To the Editor:
We have read with interest the report by Cangelosi et al1 on a rare cutaneous adnexal tumor with an unusual presentation.
In the report, the authors mentioned a metastatic breast carcinoma as their first challenging diagnostic alternative, because the patient had a history of invasive ductal carcinoma of the breast. Among the antibodies included in their immunohistochemical panel, they used mammaglobin, which failed to stain the tumor.
The authors also mentioned how the tumor showed conspicuous glandular differentiation, and although it was not shown at high power, it seems to us that figure 3A demonstrates some decapitation secretion in the ductular structures. This is not incompatible with the diagnosis proposed by the authors of porocarcinoma (a tumor thought in the past as “eccrine”). Recently, some groups have demonstrated apocrine features in poroid neoplasms.2
The differential between cutaneous metastases from breast carcinoma and a primary cutaneous adnexal tumor is one of the most difficult tasks in the field of dermatopathology, and immunohistochemistry has only been partly helpful in solving this conundrum. In some instances, the expression of certain markers, may give a clue to the possible primary cutaneous tumor. That is the case of p63, one of the most promising markers in this respect.3-5 However, that is not always the case with cutaneous apocrine carcinoma (CAC), one of the most elusive primary cutaneous malignancies. CAC does not usually express p63, and its metastases are also commonly negative for such a marker.5
In the past, it was suggested that the expression of estrogen receptors (ER)−, progesterone receptors (PR)−, androgen receptors (AR)+, was very suggestive of an apocrine phenotype. However, Robson et al6 studied a large series of CACs and demonstrated that 62% were ER+, 60% were PR+, and 36% were AR−.
Something similar happened to the marker for gross cystic disease fluid protein 15 (GCDFP-15). It was once thought as a useful marker to detect neoplasms of mammary origin.7,8 In fact, many of the CACs reported have shown a weak and focal expression of GCDFP-15,9 or have failed to show any expression of the marker at all.10-13 This is despite the fact that GCDFP-15 is considered as a very specific marker for apocrine differentiation.7,11 Nevertheless, in a series, GCDFP-15 failed to mark 4 ductal breast carcinomas, whereas it marked the only CAC studied.14
Other markers are, as well, of relative help when facing a possible CAC. Cytokeratin (CK) 5/6, for instance, is usually expressed strongly and diffusely by primary cutaneous adnexal neoplasms.15 On the contrary, only a small percentage of cutaneous metastases express CK 5/6 and they usually do it weakly.3 Nevertheless, we now know that breast carcinoma can express CK 5/6 and it usually carries a bad prognosis.16
CK7 is another marker commonly used to differentiate between a primary cutaneous adnexal tumor and a metastasis: Focal CK7 expression is suggestive of a primary adnexal tumor, whereas diffuse immunostaining is mainly seen in metastases.15 Nevertheless, some have not found it useful, unless used as a part of an antibody panel.15 Moreover, CK7 can be strongly and diffusely expressed by primary CAC.17
Epidermal growth factor receptor is another example in this long list. It was once demonstrated as more frequently expressed in sweat gland carcinomas than in breast carcinomas.18 Nevertheless, some series have demonstrated expression of epidermal growth factor receptor by up to 22% of their cases of primary mammary carcinomas.18,19
One of the reasons why the differential diagnosis between metastatic breast carcinoma and primary CAC is so complex is that, as some authors have recently insisted, that the mammary gland is nothing but a modified apocrine gland.20-22 Despite this, there are some immunohistochemical clues that may help to solve this complicated problem.
We have recently used mammaglobin in a small series of CACs, with promising results in the differential with a metastatic breast carcinoma.22 In our study, breast carcinomas expressed diffusely and intensively the marker, whereas CAC showed only scattered positive cells. Nevertheless, nearly half of our breast carcinomas also showed the same immunostaining pattern as CAC. We therefore concluded that the marker had a great value when positive, then favoring a metastasis. On the contrary, a negative staining or one with only scattered positive cells would not be conclusive.
Our biggest limitation was the few number of CACs studied, because this is not a common tumor. For instance, a recent publication, involving several institutions from all over the world, achieved to collect 24 cases of CACs.6 Despite this difficulty, immunostaining with mammaglobin on a larger series of CACs would be of great interest to corroborate or deny the pattern of staining that we found. We have expectations about the possible forthcoming results.
Mammaglobin is a 93 amino acids protein, which originally was identified in breast carcinoma cell lines,23 and is secreted as a glycosylated peptide.24 Some have asserted that “mammaglobin does not seem to be a useful stain to distinguish breast from sweat gland carcinomas.”25 The assertion by these authors was based on the expression of mammaglobin by 4/10 skin sweat gland carcinomas investigated.25 However, the expression was patchy (as in our study) in 2 cases. Moreover, the authors did not mention if the other 2 cases (which showed a diffuse pattern) were CACs or any other type of sweat gland carcinomas. This latter point is quite relevant: First, because CAC is usually the most difficult one to distinguish from a breast carcinoma. Second, because normal apocrine glands show a scattered expression of mammaglobin, whereas eccrine glands show strong cytoplasmic staining of the coiled cells.26 Therefore, it would be expected that allegedly eccrine tumors express mammaglobin in a strong way, whereas apocrine tumors do it in a scattered way. Nevertheless, to the best of our knowledge, the answer to that hypothesis is not known. Some reports on mammaglobin and sweat gland tumors have centered on allegedly apocrine tumors, such as hidradenoma papilliferum or apocrine hidrocystoma.27 Cylindroma did not show expression of mammaglobin or expressed the marker by a few small groups of cells.27 Therefore, this does not satisfactorily answer the question, because cylindroma has been alleged to be eccrine by some28-32 and apocrine by others.33,34
We are planning to investigate some phenotypic and molecular aspects of CACs, which includes their mammaglobin expression. We need to collect as many cases as possible. Therefore, we would be grateful about any cases of CAC (paraffin block) which could be sent to our address during this current year, accompanied by minimal clinical information. Needless to say that all blocks will be returned.
Angel Fernandez-Flores, MD, PhD
Service of Cellular Pathology, Clinica Ponferrada, Ponferrada, Spain
1. Cangelosi JJ, Nash JW, Prieto VG, et al. Cutaneous adnexal tumor with an unusual presentation-discussion of a potential diagnostic pitfall. Am J Dermatopathol
2. Kazakov DV, Kutzner H, Spagnolo DV, et al. Sebaceous differentiation in poroid neoplasms: report of 11 cases, including a case of metaplastic carcinoma associated with apocrine poroma (sarcomatoid apocrine porocarcinoma). Am J Dermatopathol
3. Plumb SJ, Argenyi ZB, Stone MS, et al. Cytokeratin 5/6 immunostaining in cutaneous adnexal neoplasms and metastatic adenocarcinoma. Am J Dermatopathol
4. Ivan D, Diwan AH, Prieto VG. Expression of p63 in primary cutaneous adnexal neoplasms and adenocarcinoma metastatic to the skin. Mod Pathol
5. Ivan D, Nash JW, Prieto VG, et al. Use of p63 expression in distinguishing primary and metastatic cutaneous adnexal neoplasms from metastatic adenocarcinoma to the skin. J Cutan Pathol
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6. Robson A, Lazar AJ, Ben Nagi J, et al. Primary cutaneous apocrine carcinoma: a clinico-pathologic analysis of 24 cases. Am J Surg Pathol
7. Watson MA, Dintzis S, Darrow CM, et al. Mammaglobin expression in primary, metastatic, and occult breast cancer. Cancer Res
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12. Nishikawa Y, Tokushashi Y, Saito Y, et al. A case of apocrine adenocarcinoma associated with hamartomatous apocrine gland hyperplasia of both axillae. Am J Surg Pathol
13. Wick MR, Ockner DM, Mills SE, et al. Homologous carcinomas of the breast, skin, and salivary glands. A histologic and immunohistochemical comparison of ductal mammary carcinoma, ductal sweat gland carcinoma, and salivary duct carcinoma. Am J Clin Pathol
14. Ansai S, Koseki S, Hozumi Y, et al. An immunohistochemical study of lysozyme, CD-15 (Leu M1), and gross cystic disease fluid protein-15 in various skin tumors. Assessment of the specificity and sensitivity of markers of apocrine differentiation. Am J Dermatopathol
15. Qureshi HS, Ormsby AH, Lee MW, et al. The diagnostic utility of p63, CK5/6, CK7, and CK20 in distinguishing primary cutaneous adnexal neoplasms from metastatic carcinomas. J Cutan Pathol
16. Shin BK, Lee Y, Lee JB, et al. Breast carcinomas expressing basal markers have poor clinical outcome regardless of estrogen receptor status. Oncol Rep
17. Fernandez-Flores A, Pol A, Juanes F, et al. Immunohistochemical phenotype of cutaneous cribriform carcinoma with a panel of 15 antibodies. Med Mol Morphol
18. Busam KJ, Tan LK, Granter SR, et al. Epidermal growth factor, estrogen, and progesterone receptor expression in primary sweat gland carcinomas and primary and metastatic mammary carcinomas. Mod Pathol
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20. Ackerman AB, Kessler G, Gyorfi T, et al. Contrary view: the breast is not an organ per se, but a distinctive region of skin and subcutaneous tissue. Am J Dermatopathol
21. Ackerman AB. The breast is not an organ. Am J Dermatopathol
22. Fernandez-Flores A. Mammaglobin immunostaining in the differential diagnosis between cutaneous apocrine carcinoma and cutaneous metastasis from breast carcinoma. Cesk Patol
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25. Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin vs GCDFP-15: an immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol
26. Sasaki E, Tsunoda N, Hatanaka Y, et al. Breast-specific expression of MGB1/mammaglobin: an examination of 480 tumors from various organs and clinicopathological analysis of MGB1-positive breast cancers. Mod Pathol
27. Sjödin A, Guo D, Hofer P-A, et al. Mammaglobin in normal human sweat glands and human sweat gland tumors. J Invest Dermatol
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29. Penneys NS, Kaiser M. Cylindroma expresses immunohistochemical markers linking it to eccrine coil. J Cutan Pathol
30. Reynes M, Puissant A, Delanoe J, et al. Ultrastructural study of cylindroma (Poncet-Spiegler tumor). J Cutan Pathol
31. Kwittken J. The hyaline eccrinoma. Mt Sinai J Med
32. Cotton DW, Braye SG. Dermal cylindromas originate from the eccrine sweat gland. Br J Dermatol
33. Hashimoto K, Lever WF. Histogenesis of skin appendage tumors. Arch Dermatol
34. Tsambaos D, Greither A, Orfanos CE. Multiple malignant Spiegler tumors with brachydactyly and racket-nails. Light and electron microscopic study. J Cutan Pathol
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