- Email: [email protected]
Recurrent apocrine carcinoma of the scrotum: A case report
Pathology – Research and Practice 211 (2015) 264–267
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching case
Recurrent apocrine carcinoma of the scrotum: A case report Davide Campobasso a , Elena Thai b,∗ , Antonio Barbieri a , Francesco Ziglioli a , Umberto Maestroni a , Giovanni Fellegara c , Roberto Ricci b a b c
Urology Unit, Surgical Department, University Hospital of Parma, Italy Surgical Pathology Unit, Oncology, Hematology and Internal Medicine, University Hospital of Parma, Italy Department of Anatomic Pathology, Italian Diagnostic Center (CDI), Milan, Italy
a r t i c l e
i n f o
Article history: Received 31 January 2014 Received in revised form 27 November 2014 Accepted 9 December 2014 Keywords: Apocrine Recurrence Scrotum
a b s t r a c t Apocrine carcinoma is a rare tumor of the skin that typically arises in areas rich in apocrine glands, such as axilla and perineum. The main differential diagnosis is a metastasis from a primary apocrine carcinoma of the breast. Several authors have attempted to define morphological and immunohistochemical parameters to differentiate metastasis from primary apocrine carcinoma of the skin, but none of these had been demonstrated to be reliable markers. Here, we report a case of primary apocrine carcinoma of the scrotum that relapsed three times within a few years, without any clinical or radiological evidence of any other tumor of breast or other sites. © 2014 Elsevier GmbH. All rights reserved.
Introduction Scrotal cancer is a rare tumor, especially after improvement of the hygienic conditions in industrial working places [9]. Recently, Johnson et al. [7] identified the incidence of scrotal cancer and assessed the impact of scrotal cancer histology on survival. A total of 766 patients with primary scrotal cancer were examined, the most common histological type was squamous cell carcinoma (35.1%), followed by Extramammary Paget’s Disease (EMPD) (21.9%), sarcoma (20.4%), basal cell carcinoma (16.7%), melanoma (3.3%) and adnexal skin tumors (2.6%). Although patients with adnexal skin tumors were classified as having high risk with low survival, the presence of a localized disease showed a relatively high survival, similar to that of EMPD, sarcoma and basal cell carcinoma. Apocrine carcinoma of the skin represents a rare group of sweatgland carcinomas. In general, it occurs in areas where apocrine glands or modified apocrine glands (ceruminous and Moll glands) are present (ano-genital regions, ear canal, scalp, mammary areola and axilla). It is an extremely rare tumor. Scrotal apocrine carcinoma is a slow-growing tumor with a tendency toward a prolonged course; it is able to metastasize to lymph nodes, lungs, liver, brain and bone [6].
∗ Corresponding author. Tel.: +39 0521702625. E-mail address: [email protected] (E. Thai). http://dx.doi.org/10.1016/j.prp.2014.12.010 0344-0338/© 2014 Elsevier GmbH. All rights reserved.
The symptoms are non-specific, often manifesting with scrotal eczema or dermatitis and pruritus. In many cases, diagnosis is delayed for these reasons. Solid or cystic masses and reddish purple subcutaneous nodules are often the first sign of presentation. We report a case of a 51-year-old man who underwent four scrotal resections between 2007 and 2013 for a primary apocrine carcinoma. Materials and methods After fixation in 10% buffered formalin, the surgical specimen, including the entire tumor, was sampled according to standard procedures and processed into paraffin. Serial 4-m thick sections were stained with hematoxylin–eosin (H&E) for conventional histology, periodic acid-Schiff (PAS) and PAS-diastase for mucin detection. Immunohistochemistry was performed on the paraffin sections with the following reagents: Ki-67 (MIB-1, DakoCytomation, Glostrup, Denmark), GCDFP-15 (EP1582Y, Ventana), S100 (4C4.9, Ventana), low molecular weight cytokeratins (CAM5.2, Ventana), CK5/6 (D5/16B4, Ventana), EMA (E29, Ventana), CEA (CEA 31, Ventana), E-cadherin (36, Ventana), estrogen receptor (SP1, Ventana), progesteron receptor (1E2, Ventana), PSA (polyclonal, Ventana), smooth muscle actin (1A4, Ventana), p53 (DO-7, Ventana), p63 (4A4, Ventana), d2-40 (d2-40, Ventana), androgen receptor (SP107, Ventana) and lysozyme (polyclonal, Ventana). Immunostaining was highlighted with a polymeric system (DAKO ADVANCE HRP)
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
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Fig. 1. (A) The patient presented with multiple scrotal reddish and whitish nodules in the scrotum. (B) Grossly, the lesions were whitish plaque-like formations, with alternating solid and cystic areas. (C) Panoramic view of the tumor showed two distinct components, cystic and solid (H&E, 20×). (D) The cystic structures contained eosinophilic secretion, lined by cells with apocrine features, forming papillae tufting in the lumen (H&E, 400×). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
and finally visualized with 3,3 -diaminobenzidine (DAB) and counterstained with hematoxylin.
Case report A 45-year-old Caucasian man came to our attention in June 2007 with some rapidly growing bilateral scrotal nodules (Fig. 1A), present for a few months. The lesions, located at the right and left hemiscrotum, measured 4 cm and 3 cm in greatest diameter respectively, the largest one was ulcerated. At admission, the patient was well, and physical examination did not show any other remarkable lesion. The past history of the patient included surgery at the age of 6 for bilateral cryptorchidism. For more than 9 years, he had been working as a clerk in a plywood factory where different kinds of glue are commonly used. Routine laboratory studies were normal. Thoraco-abdominal computed tomography, bone scan and breast ultrasound were negative. He received local excision of 4 × 3 cm and 3 × 1.5 cm wide skin flaps, in both right and left hemi-scrotum. Grossly, the lesions were whitish plaque-like formations, with alternating solid and cystic areas (Fig. 1B). Histologically, two distinct components were evident at panoramic observation, cystic and solid (Fig. 1C). The cystic dilated structures contained eosinophilic, PAS positive-diastase resistant secretion, were bordered by cells with apocrine features (with abundant eosinophilic cytoplasm, “decapitation” secretion in the form of apical snouts, vesicular nuclei with prominent nucleoli)
forming papillae, tufting in the lumen and sometimes growing in a cribriform pattern (Fig. 1D). Infiltration and ulceration of the covering skin were present, with focal pagetoid spread (Fig. 2A). The solid component of the lesions was a malignant tumor infiltrating the dermis, with apocrine features, growing in tubular, cribriform and trabecular patterns (Fig. 2B and C). Cytologically, the cells had a more undifferentiated, high grade appearance. Endolymphatic emboli were evident (Fig. 2D). Hyperplastic apocrine glands were observed at the margins and intermixed with the malignant glandular structures. The apocrine nature of this malignant neoplasm was supported by the strong expression of GCDFP-15 and lysozyme. The tumor stained also positively for androgen receptor, low molecular weight cytokeratins, EMA, CK5/6 (focal) and E-cadherin. Immunostains for CEA, d2-40, S100, smooth muscle actin, p53, PSA, estrogen and progesteron receptors were negative. Immunohistochemical staining for P63 detected myoepithelial cells only at the basal layer of the normal and hyperplasic apocrine glands but was completely negative in the malignant component. Frequent atypical mitosis and cellular pleomorphism were evident in the less differentiated areas. All these findings were consistent with the diagnosis of multicentric apocrine adenocarcinoma of the scrotum associated with apocrine gland hyperplasia. The assumption of a metastasis from a mammary apocrine adenocarcinoma was excluded by an accurate clinical and instrumental examination of the patient. The patient developed three local recurrences in 2008, 2010 and 2013 respectively, all with the same diagnosis. The follow-up
266
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
Fig. 2. (A) Pagetoid spread of the covering skin (H&E, 200×). (B and C) The solid component of the tumor was constituted by neoplastic cells with apocrine features, growing in tubular, cribriform and trabecular patterns (H&E, 200×). (D) Neoplastic emboli were present in lymphatic vessels (H&E, 200×).
investigations with annual CT scan, breast US and chest X-ray every 6 months were negative. Discussion Apocrine adenocarcinoma is a rare malignant tumor of the sweat glands, with unknown etiology. Sweat gland carcinomas have a peak of incidence in the fifth and sixth decades of life [11]. The lesions tend to arise in areas with high concentration of apocrine sweat glands, like the axilla and, less frequently, the anogenital region, followed by trunk (26.4%), head and neck (18.3%) and lower extremities (13.9%) [3,5]. It is a slow growing lesion, with low overall mortality, despite frequent recurrences and regional lymph nodes metastasis. Distant metastasis may be a late event. Therefore, prolonged follow-up is mandatory [8]. Benign apocrine carcinoma is much more common than the malignant counterpart. The presence of metastasis or a history of a rapidly growing lesion may help in the diagnosis of malignant apocrine carcinoma. Histological features, such as an infiltrative growth pattern, cytologic atypia, vascular invasion and mitotic activity, generally allow for assessment of malignancy [8]. Anyway, reliable predictive factors have not been established yet. The main differential diagnosis is a metastasis from a mammary apocrine carcinoma. Apocrine carcinomas of the skin and breast are androgen receptor-positive [2]. Recently, adipophilin has been reported to be positive in 88% of mammary apocrine carcinomas versus 36% of cutaneous apocrine carcinomas [13]. Our case stained positively for androgen receptor, but excluding the possibility of a metastasis is needed.
Apocrine carcinoma of the breast is very rare, with an incidence of <1% of female invasive breast carcinomas [4]. It tends to show estrogen and progesterone receptor negativity and expression of Gross cystic disease protein fluid-15 (GCDPF-15) [18]. This pattern is analogous to primary skin apocrine carcinoma. Therefore, it is impossible to make a differential diagnosis exclusively on currently used pathological parameters. Moreover, it has been demonstrated that that gross cystic disease fluid protein-15, ER, PR, and Her2/neu have all been shown to be expressed in cutaneous adnexal neoplasms as well [19], which is why these markers cannot be used to distinguish primary from metastatic apocrine carcinoma. Several authors have attempted to identify additional immunohistochemical markers that can help to distinguish primary from metastatic skin adnexal carcinomas. These included p63 and CK5/6, which have been demonstrated to be relatively specific and sensitive for primary cutaneous adnexal neoplasms [14]. Some authors have proposed other immunohistochemical markers, like p63, d2-40 and CK15 to distinguish metastasis from primary adnexal carcinoma [10]. According to these authors, a positivity to these markers should be in favor of primitivity. In our case, only a focal positivity for CK5/6 was assessed, while all the other markers were negative. Nevertheless, in the paper by Mahalingam et al. [10], two cases of apocrine carcinomas were negative for p63; thus, in accordance with our finding. Moreover, there was no clinical, ecographic and radiological evidence of a primary carcinoma of the breast or other sites, questioning the reliability of immunohistochemistry to make a correct diagnosis. As long as new data are not available, morphological and clinical features are still our main diagnostic means. Pagetoid epidermal spread is uncommon in apocrine carcinoma [16,17], it can help to confirm the primitivity of the lesion, but
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
nevertheless cannot exclude a cutaneous metastasis [1]. In our case, the presence of foci of intraepithelial pagetoid diffusion, together with clinical and radiological exclusion of other neoplasms, helps to confirm the primitivity of the tumor. Extramammary Paget Disease (EMPD), similarly to the mammary counterpart, is an intraepidermal adenocarcinoma characterized by large atypical and pale staining cells scattered throughout the epidermis, in a single cell fashion or in small clusters. It is thought to derive from apocrine glands or epidermal basal stem cells. Unlike mammary Paget disease, most cases of EMPD do not show underlying malignancies. Anyway, no accurate epidemiologic data is available yet for EMPD. Tumors associated with EMPD include rectal adenocarcinoma, transitional cell carcinoma of urethra and bladder, carcinoma of the Bartholins glands, prostate adenocarcinoma, cutaneous adnexal carcinoma and carcinoma of the vagina and cervix [8]. In our case, the presence of bilateral scrotal lesion and the coexistence of apocrine gland hyperplasia gave rise to the hypothesis that unknown genetical or environmental factors may act as promoters, stimulating apocrine gland proliferation. Given the well-known role that hormonal factors play in the development of apocrine glands and given the expression of androgen receptor in neoplastic apocrine cells [2], we hypothesize that an endocrine disequilibrium could play a central role in the genesis and progression of apocrine carcinoma of the skin. Overall mortality is low. Complete surgical resection is the treatment of choice. Positive surgical margins remain one of the most important risk factors for local recurrence of the tumor. Some authors [20] suggest multiple biopsies with 3 cm-free margins to decrease recurrence in scrotal EMPD. Regional lymph node dissection must be considered in the presence of clinically positive nodes. Lymph nodes metastases are present in 16% of cases, and it is associated with worse prognosis. If lymph node metastases are present, chemotherapy is mandatory, but at present there is no consensus on the chemotherapy regimen [12,15]. Conclusion Apocrine carcinomas tend to arise in areas with high concentration of apocrine sweat glands, such as the axilla and anogenital region. They are slow growing lesions with low overall mortality, despite frequent recurrences and regional nodes metastasis. Diagnosis is often delayed until the appearance of regional lymph nodes involvement or skin ulceration. Distant metastasis may be a late event and associated with poor prognosis; therefore, prolonged follow-up is mandatory [8]. Anyway, reliable predictive factors have not been established yet. A wide surgical excision with multiple biopsies is the treatment of choice. Regional lymphadenectomy is mandatory in the presence of lymph nodes
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enlargements. Sentinel lymph node biopsy is under debate to determine if there is an improvement in survival. References [1] I. Alcaraz, L. Cerroni, A. Rütten, H. Kutzner, L. Requena, Cutaneous metastases from internal malignancies: a clinicopathologic and immunohistochemical review, Am. J. Dermatopathol. 34 (4) (2012) 347–393. [2] G.L. Bratthauer, R.A. Lininger, Y.G. Man, F.A. Tavassoli, Androgen and estrogen receptor mRNA status in apocrine carcinomas, Diagn. Mol. Pathol. 11 (June (2)) (2002) 113–118. [3] R.D. Chintamani, R.B. Sharma, V. Singhal, et al., Metastatic sweat gland adenocarcinoma: a clinic-pathological dilemma, World J. Surg. Oncol. 1 (2003) 13. [4] G. Gayatri, B. Mondita, B. Asha, A. Vishal, Study on apocrine carcinoma of breast: histomorphologic features and immunohistochemical behavior, Int. J. Basic Appl. Med. Sci. 2 (3) (2012) 190–193. [5] K. Hashimoto, Adnexal carcinoma of skin, in: R.J. Freidman, D.S. Rigel, A.W. Kopf (Eds.), Cancer of Skin, WB Saunders, Philadelphia, 1991, pp. 209–216. [6] K. Hollowell, S. Agle, E. Zervos, T. Fitzgerald, Cutaneous apocrine adenocarcinoma: defining epidemiology, outcomes, and optimal therapy for a rare neoplasm, J. Surg. Oncol. 105 (2012) 415–419. [7] T. Johnson, W. Hsiao, K. Delman, et al., Scrotal cancer survival is influenced by histology: a SEER study, World J. Urol. 31 (2013) 585–590. [8] P.E. LeBoit, G. Burg, D. Weedon, A. Sarasain (Eds.), World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours, IARC Press, Lyon, 2006. [9] F.C. Lowe, Squamous-cell carcinoma of the scrotum, Urol. Clin. North Am. 19 (1992) 397–405. [10] M. Mahalingam, L.P. Nguyen, The diagnostic utility of immunohistochemistry in distinguishing primary skin adnexal carcinomas from metastatic adenocarcinoma to skin: an immunohistochemical reappraisal using cytokeratin 15, nestin, p63, D2-40, and calretinin, Mod. Pathol. 23 (5) (2010) 713–719. [11] D. Panoussopoulos, A. Darom, A. Lazaris, P. Misthos, K. Papadimitrion, G. Androulakis, Sweat gland carcinoma with multiple local recurrences: a case report, Adv. Clin. Pathol. 3 (1999) 63–68. [12] J.W. Patterson, M.R. Wick, Neoplasms and pseudoneoplastic proliferations of the sweat glands, in: S.G. Silverbeg, L.H. Sobin (Eds.), AFIP Atlas of Tumor Pathology. Non-melanocytic Tumors of the Skin, Armed Forces Institute of Pathology, Washington, DC, 2006, pp. 137–199. [13] A. Piris, Y. Peng, C. Boussahmain, et al., Cutaneous and mammary apocrine carcinomas have different immunoprofiles, Hum. Pathol. 45 (2014) 320–326. [14] H.S. Qureshi, A.H. Ormsby, M.W. Lee, et al., The diagnostic utility of p63, CK5/6, CK7, and CK20 in distinguishing primary cutaneous adnexal neoplasms from metastatic carcinomas, J. Cutan. Pathol. 31 (2004) 145–152. [15] L. Requena, Y.M. Mengesha, H. Kuntzer, et al., Malignant tumours with apocrine and eccrine differentiation, in: P.E. Leboit, G. Burg, D. Weedon, A. Sarasin (Eds.), World Health Organization Classification of Tumour: Pathology and Genetics of Skin Tumours, IARC Press, Lyon, 2006, pp. 125–148. [16] A. Robson, A.J. Lazar, J. Ben Naji, et al., Primary cutaneous apocrine carcinoma: a clinico-pathologic analysis of 24 cases, Am. J. Pathol. 32 (2008) 682–690. [17] T. Terada, M. Kamo, M. Sugiura, Apocrine carcinoma of the scrotum with extramammary Paget’s disease, Int. J. Dermatol. 52 (4) (2013) 504–506. [18] Y. Tsutsumi, Apocrine carcinoma as triple-negative breast cancer: novel definition of apocrine-type carcinoma as estrogen/progesterone receptor-negative and androgen receptor positive invasive ductal carcinoma, Jpn. J. Clin. Oncol. 42 (5) (2012) 375–386. [19] M.L. Wallace, T.A. Longacre, B.R. Smoller, Estrogen and progesterone receptors and anti-gross cystic disease fluid protein 15 (BRST-2) fail to distinguish metastatic breast carcinoma from eccrine neoplasms, Mod. Pathol. 8 (1995) 897–901. [20] Z. Wang, M. Lu, G. Dong, et al., Penile and scrotal Paget’s disease: 130 Chinese patients with long-term follow-up, BJU Int. 102 (2008) 485–488.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching case
Recurrent apocrine carcinoma of the scrotum: A case report Davide Campobasso a , Elena Thai b,∗ , Antonio Barbieri a , Francesco Ziglioli a , Umberto Maestroni a , Giovanni Fellegara c , Roberto Ricci b a b c
Urology Unit, Surgical Department, University Hospital of Parma, Italy Surgical Pathology Unit, Oncology, Hematology and Internal Medicine, University Hospital of Parma, Italy Department of Anatomic Pathology, Italian Diagnostic Center (CDI), Milan, Italy
a r t i c l e
i n f o
Article history: Received 31 January 2014 Received in revised form 27 November 2014 Accepted 9 December 2014 Keywords: Apocrine Recurrence Scrotum
a b s t r a c t Apocrine carcinoma is a rare tumor of the skin that typically arises in areas rich in apocrine glands, such as axilla and perineum. The main differential diagnosis is a metastasis from a primary apocrine carcinoma of the breast. Several authors have attempted to define morphological and immunohistochemical parameters to differentiate metastasis from primary apocrine carcinoma of the skin, but none of these had been demonstrated to be reliable markers. Here, we report a case of primary apocrine carcinoma of the scrotum that relapsed three times within a few years, without any clinical or radiological evidence of any other tumor of breast or other sites. © 2014 Elsevier GmbH. All rights reserved.
Introduction Scrotal cancer is a rare tumor, especially after improvement of the hygienic conditions in industrial working places [9]. Recently, Johnson et al. [7] identified the incidence of scrotal cancer and assessed the impact of scrotal cancer histology on survival. A total of 766 patients with primary scrotal cancer were examined, the most common histological type was squamous cell carcinoma (35.1%), followed by Extramammary Paget’s Disease (EMPD) (21.9%), sarcoma (20.4%), basal cell carcinoma (16.7%), melanoma (3.3%) and adnexal skin tumors (2.6%). Although patients with adnexal skin tumors were classified as having high risk with low survival, the presence of a localized disease showed a relatively high survival, similar to that of EMPD, sarcoma and basal cell carcinoma. Apocrine carcinoma of the skin represents a rare group of sweatgland carcinomas. In general, it occurs in areas where apocrine glands or modified apocrine glands (ceruminous and Moll glands) are present (ano-genital regions, ear canal, scalp, mammary areola and axilla). It is an extremely rare tumor. Scrotal apocrine carcinoma is a slow-growing tumor with a tendency toward a prolonged course; it is able to metastasize to lymph nodes, lungs, liver, brain and bone [6].
∗ Corresponding author. Tel.: +39 0521702625. E-mail address: [email protected] (E. Thai). http://dx.doi.org/10.1016/j.prp.2014.12.010 0344-0338/© 2014 Elsevier GmbH. All rights reserved.
The symptoms are non-specific, often manifesting with scrotal eczema or dermatitis and pruritus. In many cases, diagnosis is delayed for these reasons. Solid or cystic masses and reddish purple subcutaneous nodules are often the first sign of presentation. We report a case of a 51-year-old man who underwent four scrotal resections between 2007 and 2013 for a primary apocrine carcinoma. Materials and methods After fixation in 10% buffered formalin, the surgical specimen, including the entire tumor, was sampled according to standard procedures and processed into paraffin. Serial 4-m thick sections were stained with hematoxylin–eosin (H&E) for conventional histology, periodic acid-Schiff (PAS) and PAS-diastase for mucin detection. Immunohistochemistry was performed on the paraffin sections with the following reagents: Ki-67 (MIB-1, DakoCytomation, Glostrup, Denmark), GCDFP-15 (EP1582Y, Ventana), S100 (4C4.9, Ventana), low molecular weight cytokeratins (CAM5.2, Ventana), CK5/6 (D5/16B4, Ventana), EMA (E29, Ventana), CEA (CEA 31, Ventana), E-cadherin (36, Ventana), estrogen receptor (SP1, Ventana), progesteron receptor (1E2, Ventana), PSA (polyclonal, Ventana), smooth muscle actin (1A4, Ventana), p53 (DO-7, Ventana), p63 (4A4, Ventana), d2-40 (d2-40, Ventana), androgen receptor (SP107, Ventana) and lysozyme (polyclonal, Ventana). Immunostaining was highlighted with a polymeric system (DAKO ADVANCE HRP)
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
265
Fig. 1. (A) The patient presented with multiple scrotal reddish and whitish nodules in the scrotum. (B) Grossly, the lesions were whitish plaque-like formations, with alternating solid and cystic areas. (C) Panoramic view of the tumor showed two distinct components, cystic and solid (H&E, 20×). (D) The cystic structures contained eosinophilic secretion, lined by cells with apocrine features, forming papillae tufting in the lumen (H&E, 400×). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
and finally visualized with 3,3 -diaminobenzidine (DAB) and counterstained with hematoxylin.
Case report A 45-year-old Caucasian man came to our attention in June 2007 with some rapidly growing bilateral scrotal nodules (Fig. 1A), present for a few months. The lesions, located at the right and left hemiscrotum, measured 4 cm and 3 cm in greatest diameter respectively, the largest one was ulcerated. At admission, the patient was well, and physical examination did not show any other remarkable lesion. The past history of the patient included surgery at the age of 6 for bilateral cryptorchidism. For more than 9 years, he had been working as a clerk in a plywood factory where different kinds of glue are commonly used. Routine laboratory studies were normal. Thoraco-abdominal computed tomography, bone scan and breast ultrasound were negative. He received local excision of 4 × 3 cm and 3 × 1.5 cm wide skin flaps, in both right and left hemi-scrotum. Grossly, the lesions were whitish plaque-like formations, with alternating solid and cystic areas (Fig. 1B). Histologically, two distinct components were evident at panoramic observation, cystic and solid (Fig. 1C). The cystic dilated structures contained eosinophilic, PAS positive-diastase resistant secretion, were bordered by cells with apocrine features (with abundant eosinophilic cytoplasm, “decapitation” secretion in the form of apical snouts, vesicular nuclei with prominent nucleoli)
forming papillae, tufting in the lumen and sometimes growing in a cribriform pattern (Fig. 1D). Infiltration and ulceration of the covering skin were present, with focal pagetoid spread (Fig. 2A). The solid component of the lesions was a malignant tumor infiltrating the dermis, with apocrine features, growing in tubular, cribriform and trabecular patterns (Fig. 2B and C). Cytologically, the cells had a more undifferentiated, high grade appearance. Endolymphatic emboli were evident (Fig. 2D). Hyperplastic apocrine glands were observed at the margins and intermixed with the malignant glandular structures. The apocrine nature of this malignant neoplasm was supported by the strong expression of GCDFP-15 and lysozyme. The tumor stained also positively for androgen receptor, low molecular weight cytokeratins, EMA, CK5/6 (focal) and E-cadherin. Immunostains for CEA, d2-40, S100, smooth muscle actin, p53, PSA, estrogen and progesteron receptors were negative. Immunohistochemical staining for P63 detected myoepithelial cells only at the basal layer of the normal and hyperplasic apocrine glands but was completely negative in the malignant component. Frequent atypical mitosis and cellular pleomorphism were evident in the less differentiated areas. All these findings were consistent with the diagnosis of multicentric apocrine adenocarcinoma of the scrotum associated with apocrine gland hyperplasia. The assumption of a metastasis from a mammary apocrine adenocarcinoma was excluded by an accurate clinical and instrumental examination of the patient. The patient developed three local recurrences in 2008, 2010 and 2013 respectively, all with the same diagnosis. The follow-up
266
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
Fig. 2. (A) Pagetoid spread of the covering skin (H&E, 200×). (B and C) The solid component of the tumor was constituted by neoplastic cells with apocrine features, growing in tubular, cribriform and trabecular patterns (H&E, 200×). (D) Neoplastic emboli were present in lymphatic vessels (H&E, 200×).
investigations with annual CT scan, breast US and chest X-ray every 6 months were negative. Discussion Apocrine adenocarcinoma is a rare malignant tumor of the sweat glands, with unknown etiology. Sweat gland carcinomas have a peak of incidence in the fifth and sixth decades of life [11]. The lesions tend to arise in areas with high concentration of apocrine sweat glands, like the axilla and, less frequently, the anogenital region, followed by trunk (26.4%), head and neck (18.3%) and lower extremities (13.9%) [3,5]. It is a slow growing lesion, with low overall mortality, despite frequent recurrences and regional lymph nodes metastasis. Distant metastasis may be a late event. Therefore, prolonged follow-up is mandatory [8]. Benign apocrine carcinoma is much more common than the malignant counterpart. The presence of metastasis or a history of a rapidly growing lesion may help in the diagnosis of malignant apocrine carcinoma. Histological features, such as an infiltrative growth pattern, cytologic atypia, vascular invasion and mitotic activity, generally allow for assessment of malignancy [8]. Anyway, reliable predictive factors have not been established yet. The main differential diagnosis is a metastasis from a mammary apocrine carcinoma. Apocrine carcinomas of the skin and breast are androgen receptor-positive [2]. Recently, adipophilin has been reported to be positive in 88% of mammary apocrine carcinomas versus 36% of cutaneous apocrine carcinomas [13]. Our case stained positively for androgen receptor, but excluding the possibility of a metastasis is needed.
Apocrine carcinoma of the breast is very rare, with an incidence of <1% of female invasive breast carcinomas [4]. It tends to show estrogen and progesterone receptor negativity and expression of Gross cystic disease protein fluid-15 (GCDPF-15) [18]. This pattern is analogous to primary skin apocrine carcinoma. Therefore, it is impossible to make a differential diagnosis exclusively on currently used pathological parameters. Moreover, it has been demonstrated that that gross cystic disease fluid protein-15, ER, PR, and Her2/neu have all been shown to be expressed in cutaneous adnexal neoplasms as well [19], which is why these markers cannot be used to distinguish primary from metastatic apocrine carcinoma. Several authors have attempted to identify additional immunohistochemical markers that can help to distinguish primary from metastatic skin adnexal carcinomas. These included p63 and CK5/6, which have been demonstrated to be relatively specific and sensitive for primary cutaneous adnexal neoplasms [14]. Some authors have proposed other immunohistochemical markers, like p63, d2-40 and CK15 to distinguish metastasis from primary adnexal carcinoma [10]. According to these authors, a positivity to these markers should be in favor of primitivity. In our case, only a focal positivity for CK5/6 was assessed, while all the other markers were negative. Nevertheless, in the paper by Mahalingam et al. [10], two cases of apocrine carcinomas were negative for p63; thus, in accordance with our finding. Moreover, there was no clinical, ecographic and radiological evidence of a primary carcinoma of the breast or other sites, questioning the reliability of immunohistochemistry to make a correct diagnosis. As long as new data are not available, morphological and clinical features are still our main diagnostic means. Pagetoid epidermal spread is uncommon in apocrine carcinoma [16,17], it can help to confirm the primitivity of the lesion, but
D. Campobasso et al. / Pathology – Research and Practice 211 (2015) 264–267
nevertheless cannot exclude a cutaneous metastasis [1]. In our case, the presence of foci of intraepithelial pagetoid diffusion, together with clinical and radiological exclusion of other neoplasms, helps to confirm the primitivity of the tumor. Extramammary Paget Disease (EMPD), similarly to the mammary counterpart, is an intraepidermal adenocarcinoma characterized by large atypical and pale staining cells scattered throughout the epidermis, in a single cell fashion or in small clusters. It is thought to derive from apocrine glands or epidermal basal stem cells. Unlike mammary Paget disease, most cases of EMPD do not show underlying malignancies. Anyway, no accurate epidemiologic data is available yet for EMPD. Tumors associated with EMPD include rectal adenocarcinoma, transitional cell carcinoma of urethra and bladder, carcinoma of the Bartholins glands, prostate adenocarcinoma, cutaneous adnexal carcinoma and carcinoma of the vagina and cervix [8]. In our case, the presence of bilateral scrotal lesion and the coexistence of apocrine gland hyperplasia gave rise to the hypothesis that unknown genetical or environmental factors may act as promoters, stimulating apocrine gland proliferation. Given the well-known role that hormonal factors play in the development of apocrine glands and given the expression of androgen receptor in neoplastic apocrine cells [2], we hypothesize that an endocrine disequilibrium could play a central role in the genesis and progression of apocrine carcinoma of the skin. Overall mortality is low. Complete surgical resection is the treatment of choice. Positive surgical margins remain one of the most important risk factors for local recurrence of the tumor. Some authors [20] suggest multiple biopsies with 3 cm-free margins to decrease recurrence in scrotal EMPD. Regional lymph node dissection must be considered in the presence of clinically positive nodes. Lymph nodes metastases are present in 16% of cases, and it is associated with worse prognosis. If lymph node metastases are present, chemotherapy is mandatory, but at present there is no consensus on the chemotherapy regimen [12,15]. Conclusion Apocrine carcinomas tend to arise in areas with high concentration of apocrine sweat glands, such as the axilla and anogenital region. They are slow growing lesions with low overall mortality, despite frequent recurrences and regional nodes metastasis. Diagnosis is often delayed until the appearance of regional lymph nodes involvement or skin ulceration. Distant metastasis may be a late event and associated with poor prognosis; therefore, prolonged follow-up is mandatory [8]. Anyway, reliable predictive factors have not been established yet. A wide surgical excision with multiple biopsies is the treatment of choice. Regional lymphadenectomy is mandatory in the presence of lymph nodes
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