Two for one! (VI)
Usually, a section of tissue that comes into a dermatopathology laboratory is “signed out” with just one diagnosis. Sometimes, however, more than one disease may be present in a specimen, and those conditions may either exist next to each other or they may overlap each other in a manner that makes it difficult to come to a specific diagnosis.
The biopsy shown in Figures 1-24 comes from the chest of a 42-year-old woman. It had clinically been a pigmented plaque overlying a firm nodule appreciated on palpation. What is your diagnosis of this lesion? Or, is there more than one disease to be diagnosed in this specimen?
What is your diagnosis of this lesion? Or, is there more than one disease to be diagnosed in this specimen?
Answer and explanation
Melanoma and fibrocystic breast disease.
There is an asymmetric proliferation of melanocytes located in the epidermis and superficial dermis. It consists of large irregularly shaped nests of epithelioid melanocytes joined by single melanocytes in the basal layer and scattered in suprabasal layers. In foci, the epidermis is almost replaced by the proliferation of melanocytes. Melanocytes are rich in cytoplasm and have enlarged and pleomorphic nuclei. Nests of melanocytes are also present in the upper part of the dermis joined by thickened collagen, melanophages, and a band-like, lymphohistiocytic infiltrate. A zone of mucinous fibrosis separates the proliferation of melanocytes from a second proliferation with similar features but a bit more regular architecture. The findings are diagnostic of melanoma with a zone of regression. Below the melanoma, bundles of muscle indicate the site of the excision, namely, the breast. A second lesion is present in the deeper parts of the excision. Fibrosis is accompanied by proliferation of ducts, blunt duct adenosis, apocrine metaplasia and hyperplasia with small papillary tufts (papillary apocrine change), and cysts, typical of fibrocystic breast disease.
Melanoma of the skin of the breast is rare. It accounts for less than 5% of all cutaneous melanomas.  In a study on 2,824 patients with melanoma, the incidence for lesions on the breast was 0.28%  The most common site of primary melanoma among women is the lower extremities, followed by the trunk, upper limbs, and finally head and neck, according to a recent large-scale prospective epidemiological study which involved almost three million individuals in Sweden followed for 16 years.  Results of a US national epidemiology study more than 20 years ago based on over 13,000 cases of cutaneous melanomas are very similar. Data indicates that melanoma incidence on the trunk, arm, and leg is not connected with cumulative sun exposure, which suggests factors other than cummulative sun exposure play an important etiological role. 
The skin of the breast is considered to be a so-called “special site” for pigmented skin lesions, just as are the mucosa, acral skin, and flexural areas.  According to the literature, melanocytic nevi located on these sites express somewhat different architectural features when compared with those of other sites. In a study which investigated 101 melanocytic nevi from the breast and 97 from other localizations, breast nevi exhibited significantly more suprabasal melanocytes, pleomorphic melanocytes, and dermal fibroplasia.  Nevertheless, a diagnosis of melanoma can be made straightforwardly in the lesion presented here because of the asymmetry, the irregularity of proliferations, the focal replacement of the epidermis by the proliferation of melanocytes, and the zones of regression.
In decades past, melanoma of the breast used to be treated with radical mastectomy, but a study of Roses et al. in 1977 of 21 patients with melanoma of the breast, optimal tumor control with improved functional and cosmetic results was achieved by wide and deep excision of the lesion down to and including the fascia of the underlying pectoralis major muscle in continuity axillary lymph node dissection in selected instances.  In the largest collection of melanomas of the breast the authors suggested that melanomas of the breast followed different metastatic patterns than primary carcinoma of the breast and required a different therapeutic approach. Lesions located below 3 cm from the clavicle metastasized exclusively to the axillary nodes regardless of the location. Microstaging of the primary lesion correlated closely with prognosis and lymph node metastasis. Treatment by mastectomy (radical, modified, extended radical) offered no advantage over local excision of the primary plus axillary dissection.  In a study of 14 primary malignant melanomas arising in the nipple and areola of the breast, four patients had axillary node involvement and all were dead within three years of the operation, while the 10 patients with no axillary node involvement were free from recurrent disease five years after surgery. The authors concluded that a wide local excision without mastectomy is adequate for treatment of nipple and areola melanomas.  Turkish authors described 12 cases of melanoma on the breast. Nine of these cases were primary melanomas while the others were metastases from a distant cutaneous melanoma. Clinical follow-up was available in all patients ranging from 10-60 months (median 24 months). Five patients died of disseminated disease and six patients were alive without clinical evidence of disease and one with disease at the time of the report. The authors suggested that melanoma on the breast should be treated exactly the same way as melanoma on other sites of the body, namely, with wide excision of the primary site and sentinel lymph node biopsy. 
Fibrocystic disease of the breast affects up to 50% of clinically normals breast and 25-40% of cancer-bearing breast.  It is rare before the age of 30 and usually affects both breasts. With menopause, the symptoms of fibrocystic disease usually disappear. To date, there is no evidence that fibrocystic breast disease is associated with a higher incidence of cutaneous melanoma. In a large prospective population study which included 91,965 subjects, breast adenoma/fibroadenoma /fibrocystic breast disease were not significantly associated with melanoma risk. The situation with some other gynecological conditions was different: a positive association between a history of gynecological conditions, endometriosis and uterine fibroma, and melanoma risk is established. Hormonal factors might be responsible for these connections, but endometriosis and melanoma may be related also through common genetic factors. 
In contrast to the situation with fibrocystic breast disease, it also has been shown that among patients with cutaneous melanoma, the incidence of breast cancer is higher than in the general population. In a large population study which included 26,916 skin cancer patients from the Netherlands (including 3,508 with cutaneous melanoma), those with cutaneous melanoma exhibited an increased risk for breast cancer, especially for advanced breast cancer. For women with a previous cutaneous melanoma at age 60 or older, the risk for breast cancer was almost twofold.  The authors explained this association with common risk factors for melanomas and breast cancer, such as higher socioeconomic status,  fewer children, older age at first child birth,  and, probably, higher medical culture (regular medical checkouts, screening procedures). Genetic factors may also contribute to the elevated risk (BRCA2 mutations). [16,17]
Malignant melanoma is among the most prevalent malignances in the developed world. However, melanoma on the skin of the breast is an unusual finding. Literature review provided few studies with larger series of melanomas on the breast. Authors agreed that microstaging of primary disease remains to be the most important prognostic factor for melanomas located on the breast, just as it is the case for melanomas on other localizations.
The presence together of the breast skin disease and fibrocystic breast disease is coincidental. However, the breast region is a unique location; it is a skin appendage derived from ectoderm. The specimen presented here shows that dermatopathologists need to have some knowledge of breast pathology so as not to miss or to misdiagnose the second lesion in this slide.
Aida Kapetanovic, M.D., is from the Department of Dermatology, Clinical Center of the University of Sarajevo; Semir Vranic, M.D., is from the Department of Pathology of the same clinic in Sarajevo, Bosnia and Herzegovina. This article was reviewed by Rajalakshmi Tirumalae, M.D., and Almut Böer-Auer, M.D. Contact author via email: firstname.lastname@example.org .
We presented a specimen excised from the breast of a 42-year-old woman in which a melanoma is present together with fibrocystic breast disease. Less than 5% of cutaneous melanomas arise on the breast skin. Large epidemiologic prospective studies show that some benign gynecologic conditions, i.e., endometriosis, are associated with higher incidence of cutaneous melanoma. However, no such association has been demonstrated for fibrocystic breast disease. Treatment and prognosis of melanoma of the breast skin are the same as on any other localization. The co-morbidity of the two diseases presented here is mere coincidence but shows that dermatopathologists need to have some knowledge of breast pathology so as not to miss or to misdiagnose the second lesion in this slide.
1. Knutson CO, Hori JM, Spratt JS. Melanoma. Curr Probl Surg.1971;12:1.
2. Ariel IM, Caron AS. Diagnosis and treatment of the malignant melanoma arising from the skin of the female breast. Am J Surg 1972;124:384.
3. Pérez-Gómez B, Aragonés N, Gustavsson P, Lope V, López-Abente G, Pollán M. Socio-economic class, rurality and risk of cutaneous melanoma by site and gender in Sweden. BMC Public Health. 2008;8:33.
4. Newwll GR, Sider JG, Bergfelt L, Kripke M. Incidence of cutaneous melanoma in the United States by histology with special reference to the face. Cancer Research. 1988;48: 5036-5041.
5. Massi G, LeBoit P. Histological Diagnosis of Nevi and Melanoma. Darmstadt: Steinkopf, 2004.
6. Rongioletti F, Urso C, Batolo D, et al. Melanocytic nevi of the breast: a histological case-control study. J Cutan Pathol. 2004;31:137-140.
7. Roses DF, Harris MN, Stern JS, Gumport SL. Cutaneous melanoma of the breast. New York: American Cancer Society, 1977.
8. Papachristou DN, KinneDW, Rosen PP, Ashikari R, Fortner JG. Cutaneous melanoma of the breast. Surgery.1979;85(3):322-28.
9. Papachristou DN, Kinne D, Ashikari R, Fortner JG. Melanoma of the nipple and areola. Br J Surg. 1979;66(4):287-8.
10. Kurul S, Ta_ F, Büyükbanani N, Mudun A, Baykal C, çamlica H. Different manifestations of malignant melanoma in the breast: a report of 12 cases and a review of the literature. Jpn J Clin Oncol. 2005;35(4):202-206.
11. Boecker W. Preneoplasia of Breast: A New Conceptual Approach to Proliferative Breast Disease. Philadelphia: Saunders 2006:31.
12. Kvaskoff M, Mesrine S, Fournier A, Boutron-Ruault MC, Clavel-Chapelon F. Personal history of endometriosis and risk of cutaneous melanoma in a large prospective cohort of French women. Arch Intern Med. 2007;167(19):2061-2065.
13. Soerjomataram I, Louwman WJ, Lemmens VEPP, Coebergh JWW, de Vries E. Are patients with skin cancer at lower risk of developing colorectal or breast cancer. Am J Epidemiol. 2008;167:1421-29.
14. MacKie RM, Hole DJ. Incidence and thickness of primary tumors and survival of patients with cutaneous malignant in relation so socioeconomic status. Br Med J. 1996;312:1125-8.
15. Braaten T, Weiderpass E, Kumle M, et al. Education and risk of breast cancer in the Norwegian-Swedish women’s lifestyle and health cohort study. Int J Cancer. 2004;110;579-83.
16. Monnerat C, Chompret A, Kannengiesser C, Avril MF, Janin N, Spatz A, Guinebretiere JM, Marian C, Barrois M, Boitier F, Lenoir GM, Bressac-de Paillerets B. BRCA1, BRCA2,TP53, and CDKN2a germline mutationsin patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6(4):453-61.
17. Nagore E, Montoro A, Garcia-Casado Z, Bottela-Estrada R, Insa A, Lluch A, López-Guerrero JA, Guillén C. Germline mutations in CDKN2A are infrequent in female patients with melanoma and breast cancer. Melanoma Res. 2009;19(4):211-4.