistochemistry is frequently needed in such cases. In some cases a penile carcinoma in situ can present with cells extending throughout the epithelium in a pagetoid and nested fashion (Pagetoid Bowen's disease) but immunohistochemistry for mucin and glandular markers will allow the distinction with EMPD.94,95

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

Get My Free Ebook


Post a comment