Božo Krušlin

Hrvoje čupić

Karla Tomić

Majda Vučić

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72Acta Dermatovenerol Croat      2007;15(2):72-75    SHORT SCIENTIFIC COMMUNICATIONAn Unusual Pattern of Pseudoepitheliomatous Hyperplasia Associated with Cutaneous Primary Melanoma: Report of Two Cases with Analysis of p53 and bcl-2 Immunoreactivity Majda Vučić1, Hrvoje Čupić1, Karla Tomić2, Božo Krušlin1 1Ljudevit Jurak University Department of  Pathology, Sestre milosrdnice University Hospital, Zagreb; 2Department of Pathology, Dr. Josip Benčević General Hospital, Slavonski Brod, CroatiaCorresponding author: Majda Vučić, MD, PhDLjudevit Jurak University Department of Pathology Sestre milosrdnice University HospitalVinogradska c. 29HR-10000 ZagrebCroatia mvucic@kbsm.hrReceived: February 9, 2007.Accepted: March 20, 2007.SUMMARY Pseudoepitheliomatous hyperplasia (PEH) is a benign, reactive epithelial proliferation. PEH is characterized by hyperplasia of the epidermis or adnexal epithelium into irregular squamous strands that extend deep down into the subjacent dermis. PEH occurs in response to underlying infections, inflammatory or neoplastic conditions. The presence of PEH overlying cutaneous melanoma is rare. The clinical and histological features of PEH can closely mimic squamous cell carcinoma and could be misinterpreted. We report two cases of cutaneous primary melanoma associated with PEH and discuss differential diagnoses and potential role of p53 and bcl-2 in the pathogenesis of PEH.KEY WORDS: pseudoepitheliomatous hyperplasia, primary melanoma, squamous cell carcinomaINTRODUCTION Pseudoepitheliomatous hyperplasia (PEH), also known as pseudocarcinomatous hyperplasia, is a benign pathological reaction pattern (1). PEH occurs in response to persistent inflammation of the subjacent dermis due to a chronic wound, retained foreign material or an infection (fungal, bacterial or viral) (2). Reactive, exuberant epithe-lial proliferation is also seen in coexistence with some dermatological conditions such as prurigo nodularis, granuloma fissuratum, chondrodermati-tis nodularis, lichen planus and lichen sclerosus of the vulva (3,4). Tumors with overlying PEH include granular cell tumor, cutaneous T cell lymphomas, and salivary gland pleomorphic adenoma (5-7). The association of PEH with benign melanocytic nevi and Spitz nevi is not uncommon and is well documented in the literature (8,9). However, re-ports documenting the association of PEH with melanoma are rare. In fact, little is known about the pathogenesis of PEH, regardless of the under-lying etiology. We report two cases of cutaneous primary melanoma associated with histological features of PEH mimicking squamous cell carci-noma.CASE REPORTS The first patient was a 38-year-old male that presented with a polypoid, grayish-brown skin tu-mor on the left thigh measuring 1.5 cm in largest diameter. The second patient was a 75-year-old 73ACTA DERMATOVENEROLOGICA CROATICAfemale with elevated, brownish tumor on the face, measuring 0.8 cm in largest diameter. Clinically, in both cases hyperkeratotic skin lesions were sus-pected for squamous cell carcinoma. Histopatho-logic analysis of excised lesions revealed abnor-mal architectural and cytological features on he-matoxylin and eosin (H&E) stained slides, which were indicative of malignant melanoma, classifed as Breslow III in the first case and Breslow V in the second case.   In each case, prominent hyperkeratosis, epi-dermal acanthosis with irregular cords of well-differentiated epithelial cells extending into the dermis and infiltrating among and around the melanoma cells, and multiple horn cysts was ob-served. The hyperplastic foci arose directly from the epidermis without association with adnexal epithelium. In both cases, admixture of the neo-plastic melanocytic and hyperplastic keratinocytic components led us to reconsider the diagnosis of malignant melanoma and concurrent invasive squamous cell carcinoma. Serial sectioning us-ing immunohistochemical analysis of HMB-45 and cytokeratin (DAKO, Copenhagen, Denmark) was performed (Fig. 1A, B). On immunohistochemical slides, the neoplastic melanocytic component was easier to identify and distinguish from the hyper-plastic epidermal component, and the possibility of squamous cell carcinoma was excluded.  Additionally, in each case immunohistochemi-cal analysis of p53 and bcl-2 (DAKO) was per-formed. In each patient, 4-μm sections were cut, slides were stained immunohistochemically by the labeled streptavidin biotin method (LSAB) as visu-alization system on Dako Tech Mate automated immunostainer using microwave streptavidin im-munoperoxidase (MSIP) protocol. Staining in-tensity in the hyperplastic superficial epithelium, strands of proliferative epithelium and epithelium of horn cysts was compared with melanoma cells and adjacent basal epidermal cells (Fig. 2A, B). The intensity of immunostaining was semi-quan-titatively scored and defined as: 0 (negative); 1+ (week staining, similar to adjacent normal basal epithelium); 2+ (moderate staining, less intense than in atypical melanoma cells); and 3+ (strong staining, equivalent to atypical melanoma cells). Results are summarized in Table 1. Table 1. p53 and bcl-2 immunohistochemical staining in two cases of pseudoepitheliomatous hyperplasia overlying primary cutaneous melanomaAntibody Case No. Overlying hyperplastic epidermis Horn cysts Infiltrating epithelial strandp53p53bcl-2bcl-21212++++++++++++++++++++++++0, negative reaction; +, week staining, similar to adjacent normal basal epithelium; ++, moderate staining, less intense than in atypical melanoma cells; +++, strong staining, equivalent to atypical melanoma cellsFigure 1A. Epithelial strands with horn cysts originating from the epidermis and infiltrating the dermis among and around melanoma cells. (CK, x100)Figure 1B. Admixture of neoplastic melanocytic and hyperplastic keratinocytic cells in the dermis. (HMB-45, x200)Vučić et al.     Acta Dermatovenerol CroatPrimary cutaneous melanoma and pseudoepitheliomatous hyperplasia     2007;15(2):72-75 74DISCUSSION PEH may mimic well differentiated, infiltrat-ing squamous cell carcinoma or complicate the diagnosis of melanoma obscuring the underlying malignant process, thus leading to inappropriate diagnosis and treatment. In the differential diag-nosis of atypical pigmented lesion, melanoma as-sociated with PEH can be confused with rare pig-mented squamous cell carcinoma of the skin (10). Unlike squamous cell carcinoma, PEH never has atypical mitotic figures, rarely has dyskeratosis or atypical nuclei, and is never involved in vascular, lymphatic or perineural invasion (11). In the literature, there are some articles that report on PEH overlying cutaneous melanoma. Kamino et al. have reported four cases, each case revealing hyperplasia of the epidermis and of up-per portion of adnexal epithelium with squamous eddies and horn cysts (12). A case of PEH with thin cords of well differentiated epithelial cells per-colating the melanoma cells originating only from the epidermis, without evidence of adnexal origin have been described by Putrino et al. (13) and Reis-Filho et al. (14). PEH originating from eccrine duct epithelia has been described by Hanly et al. (15).   Mott et al. collected the largest reported series of 13 cases of PEH in association with melanoma. Seven cases of described PEH overlying mela-noma originated from the epidermis, five cases arose directly from follicular epithelium, and one from eccrine epithelium (16). The majority of cas-es (69%) exhibited acanthosis, hyperkeratosis, papillomatosis, and irregular infiltrating epithe-lial cords with squamous eddies. The remaining cases (31%) demonstrated basaloid acantho-sis, laminated orthokeratosis and horn cysts. Several reports have documented melanoma in conjunction with, or simulating seborrheic kerato-sis. While most cases represent a collision of the two entities, some authors suggest the possibil-ity that epidermal changes resembling seborrheic keratosis within the confines of the melanoma could be an induced phenomenon (17,18).   The mechanism of PEH is unknown. Some theories speculate that the histogenesis of PEH is due to the proliferative effect of cytokines re-leased by inflammatory or tumor cells within the subjacent dermis. Epidermal proliferation is co-ordinated by a variety of mediators including epi-dermal growth factor (EGF), transforming growth factor α (TGF-α) and epidermal growth factor re-ceptor (EGFR), and it is postulated that dysregu-lation of these growth factors may be important in the development of PEH (19,20). Among the three growth factors mentioned in literature reports, only TGF-α appears to be related to the development of PEH (21,22). Other peptide growth factors such as fibroblastic growth factor and platelet-derived growth factor may be important for exuberant epi-thelial proliferation in PEH. The reason for PEH development in the absence of growth factors is still unknown.  Expression of p53 in the skin is common and is an early event indicating immaturity and pro-liferative capacity of the keratinocytic cell. This expression of p53 need not necessarily indicate neoplastic or malignant transformation. Lee and The observed positive staining for p53 in six cas-es of PEH of the skin (20). The bcl-2 protein sup-presses apoptosis and overexpression of the bcl-2 protein has been reported in malignant melanoma of the skin (21). Results of our analyses of p53 and bcl-2 protein expression suggested a differ-ence in the proliferating capacity of infiltrating epi-thelial strands compared with horn cysts. p53 was expressed mainly in the cells at the base of the Figure 2. Expression of p53 (A) and bcl-2 (B) in infiltrating keratinocytic cells and horn cysts in the dermis. (A and B, x400)Vučić et al.     Acta Dermatovenerol CroatPrimary cutaneous melanoma and pseudoepitheliomatous hyperplasia     2007;15(2):72-75 ACTA DERMATOVENEROLOGICA CROATICA75ACTA DERMATOVENEROLOGICA CROATICAepidermis. Moderate intensity staining was ob-served in basal cells of the infiltrating strands and overlying epidermis, and week staining in basal cells of horn cysts. Infiltrating strands of the epi-thelium, basal and parabasal cells of the hyper-plastic epithelium compared with horn cysts also expressed stronger positivity for bcl-2 protein. It is possible that dysregulation of members of the bcl-2 protein family could play a role in the patho-genesis of PEH. Additional studies are necessary to identify the possible cause and prognostic impli-cations for this variant of skin melanomas. References1.   Grunwald MH, Lee JY, Ackerman AB. Pseu-docarcinomatous hyperplasia. Am J Dermato-pathol 1988;10:95-103.2.   Goel R, Wallace ML. Pseudoepitheliomatous hyperplasia secondary to cutaneous aspergil-lus. Am J Dermatopathol 2001;23:324-6.3.   Tan E, Malik R, Quirk CJ. Hypertrophic lichen planus mimicking squamous cell carcinoma. Australas J Dermatol 1998;39:45-7.4.   Lee ES, Allen D, Scurry J. Pseudoepithelio-matous hyperplasia in lichen sclerosus of the vulva. Int J Gynecol Pathol 2003;22:57-62.5.   Wolber RA, Talerman A, Wilkinson EJ, Clement PB. Vulvar granular cell tumors with pseudo-epitheliomatous hyperplasia: a comparative analysis with well-differentiated squamous cell carcinoma. Int J Gynecol Pathol 1991;10:59-62.6.   Krasne DL, Warnke RA, Weiss LM. Malignant lymphoma presenting as pseudoepithelioma-tous hyperplasia: a report of two cases. Am J Surg Pathol 1988;12:835-42.7.   Takeda Y, Sasou S, Obata K. Pleomorphic adenoma of the minor salivary gland with pseudoepitheliomatous hyperplasia of the overlying oral mucosa: report of two cases. Pathol Int 1998;48:389-95.8.   Scott G, Chen KT, Rosai J. Pseudoepithelio-matous hyperplasia in Spitz nevi. A possible source of confusion with squamous cell carci-noma. Arch Pathol Lab Med 1989;113:61-3.9.   Dorji T, Cavazza A, Nappi O, Osai J. Spitz nevus of the tongue with pseudoepithelioma-tous hyperplasia: report of three cases of a pseudomalignant condition. Am J Surg Pathol 2002;26:774-7.10. Chapman MS, Quitadamo MJ, Perry AE. Pig-mented squamous cell carcinoma. J Cutan Pathol 2000;27:93-5.11. Gacek MR, Gacek RR, Gantz B, McKenna M, Goodman M. Pseudoepitheliomatous hy-perplasia versus squamous cell carcinoma of the external auditory canal. Laryngoscope 1998;108:620-3.12. Kamino H, Tam ST, Alvarez L. Malignant mela-noma with pseudocarcinomatous hyperplasia – an entity that can simulate squamous cell carcinoma. A light microscopic and immuno-histochemical study of four cases. Am J Der-matopathol 1990;12:446-51.13. Putrino I, Baccarini P, Bracko M, Foschini MP, Collina G. Malignant melanoma with pseudoe-pitheliomatous reaction marker. A case report. Pathologica 1998;90:397-402.14. Reis-Filho JS, Gasparetto EL, Schmitt FC, Fillus-Neto J. Pseudoepitheliomatous hyper-plasia in cutaneous malignant melanoma: a rare and misleading feature. J Cutan Pathol 2001;28:496-7.15. Hanly AJ, Jorda M, Elgart GW. Cutaneous ma-lignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Report of a case and discussion of the origin of pseudo-epitheliomatous hyperplasia. J Cutan Pathol 2001;28:325-6.16. Mott RT, Rosenberg A, Livingston S, Morgan MB. Melanoma associated with pseudoepit-heliomatous hyperplasia: a case series and investigation into the role of epidermal growth factor receptor. J Cutan Pathol 2002;29: 490-7.17. Field LM. Clinical misdiagnosis of melanoma as well as seborrheic keratosis. J Dermatol Surg Oncol 1994;20:222.18. Jones-Caballero M, Penas PF, Buezo GF, Fra-ga J, Aragues M. Malignant melanoma appea-ring in a seborrhoic keratosis. Br J Dermatol 1995;133:1016-8.19. Morgan MB, Howard HG, Everett MA. Epithe-lial induction in dermatofibroma: a role for the epidermal growth factor (EGF) receptor. Am J Dermatopathol 1997;19:35-40. 20. Lee YS, The M. p53 expression in pseudoepit-heliomatous hyperplasia, keratoacanthoma and squamous cell carcinoma of skin. Cancer 1994;73:2317-23.21. Nakagawa K, Yamamura M, Maeda S, Ichi-hashi M. Bcl-2 expression in epidermal kerati-nocytic diseases. Cancer 1994;74:1720-4.Vučić et al.     Acta Dermatovenerol CroatPrimary cutaneous melanoma and pseudoepitheliomatous hyperplasia     2007;15(2):72-75 

An Unusual Pattern of Pseudoepitheliomatous Hyperplasia Associated with Cutaneous Primary Melanoma: Report of Two Cases with Analysis of p53 and bcl-2 Immunoreactivity

An Unusual Pattern of Pseudoepitheliomatous Hyperplasia Associated with Cutaneous Primary Melanoma: Report of Two Cases with Analysis of p53 and bcl-2 Immunoreactivity

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