Extramammary Paget s disease

Transcription

1 Original Study Inconsistent Immunostaining and Racial Difference in Extramammary Paget s Disease Fu-Chiang Chiang Szu-Ying Chu Yun-Ting Chang Background: Extramammary Paget s disease (EMPD), an uncommon neoplastic disorder, usually presents as an eczematous patch on the apocrine-rich area. It can be further classified into primary and secondary EMPD by its association with underlying malignancies. The histopathology shows a characteristic intraepidermal atypical clear cell infiltrate. Objective: To determine whether the histopathologic or immunohistochemical features of EMPD could be used to predict clinical behavior or association with underlying malignancies. Methods: Twenty-two freshly-diagnosed EMPD cases were collected retrospectively in the past 10 years. All were Chinese and their medical records were reviewed. Histopathology of skin specimens were examined and immunohistochemical staining of cytokeratin 7 (CK7), cytokeratin 20 (CK20), and gross cystic disease fluid protein-15 (GCDFP-15) were performed. Results: None of the cases were proven to be secondary EMPD. The Paget s cells from all cases were immunopositive for CK7. In 58% of primary EMPD cases, the Paget s cells had the immunophenotype CK20(-)/GCDFP-15(+). Conclusion: In Chinese patients with EMPD, routine invasive surveys for associated malignancies might be unnecessary. CK7 is a suitable marker for the diagnosis of EMPD due to its high sensitivity. It is unreliable to distinguish between primary and secondary EMPD from their reactivity of CK20 and GCDFP-15. (Dermatol Sinica 27: , 2009) Key words: Extramammary Paget s disease, Cytokeratin 7, Cytokeratin 20, Gross cystic disease fl uid protein-15 INTRODUCTION Extramammary Paget s disease (EMPD) is a heterogenous entity sharing similar clinical and histopathologic features. EMPD usually presents as an irritating, slowgrowing, well-defined, reddish, scaly patch on the genital, perineal, perianal, groin, and axillary areas. Ulceration, local invasion, and metastasis may occur. It is subdivided into primary and secondary EMPD according to different pathogenesis. Primary EMPD is thought to originate intraepidermally, and secondary EMPD is due to epidermal invasion of malignant cells coming from an underlying adnexal neoplasm (upward invasion), regional neoplasm (contiguous spreading), or distant neoplasm (epidermotrophic metastasis). 1, 2 Unlike the mammary Paget s From the Department of Dermatology, Taipei Veterans General Hospital Corresponding author: Fu-Chiang Chiang, Department of Dermatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan TEL: FAX: chungoooo@yahoo.com.tw Funding source: none Conflict of interest: none declared Received: November 26, 2008 Revised: February 13, 2009 Accepted: April 14,

2 Fu-Chiang Chiang, et al disease which is almost always secondary to an underlying breast cancer, primary EMPD predominates over secondary EMPD. The true incidence of secondary EMPD remains unclear because most documented data assessed the relationship between EMPD and internal malignancies (coexistent), rather than contiguous malignancies (causative). A previous study by Chanda in 1985 demonstrated that 12% of EMPD patients had a concurrent underlying internal malignancy close to the skin lesion, and 24% had an associated adnexal adenocarcinoma. 3 When confined to male patients with EMPD on their genitalia, the existence of an underlying carcinoma of the prostate, bladder, testicles, ureter, or kidney accounted for 11% of these cases. 1, 3 Histopathologically, large atypical mucin-containing cells (Paget s cells) infiltrating the epidermis can be seen. Glandular structure, adnexal infiltration, and dermal invasion of Paget s cells are also occasionally found. Although dermal invasion was proposed to be a poor prognostic factor, it remains unclear whether the infiltrating patterns of Paget s cells and pigment incontinence are of prognostic significance, but rather would reflect the tumor s destructive behavior. 4 Theoretically, Paget s cells expressing cytokeratin 20 (CK20, found in most gastrointestinal and urothelial carcinomas) or gross cystic disease fluid protein-15 (GCDFP-15, found in apocrine-origin neoplasms) represent their different origins. It has been proposed that primary EMPD is usually CK20(- )/GCDFP-15(+) and secondary EMPD is usually CK20(+)/GCDFP-15(-). 1, 2 Cytokeratin 7 (CK7), a kind of low molecular weight keratins, presents in sweat glands, Toker cells, Merkel cells, and Paget s cells. 2, 5 In contrast with the adjacent epidermal cells, Paget s cells react with antibodies of low molecular weight keratins rather than the high ones. 2, 6 Due to the malignant nature of EMPD and possible association with internal neoplasms, the correct diagnosis and further follow-up are essential. Until now, the immunohistochemical staining of CK7, CK20, and GCDFP-15 in EMPD patients in Taiwan has never been reported in the literature. This study s objectives are to determine the frequency of secondary EMPD, and to investigate whether a more destructive histopathologic pattern implied a poorer prognosis and whether CK20 and GCDFP-15 were reliable markers for differentiating between primary and secondary EMPD in one patient. MATERIAL AND METHOD In the past 10 years ( ), a total of 23 biopsy-proven EMPD patients was diagnosed in our hospital. Excluding one recurrent case, 22 freshly-diagnosed cases were included. Everyone received a skin biopsy from the lesion site which was photographed as well. The histories, photographs, and prognosis of every patient were reviewed from the medical charts and/or telephone interviews. We recorded items of age of onset, age of diagnosis, delay of diagnosis, sex, lesion site, and the presence of internal malignancies. If the EMPD lesions were multifocal, the main involved site was recorded. Further surveys for internal malignancies were done. According to these surveys validity, we classified them into: class I - endoscope, image study (computed axial tomography scan, sonography, whole body bone scan); class II - laboratory study (urine test, stool test, serum tumor marker); and class III - no clinical symptoms or physical examination findings of malignancies. Among the enrolled 22 patients, 15 patients underwent the class I survey, 2 patients the class II survey, 3 patients the class III survey, and 2 patients had lost follow-up. The above arrangements were made in compliance with 162 Dermatol Sinica, Sep 2009

3 Extramammary Paget, s Disease Table. 1 The Results of Clinical Data patients wills. The histopathologic features of 22 specimens were evaluated by hematoxylin-eosin stain. We recorded the presence of infiltrating patterns (nest or single unit predominance), glandular structure, dermal invasion, and pigment incontinence. Infiltrating patterns were evaluated by two dermatologists. All 22 specimens were stained with CK7, CK20, and GCDFP-15 (NeoMarkers, California, USA). Exceptionally, one specimen failed to be stained due to insufficient tissue amount. The staining results were labeled as negative if 0% of the atypical cells Dermatol Sinica, Sep

4 Fu-Chiang Chiang, et al Table. 2 The Results of Histopathology and Immunohistochemical Staining RESULTS Twenty males and 2 females were inshowed reactivity, as focal positive if 10% or less of them showed reactivity, and as positive if more than 10% of them showed reactivity. Statistical analysis was performed by Fisher s exact test with two-tailed P values. P < 0.05 was considered to be significant. 164 Dermatol Sinica, Sep 2009

5 Extramammary Paget, s Disease Fig. 1 Extramammary Paget s disease is characterized with intraepidermal atypical clear cell infiltration. Excess incontinent pigments are noted in this case. (H&E, original magnification x100) Fig. 2 Paget s cells are arranged in single units (S) or nests (N) with the occasional presence of glandular structure (G). (H&E, original magnification x400) Fig. 3 Paget s cells are immunopositive for CK7. Dermal invasion is highlighted in this case. (CK7, original magnification x100) cluded in this study (Table 1). The mean age of onset, age of diagnosis, and delay of diagnosis were 73, 76, and 3 years old respectively. The median age of onset was 75 years old. The younger group (age 75 y/o) was prone to have longer delay ( > 3 years) than the older group (age > 75 y/o) (p = ). The frequency of lesion sites are listed below: genitalia (penoscrotum and vulva, 59%), groin and pubic area (23%), perianal area (14%), and axilla (5%). Clinical parameters including patient s age, delay of diagnosis, sex, lesion site, and coexistence of a malignancy were irrelevant to the histopathologic and immunohistochemical findings of skin lesions except for lesions involving the periorificial area (including 2 cases of the perianal area and 1 case of the glans penis), which were prone to be GCDFP-15 negative (p = ). Excluding the 2 cases that lost followup, 5 out of 20 (25%) cases were found to have coexistent distant malignancies in which 3 cases (15%) had internal adenocarcinomas or pre-adenocarcinoma (dysplastic tubulovillous adenoma of colon). All these 20 cases were likely to be primary EMPD since no underlying adnexal or regional cancers were found. No one died from EMPD or its complication during , either. Histopathologically, all specimens showed Paget s cells infiltrating the epidermis in nests and single units (Fig. 1, 2). A nest was defined as 4 or more grouped cells. Fourteen out of 22 (64%) specimens were nest-predominant, while 5 specimens were single-unit-predominant and the remaining 3 specimens showed mixed patterns (Table 2). In addition, 4 specimens (18%) had glandular structure, 9 specimens (41%) had dermal invasion, and 5 specimens (23%) had pigment incontinence. Immunohistochemical staining of CK7, CK20, and GCDFP-15 was performed in 21 out of 22 specimens (Fig. 3, 4, 5). The Dermatol Sinica, Sep

6 Fu-Chiang Chiang, et al Paget s cells of all 21 specimens (100%) were CK7 positive, while 4 specimens (19%) were CK20 positive (or focal positive) and 13 specimens (62%) were GCDPF-15 positive (or focal positive). Altogether, 11 out of 19 (58%) cases of primary EMPD had the immunophenotype CK20(-)/GCDFP-15(+). There was no correlation between the outcome of CK20 and GCDFP-15 staining (p = 0.62), which also failed to predict the coexistence of malignancies. Moreover, no correlation was observed between the histopathologic features (infiltrating pattern, dermal invasion, and pigment incontinence) and the reactivity of CK20 and GCDFP-15. DISCUSSION Excluding 2 cases that had lost followup, the remaining 20 cases in our study appeared all to be primary EMPD. Although most patients had undergone extensive surveys, no associated adnexal or regional cancer could be found. The value of routine invasive examinations for associated malignancies in asymptomatic patients seems doubtful considering patients discomfort and cost-effectiveness. Similar to other Asian studies, the incidence of secondary EMPD was considerably lower than that reported in 1-3, 7-9 Caucasians. Five out of 22 cases had coexistent malignancies which failed to show their connection to the skin lesion of EMPD and might represent as a coincident finding. Such coexistence had been shown with ovarian carcinoma, bile duct carcinoma, hepatocellular carcinoma, and renal cell carcinoma. 2, 10 In fact, it is still controversial whether EMPD patients has an increased risk of internal malignancies. 3, 7, 8, 11 Histopathologically, 100% of these 22 specimens showed characteristic Paget s cell infiltration. We presumed that the more single Paget s cell infiltration in the specimen, the less organized and more aggressive the Fig. 4 These Paget s cells are immunopositive for CK20. (CK20, original magnification x100) Fig. 5 These Paget s cells are immunopositive for GCDFP-15. The eccrine glands are highlighted, too. This is the same case as in Fig. 4. (GCDFP-15, original magnification x40) lesion. In addition, we also assessed tumor s aggression by dermal invasion and pigment incontinence. However, no correlation was observed between the above histopathologic features and EMPD-related death although longer follow-up period would be needed. A single factor may not be sufficient to explain the behavior of Paget s cells, as other factors such as inflammation or host response might also play a role. A recent study in Japan showed that about 43.4% of EMPD cases had dermal invasion, which was associated with a poorer survival. 4 The EMPD patients in our study 166 Dermatol Sinica, Sep 2009

7 Extramammary Paget, s Disease also had a similar dermal invasion rate (41%). As our study did not include treatment modality and follow-up period was not long enough, we could not compare the survival between these two studies. Immunohistochemically, 100% of these 21 specimens were CK7 positive. The sensitivity of anti-ck7 antibodies was quite high. Therefore, in clinical practice to differentiate a pagetoid lesion with an undetermined diagnosis, EMPD can be excluded if its CK7 stain was negative. Theoretically, primary EMPD has the immunophenotype CK20(-)/GCDFP-15(+) and secondary EMPD has the immunophenotype CK20(+)/GCDFP-15(-). However, only 58% of primary EMPD cases in our study were CK20(-)/GCDFP-15(+). This finding was similar to an American study showing that 4 out of 6 (67%) cases of perianal primary EMPD were CK20(-)/GCDFP-15(+). 12 Furthermore, EMPD cases with CK20(+)/ GCDFP-15(+) or CK20(-)/GCDPF-15(-) 12, 13 were previously reported. Inconsistent immunophenotypes might imply the heterogenous origins of Paget s cells, which have been proposed to be undifferentiated pluripotent cells (from the epidermis or adnexa), Toker cells, and ectopic mammary glands. 5, 14, 15 The remaining 8 cases in our study with immunophenotype other than CK20(-)/GCD- FP-15(+) could not be proven as secondary EMPD, and they failed to present increase in internal malignancies, EMPD-related death, or dermal invasion. Therefore, it seems unreliable to distinguish between primary and secondary EMPD merely from these immunostaining results. In our study, EMPD was prone to develop in the elderly, and the younger group had longer delay of diagnosis which was possibly because of patients awareness and doctors caution, although recall bias could not be ruled out totally. Male predominance was noted (male: female = 10:1) although selection bias may be in play due to the major patient population of our hospital being constituted by veterans. However, male predominance was also observed in several other Asian studies of Taiwan, Hong Kong, Korea, and Japan. 7, 8, 11 In contrast, female predominance was noted in Caucasians patients 1, 2, 5 with EMPD. EMPD almost always develops on the apocrine-rich area. Our study showed that the genitalia was the most frequent site (12 males and 1 female out of 22 cases), which was compatible with a Korea s study (penoscrotal area 75%). 11 In Caucasians patients with EMPD, the frequency of involved sites was listed below: vulva (65%), perianal area 1, 2, 16 (20%), and male genitalia (14%). Our study had limitations in many ways: the retrospective mode of studying, the insufficient follow-up period, the referral bias of gathering patients from a medical center, and selection bias due to limited patient source. We used disease-related death for evaluating the prognosis of EMPD, which might not be enough. Local recurrence, lymph node involvement, systemic metastasis, and quality of life would be included as well as treatment modalities. CK7 was a sensitive marker for Paget s cells, but its specificity was not demonstrated here. In conclusion, our study includes 22 fresh cases of EMPD diagnosed in our hospital during the past 10 years. None of them was proven to be secondary EMPD. The necessity of routine invasive surveys in asymptomatic patients might be doubtful. The immunostaining of CK7 may serve for ruling in the diagnosis of EMPD since it is always positive in Paget s cells. It seems unreliable to distinguish primary and secondary EMPD merely from immunostaining results of CK20 and GCDFP-15. REFERENCES 1. J Kanitakis: Mammary and extramammary Pag- Dermatol Sinica, Sep

8 Fu-Chiang Chiang, et al et s disease. J Eur Acad Dermatol Venereol 21: , Lloyd J, Flanagan A: Mammary and extramammary Paget s disease. J Clin Pathol 53: , Chanda JJ: Extramammary Paget s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 13: , N. Hatta, M. Yamada, T. Hirano, et al.: Extramammary Paget s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 158: , Urabe A, Matsukuma A, Shimizu N, et al.: Extramammary Paget s disease: comparative histopathologic studies of intraductal carcinoma of the breast and apocrine adenocarcinoma. J Cutan Pathol 17: , Smith KJ, Tuur S, Corvette D, et al.: Cytokeratin 7 staining in mammary and extramammary Paget s disease. Mod Pathol 11: , Chang YT, Liu HN, Wong CK: Extramammary Paget s disease: a report of 22 cases in Chinese males. J Dermatol 23: , Chiu TW, Wong PS, Ahmed K, et al.: Extramammary Paget s disease in Chinese males: a 21-year experience. World J Surg 31: , Lai YL, Yang WG, Tsay PK, el al.: Penoscrotal extramammary Paget s disease: a review of 33 cases in a 20-year experience. Plast Reconstr Surg 112: , Nakano S, Narita R, Tabaru A, et al.: Bile duct cancer associated with extramammary Paget s disease. Am J Gastroenterol 90: , Sang Nam Yoon, In Ja Park, Hee Cheol Kim: Extramammary Paget s disease in Korea: its association with gastrointestinal neoplasms. Int J Colorectal Dis 23: , Nowak MA, GuerriereKovach P, Pathan A, et al.: Perianal Paget s disease-distinguishing primary and secondary lesions using immunohistochemical studies including gross cystic disease fluid protein-15 and cytokeratin 20 expression. Arch Pathol Lab Med 12: , J. C. Pascual, M. Perez-Ramos, J. P. Devesa, et al.: Extramammary Paget s disease of the groin with underlying carcinoma and fatal outcome. Clin Exp Dermatol 33: , Hashimoto T, Inamoto N, Nakamura K: Triple extramammary Paget s disease. Dermatologica 173: , Belousova I, Kazakov D, Michal M, et al.: Vulvar Toker cells: the long-awaited missing link: a proposal for an origin-based histogenetic classification of extramammary Paget s disease. Am J Dermatopathol 28: 84-86, Shepherd V, Davidson E, Davies-Humphreys J: Extramammary Paget s disease. BJOG 112: , Dermatol Sinica, Sep 2009

9 Extramammary Paget, s Disease 乳房外柏哲德氏病之免疫染色與人種差異性研究 蔣富強朱思穎張雲亭 台北榮民總醫院皮膚部 背景 : 乳房外之柏哲德氏病 (Paget, s disease) 為一少見之皮膚癌病, 常發生於大汗腺豐富處, 呈濕疹樣斑塊 依據癌細胞的來源, 可區分該疾病為原發性或次發性 病理下可見非典型明亮細胞之表皮內浸潤 目的 : 探討乳房外柏哲德氏病之病理與免疫染色特徵能否預測其臨床表現或是否伴隨內部腫瘤 方法 : 我們回溯性地收集過去十年間 22 例新診斷的乳房外柏哲德氏病, 所有病患皆為華人, 歸納分析患者的病歷, 並重新檢視其皮膚病理以及免疫染色下的發現 免疫染色試劑選用 cytokeratin 7 (CK7) cytokeratin 20 (CK20), 以及 gross cystic disease fluid protein-15 (GCDFP-15) 結果 : 沒有任何病患被診斷為次發性乳房外柏哲德氏病 所有的病灶標本裡, 柏哲德氏細胞的 CK7 免疫染色皆呈陽性 原發性的案例裡,58% 的病灶標本其柏哲德氏細胞呈現 CK20(-)/ GCDFP-15(+) 的結果 結論 : 對乳房外柏哲德氏病的華人患者而言, 常規性的安排侵入性檢查或許並非必要 CK7 因具高敏感性, 可以幫助診斷乳房外柏哲德氏病 以 CK20 與 GCDFP-15 的染色結果區分原發性或次發性並不可靠 ( 中華皮誌 :27: , 2009) Dermatol Sinica, Sep