Clinical s tud y Cutaneous metastatic breast carcinoma Cutarieous metastatic breast carcinoma: A study of 164 patients C. Mordenti, K Peris, M. Concetta Fargnoli, L. Cerroni and S. Chimenti ABSTRACT Background. Cancer metastasis represents the most devastating aspect of malignancy since mortality of tumor patients is mainly related to the metastatic behavior of the primary neoplasm. Excluding mela- noma, the most common tumor to metastasize to the skin is breast cancer. Materials and Methods. We examined retrospectively the clinical, histopathologic and immunohisto- chemical features of 164 cases of skin metastases tram breast carcinoma. Results. Glinica! features included papules and/or nodules in 131 patients (80%), telangiectatic carcinoma in 19 (11.2%), erysipeloid carcinoma in 5 (3%), "en cuirasse" carcinoma in 5 (3%), alopecia neoplastica in 3 (2%) and a zosteriform pattern in 1 patient (0.8%). Sites of cutaneous metastases were the trunk (145), head and neck (14) and extremities (5). Histopathologic features of adenocarcinoma with varying degrees of celi differentiation were observed although distinctive findings were associated with each clinical pattern. lmmunohistochemical studies showed a positive staining with anti-cytokeratin and anti-EMA antibodies whereas reactivity with anti-CEA was detected in 11 O of 164 cases (67%). Conclusion. In conclusions, cutaneous metastatic breast carcinoma is characterized in most cases by suggestive clinical and histopathologic features and is usually associated with late stages of the disease. Introduction Cancer metastasis represents the most devastating aspect of malignancy since mortality of tumor patients is mainly related to the metastatic behavior of the primary neoplasm. The process of metastasis deve- lopment involves a cascade of sequential steps, each of which has to be successfolly completed in order to pro- ceed to tumor progression. Malignant cells dissociate from the prima1y tumor, invade the surrounding extra- cellular matrix, attach to bost cellular and extracellular determinants and promote enzymatic degradation of barriers, such as the basement memb,:ane, to permit extravasation into the blood o r lymphatic system. Furthermore, locomotion within the vessels followed by attachment to the target organs is an essential step in the development of metastasis. Nevertheless, t11mor cells that eventually give rise to metastasis must evade des- Acta Dermatoven APA Vol 9, 2000, No 4 - - --- - - - - - ------- - 143 Cutaneous metastatic breast carcinoma truction by bost defenses, including specific and non- specific immune responses (1-3). Cutaneous metastases from visceral malignancies are relatively rare. The overall incidence is estimated to ran- ge from 0.7%-10.4% (4, 5). This discrepancy is likely due to the characteristics of the selected patients in each study, the types of tumor included in the statistics and the tirne of clinicopathological evaluation. In addition, the frequency of cutaneous metastases varies according to the incidence of the primary tumor. Excluding mela- noma, the most common tumor to metastasize to the skin is breast cancer with an incidence of 23.9% and this correlates well with the frequency of occurrence of the primary tumor itself in women. In this study, we examined retrospectively the cli- nical, histopathologic and immunohistochemical fea- tures of cutaneous metastatic breast carcinoma. Materials and methods A series of 164 cases of skin metastases from breast carcinoma observed at the Departments of Dermatology of the Universities of L' Aquila, Italy, and Graz, Austria, were reviewed. Cutaneous metastases from breast carcinoma were defined as direct extension from the primary tumor or as non-continuing spread of tumor cells through lymphatic or blood vessels. Ali patients were women aged 37-87 y (mean age: 62 y). In each case, tissue sections were stained with hematoxylin and eosin for histopathologic examination. Immunohisto- ·chemical studies were performed on paraffin sections using a three-step immunoperoxidase technique with PKK-1 , AE-1/ AE-3, LU-5, CK, EMA and CEA monoclonal antibodies. Results Clinical jeatures Metastatic cutaneous lesions were located at the site of mastectomy in 50 patients and elsewhere on the anterior aspect of the chest in 75, axilla (8), back (8), scalp (5), periauricular area (5), supraclavicular area ( 4), face (2), neck (2), upper (3) and lower (2) extremities. In ali patients, appearance of cutaneous lesions followed the diagnosis of breast carcinoma (range: 2 months-8 years; mean: 4.1 years). Cutaneous lesions did not occur as a first sign of the disease in any of the patients examined. Clinical features included papules and/ or nodules in 131 patients (80%), telangiectatic carcinoma in 19 (11.2%), erysipeloid carcinoma in 5 (3%), "en cuirasse" carcinoma in 5 (3%), alopecia neoplastica in 3 144 Figure 1. Multiple metastatic nodules at the site of mastectomy. (2%) and a zosterifom pattern in 1 (0.8%). Nodular car- cinoma, which was the most frequent clinical presen- tation, appeared as cutaneous or subcutaneous, solitary or multiple, pink to reddish, firm, rarely ulcerated nodules. Lesions were mainly located over the chest wall although face, neck, upper and lower extremities were involved too (Fig. 1). Telangiectatic metastatic breast carcinoma was characterized by purpuric papules, nodules or plaques on the trunk usually located in continuity with the surgical scar (Fig. 2). Erysipeloides Figure 2. Erythematous nodule located on the chest wall. Clinical study Acta Dermatoven APA Vol 9, 2000, No 4 Clinical siudy or inflammatory metastatic carcinoma presented as an erythematous, warm, tender patch or plaque with a raised well-defined margin affecting the breast and the surrounding skin. "En cuirasse" metastatic carcinoma appeared as an infiltrated and extensive plaque in the • mammary region (Fig. 3). Metastatic lesions of the scalp were observed in 3 patients as asymptomatic, red to pink, well-demarcated nodules or plaques resulting in circumscribed areas of hair loss, also referred as alopecia neoplastica. A zosteriform distribution of papulovesicles over the right breast occurred in 1 patient. Histopathologic and immunohistochemical findings In all skin biopsy specimens, histopathologic fea- tures of adenocarcinoma with varying degrees of cell differentiation were observed. The most frequent histo- pathologic findings were single or multiple nodules located in the dermis and subcutaneous tissue , com- Figure 3. "En cuirasse" metastatic carcinoma appearing as an infiltrated, extensive plaque with papules and nodules on the anterior chest wall. Figure 4. Histopathologic examination of a cutaneous metastasis from breast carcinoma reveals dennal aggregates of neoplastic cells arranged in a gland-like pattern (H&E; x250). Figure 5. Positivity of neoplastic cells for pan- cytokeratins (LUS; x200). Cutaneous metastatic breast carcinoma ... ' • ... Acta Dermatoven APA Vol 9, 2000, No 4 ------------- - - - -- 145 Cutaneous metastatic breast carcinoma posed of small to large aggregates of tumor cells su- rrounded by fibrosis. Neoplastic cells were typically arranged in gland-like structures (Fig. 4) or in a linear distribution between collagen bundles in an "indian file" pattern. Telangiectatic carcinoma was characterized by aggregates of tumor cells and erythrocytes as well as dilated blood vessels in the papillary dermis . In erysi- peloici ca rcinoma, histopathologic features were meta- static cells tigbtly packed within d ilatecl superficial ancl deep lympbatic vessels ancl a sligbt perivascular infiltrate of lymphocytes ancl plasma cells . In carcinoma "en cuirasse", fibrosis witb few neoplastic cells sometimes exbibiting a cbaracteristic "inclian file " pattern was de- tected. Histopatbologic findings of noclular carcinoma or "en cuirasse" carcinoma associatecl with atropby of tbe hair fo ll icle as a result of fibrosis were observecl in metastatic lesions of the scalp. Finally, an epidermo- tropic pattern cbaracterizecl by neoplastic cells, single or in small nests, within tbe epidermis and dermal aggre- gates o f neoplastic cells in a sclerotic stroma was iclen- tified in 7 / 164 patients (4%) . Immunohistocbemical investigations sbowed in ali patients a strong positivity of tumor celi s for pan-cyto- keratins (PKKl, AEl/ AE3, LUS , CK) and epithelial mem- brane antigen (EMA) (Fig. S). In acldition, a positive reaction for carcinoembryonic antigen (CEA) was detected in 110/164 oftbe cases (67%) . Discussion Cutaneous involvement from breast ca rcinoma preferentially occurs in the skin overlying or proximal to tbe area of the prima1y tumor by direct extension or througb lympbatic vessels. Nodular carcinoma, infla- mmato1y or e1ysipeloides _carcinoma, telangiectatic and "en cuirasse" carcinoma are the typical clinical manife- stations of tbe lymphatic dissemination to tbe skin. Inflammato1y carcinoma occurs w ben neoplastic cells disseminate through the lymphatics of the entire tbickness of the dermis and subcutaneous tissue. In con- trast, telangiectatic carcinoma is cbaracterized by disse- mination tbrougb superficial lymphatics and blood vessels of the c\ermis. In nodular carcinoma and "en cuirasse" carcinoma, the tumor celi.s disseminate largely along tissue space5 and only to a minor clegree tbrougb lympbatic vessels (6). Altbougb tbe above mentionecl clinical man ifesta tions are bigbly suggestive of cutane- ous metastatic breast carcinoma, tbey may mimic a varie ty of benign anc\ malignant cutaneous disorders as well as occur with cancers of otber organ.s. Inflammato1y skin metastases may clinically resemble e1ysipelas but, in contrast to trne infection, there is no fever, cbills and leukocytosis, and bacterial cultures are negative (7-11). 146 This clinica l pattern may also develop with cancers from other site.s such as pancreas, colon and rectum, lung, ova1y, prostate ancl parotid glancl. Telangiectatic lesions bave also been reported in carcinoma of tbe uterine cervix ancl parotid gland, and "en cuirasse" metastatic carcinoma may rarely be seen in kidney, lung and ga- strointestina l malignancies. Hematogenous spread of neoplastic cells is responsible for alopecia neoplastica, wbich may simulate alopecia areata, sebaceous cyst, scleroderma, morpbea-like basal celi carcinoma and cliscoicl lupus e1ythematosus (12 ,13). Unusual and nonspecific clinical appearances of cutaneous metas tatic breast carcinoma have been described. A zosteriform eruption, as observed in one of our patients, bas been rarely reportecl and most likely results from a perineural lymphatic metastatic disse- mination (14,15) . The dermatomal distribution ofvesi- cular lesions may clinically resemble herpes zoster. However, the site of cutaneous lesions, the p resence of malignant cells within the vesicles ancl a negative vira! PCR or culture allow to establish the definite diagnosis of cutaneous metastasis. Metastatic breast carcinoma presenting as a recklish nodule on the tip of tbe nose bas been clescribed and defined "clown nose" for its peculiar clinical feature (16). In addition, breast cancer of the inframammary crease may appear, mainly in women w ith pendulous breast, as cu taneous exophytic nodules clinically suggestive of a prima1y cutaneous squamous or basal cell carcinoma (17). Finally, meta- static breast cancer in the eyelicl has been reported as a painless swelling of tbe eyelicl associated with inclu- ration or noclule formation . Histologically, it may show characteristics of dueta! or pleomorphic carcinoma as well asa histioid appearance (18). Immunohistochemical studie.s may be helpful to iclentify tbe site of the prima1y tumor. In our series ancl previous reports, cutaneous metastatic breast carcinoma stained positively with antiboclies to keratin proteins , as well as with anti-CEA and anti-EMA antibodies (6,19) . In addition to estrogen ancl progesterone recep tors, the gross cystic disease fluid protein-IS (GCDFP-15), a monoclonal glycoprotein expressed in apocrine epithe- lial cells and metaplastic apocrine tissue, bas been described as a useful diagnostic marker for iclentifying primary as well as metastatic breast ca rcinoma (20-22) . Recently, Bayer-Garners and Smoller suggested that androgen receptors might serve as aclclitional immuno- bistocbemical markers to increase sensitivity for detec- ting breast cancer in skin metastasis (23). The prognosis of patients witb cutaneous metastasis depends on the type and biological behavior ofthe tm- derlying primaiy tumor ancl on its response to treatment. Skin metastases from breast carcinoma are usually associated with advanced stages of the disease as ob.ser- Clinical study Acta Dermatoven APA Vol 9, 2000, No 4 Clinical study Cutaneous metastatic breast carcinom.a ved in our study and, therefore, in most cases, they represent a poor prognostic sign. of the patient. Surgical excision, radiotherapy, intrale- sional chemotherapy or immunotherapy can be used when solitary lesions develop or in the late stages of the disease in orcler to improve the quality of life of the patient. Systemic chemotherapy is the most commonly used treatment whereas the specific protocol depencls on the histopathologic type of the prima1y tumor and staging D L'J?VH t?T'