Journal of Surgical Oncology 48:112-116 (1991)
Metastases to the Breast: Differential Diagnosis From Primary Breast Carcinoma BEATRICE VERGIER, MD, MONIQUE TROJANI, MD, ISABELLE DE MASCAREL, M D , JEAN-MICHEL COINDRE, MD, AND ALAIN LE TREUT, MD From the Departments of Pathology (B.V., M.T., I.D.M., I.-M.C.) and Radiology (A.L.J.), Fondation Bergonig, Bordeaux, France
Eight patients with breast metastases from primary tumors other than breast carcinoma were studied: 3 malignant melanomas, 2 rhabdomyosarcomas, 1 malignant mesothelioma, 1 appendiceal carcinoid, and 1 epidennoid cervical carcinoma. All had mammographic, histopathologic, and immunohistochemical examinations. The main problem was differential diagnosis from primary breast carcinoma. History of extramammary primary tumor was helpful but breast metastasis was the first clinical feature in 2 cases. Patients had noticed palpable, round, rapid growth masses which were mammographically benign. Pathologic diagnosis was difficult and immunohistochemical studies necessary, whenever the proliferation had histologic features of primary breast carcinoma or when no primary tumor was known. However, some histologic features were of value for diagnosis of metastasis: atypical histologic features for a primary breast carcinoma, a well-circumscribed tumor with multiple satellite foci, the absence of an intraductal component, and the presence of many lymphatic emboli. In adults, the most frequent types of tumors metastasizing in the breast are malignant melanoma and neuroendocrine-like tumors, especially small cell carcinoma and carcinoid. In children, rhabdomyosarcoma is the most common. Accurate diagnosis of breast metastasis is important to avoid unnecessary mastectomy and to implement an appropriate systemic therapy. KEYWORDS:breast carcinoid, melanoma, rhabdomyosarcoma, mesothelioma, squamous carcinoma
INTRODUCTION
MATERIALS AND METHODS
Breast metastases from non-mammary malignant neoplasms are rare, accounting for approximately 2% of breast tumors [ l ] . Apart from leukemia, lymphoma and contralateral breast carcinoma, malignant melanoma, lung carcinoma, and carcinoid tumor are the most commonly reported primary tumors. Clinical and pathologic features of 8 new cases, excluding contralateral breast carcinoma and the leukemia-lymphoma group, are the subject of this report which attempts to establish differential criteria from primary carcinoma.
We studied 8 pathologically-proven cases of breast metastasis from primary tumors other than breast carcinoma, over a period of 10 years. All patients were women. Mammography was performed in every case. Pathologic proof was obtained by tumorectomy in 6
0 1991 Wiley-Liss, Inc.
Accepted for publication June 13, 1991. Address reprint requests to Dr. Monique Trojani, Department of Pathology, Fondation Bergonie, 180 rue de Saint-Genks, 33076 Bordeaux Cedex, France.
Metastases to the Breast
113
Microscopic and Immunohistochemical Findings All tumors, particularly malignant mesotheliomas, were rather sharply demarcated from the surrounding breast tissue but were not encapsulated. They had prominent periductal and perilobular distribution, except in the carcinoid where malignant tumor cells infiltrated between the acini. However, there was no in situ change in the breast ducts or lobules. Calcifications were never seen. Necrosis was not uncommon and noticeable in metastases from melanomas, squamous carcinoma, and embryonal rhabdomyosarcomas. Surrounding breast parenchyma showed no signs of hyperplasia or atypia. Lymphatic invasion was seen in carcinoid metastasis. In the majority of cases, pathologic diagnosis of metastatic tumor was obvious when the proliferation looked like the RESULTS primary source, e.g., in 2 of the 3 melanomas, the Primary tumors in the 8 cases were as follows: 3 epidermoid carcinoma and the rhabdomyosarcomas . Immalignant melanomas, 2 rhabdomyosarcomas, 1 malig- munohistochemical studies enabled us to confirm the nant mesothelioma, 1 carcinoid of the appendix, and 1 diagnosis in the last 3 cases. The first was an achromic melanoma presenting as an anaplastic tumor. This tumor epidermoid cervical carcinoma. expressed S 100 protein but not cytokeratin and vimentin Clinical and Mammographic Findings immunoreactivity . The second case concerned the carciBreast metastasis appeared on the average 4 years after noid with cytologic features and an infiltration pattern discovery of the primary lesion in 6 cases and was compatible with primary breast carcinoma; however, the synchronous with the primary neoplasm in 2 patients notion of primary carcinoid of the appendix required (Table I). When breast metastasis was discovered, the special stains (Fig. 2). Tumor cells stained very positive mean age was 41 years (range 16-69). One patient (case with Grimelius, Masson-Fontana, and chromogranin A 2) was 7 months pregnant and had presented a primary (Fig. 3). The last case was a malignant mesothelioma; melanoma during a first pregnancy. In the 3 cases of this patient had a history of primary breast carcinoma 20 melanoma and 1 case of cervical carcinoma, the breast years previously and now complained of constipation, lesion was the first and only metastasis. In 3 other cases, abdominal pain, ascites, and a breast nodule. Microscopmetastatic disease was present elsewhere 1 or 2 years ically the tumor consisted of a mixture of epithelial before, and in the last 2, breast metastasis was concom- tubulopapillary and sarcomatous components (Fig. 4). itant with metastatic disease. Symptoms were similar to Epithelial cells and a few spindle cells stained positively those of primary mammary carcinoma. All 8 patients had for cytokeratin and to a lesser extent for EMA and noticed palpable rounded breast masses, firm in consis- vimentin. So we encountered 2 completely different and tency, usually freely mobile without skin tethering. difficult scenarios: a known extramammary primary Rapid growth suggested malignancy. The masses were tumor, with breast metastasis having the histologic solitary in 6 cases, multiple in 1 rhabdomyosarcoma features of primary breast carcinoma; and a lesion case, and bilateral in the second. Axillary adenopathy microscopically quite unusual for primary breast carciwas present in this latter case and 2 other cases had node noma in spite of an unknown primary tumor. involvement proven by axillary node dissection. The DISCUSSION right breast was involved in 5 patients, the left breast in Breast metastases are uncommon, with about 300 2, and both breasts in 1 patient. Tumors were located in the upper outer quadrant in 4 patients. Mammography cases reported in the literature [2]. McIntosh et al. even was positive in all cases. Mammographically , metastases suggests that dual primaries are more common than 1 were round with slightly irregular margins. They were primary tumor metastasizing to the breast [3]. Women 1.2-10 cm in diameter, with a mean size of 4 cm. are affected 5-6 times more frequently than men with an Microcalcifications were never seen but spiculation was average age at diagnosis of 48 vs. 61 years [1,4]. The present in one case (Fig. 1). Prognosis was poor; 5 younger age of women suggests that after the fourth patients died within 2 years or less. Two women, those decade, the breast is not a favorite site for metastasis, with embryonal rhabdomyosarcoma and carcinoid are in because there are large areas of fibrous tissue and a good general condition, respectively, 7 and 15 months relatively poor blood supply [5]. The role of hormonal after discovery of their primary malignancy. The last status as a predisposing factor is debatable. Indeed, Baranzelli et al. explain the high occurrence of breast patient has been lost to follow-up.
patients, fine needle aspiration cytology then mastectomy in 1, and biopsy of associated skin nodule in the other. Axillary node dissection was associated in 3 cases. Tumor specimens were fixed in Bouin’s fluid and special stainings were performed on paraffin sections: Grimelius, Masson-Fontana, and immunohistochemical stains using the peroxydase-antiperoxydase technique with monoclonal and polyclonal antibodies: cytokeratin : KL 1 (Immunotech, Marseille, France), epithelial membrane antigen: (EMA) (Dako, Dakopatts, Copenhagen, Denmark), vimentin (Dako), leukocyte common antigen (Dako), desmin (Euro-diagnostics BV, Apeldoorn, Holland), S 100 protein (Dako), chromogranin A (Immunotech), HMB 45 (Enzo, New-York).
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TABLE I. Clinical Details of Eight Patients With Metastases to the Breast From Non-Breast Primary Tumors*
Age 29
Primary site
Time since diagnosis of primary tumor
Tumor nodules
Side and size (mm)
Axillary node dissection
Survival from breast metastasis
2 years
Solitary
ND
?
4 years
Multiple
5 years
Solitary
Right ? Right 65 Left 100 Bilateral
Synchronous
42
Malignant melanoma (finger) Malignant melanoma (armpit) Malignant melanoma (subungual) Embryonal rhabdomyosarcoma (elbow) Alveolar rhabdomyosarcoma (maxillary sinus) Malignant mesothelioma (peritoneal) Appendiceal carcinoid
1 year
Solitary
69
Epidermoid
10 years
Solitary
32 61 18
16 59
2 years Synchronous
Multiple Solitary Solitary
Right 50 Right 12 Right 15 Left 15
N S 3
12 months
ND
5 months
ND ND
Alive after 7 months 28 months
ND
4 months
N+l
Alive after 15 months 12 months
N-
*Abbreviations: ND, not done; N+: nodal involvement.
Fig. 1. Mammography of epidermoid carcinoma metastatic to the breast (case 8).
Fig. 2. Tumor cells of carcinoid metastasis infiltrating between acini. Much lymphatic invasion is present (case 7).
metastasis in pubescent girls by the greater vascularity of the breast due to hormonal impregnation during puberty [6]. Moreover, breast metastasis during pregnancy or lactation, as observed in 1 of our patients, is found in the literature [ 71. Finally, breast metastasis of prostatic adenocarcinoma is more frequent when men receive estrogens [ 11. The major problem for establishing such a diagnosis is to differentiate primary and metastatic mammary neoplasms. The easiest situation is the occurrence of metastases on average 1-9 years after a known nonbreast primary malignancy [8]. The breast is often the first metastatic site (18/29 cases of McIntosh et al.’s clinical
report [ 3 ] ) . It is the first sign of malignant disease in 2 5 4 0 % of patients [ 1,4,9]. The clinical features are not very helpful because they are often those -of malignant disease with rapid growth and a 1-3 cm solitary nodule [8-lo]. In about half of the cases, tumors are adherent to the skin and superficially located, but nipple retraction or discharge is not observed [9]. The tumor is usually palpable in the upper outer quadrant and is bilateral in up to 8-25% of patients [ 1,2]. Axillary node involvement is frequently encountered (25-58%) [ 11. Even if clinical features are not specific, the mammographic pattern must suggest such a diagnosis. The mass is well-defined, tends to be of the same size as when palpated, and is generally
Metastases to the Breast
Fig. 3. Tumor cells strongly stained with chromogranin A (case 7).
not associated with spiculations or microcalcifications (except in a metastasis of ovarian carcinoma) [lo]. Therefore, differential diagnosis on mammograms could prove difficult because this pattern is found both in benign lesions like fibroadenoma and in certain malignant neoplasms, particularly medullary carcinoma and intracystic carcinoma [3,5]. Microscopically, breast metastasis is suspected on the basis of several factors: 1. Atypical histologic features for a primary breast carcinoma (as in our 2 rhabdomyosarcoma cases). 2. A well-circumscribed but non-encapsulated tumor with periductal and/or perilobular distribution [9]. 3. An absence of associated in situ carcinoma [ 111. 4. Multiple microscopic foci of tumor in addition to the grossly evident masses [4]. 5 . Many lymphatic tumor emboli [4]. Immunohistochemical studies could be helpful in cases mimicking primary carcinoma, for instance positivity of chromogranin A in carcinoid tumor. In adults, the most frequent types of tumors which metastasize to the breast are malignant melanoma and neuroendocrine-like tumors, especially small cell carcinoma and carcinoid tumor. In most cases, intramammary malignant melanoma corresponds to metastasis of cutaneous tumor, even with superficial invasion [ 1 11. However, a few primary cases have been described [ 121. Metastatic melanoma to the breast was indicative of very poor prognosis with less than 1 year survival [ 131. Lung carcinoma is the second most common primary neoplasm responsible, accounting for almost a third of cases. Within this group, the small cell type represents about 80% of cases [14]. All other histologic types of lung carcinoma have been described, even clear cell carcinoma [15]. The third primary neoplasm incriminated is carcinoid with about 12 cases
115
Fig. 4. Metastasis of mesothelium showed epithelial tubulopapillary and sarcomatous components (case 6).
reported (our patient included): 7 of the ileum, 1 of the ileocecal area, 1 of the duodenum, 2 of the appendix, and 2 of the lung [ 16261. The existence of primary carcinoid tumors of the breast is debatable [27], they would always be argyrophilic and never argentaffnic as was our appendiceal carcinoid case [lo]. Positivity of estrogen receptors is not helpful, because this would be observed in both primary mammary and gastrointestinal carcinoids [28]. However, the diagnosis of primary breast carcinoid tumor remains one of exclusion, requiring that no other primary carcinoid tumor should be demonstrated elsewhere. Prognosis of metastatic carcinoid seems to be favorable, with 6 year survival reported [ 181. Other common breast metastatic cancers are ovarian cancer [2,29,301, renal carcinoma [3 11, and epidermoid cervical carcinoma [7] in decreasing order of frequency. In men, the most common primary neoplasm observed is adenocarcinoma of the prostate [32]. Indeed, Sayler and Sayler examined the breast tissue of 46 patients who died of metastasis of prostatic carcinoma; they found microscopic disease in 11 patients (24%), none of whom had clinical evidence of breast disease [33]. In children and adolescents, breast metastases other than hematologic diseases are rarely found. They are most often linked to rhabdomyosarcoma. Other primary tumors described are Ewing’s sarcoma, neuroblastoma, synovial sarcoma, and yolk sac tumor [6,34,35]. Breast metastasis of a rhabdomyosarcoma usually occurs in adolescent females (older than the median age for rhabdomyosarcoma), with primary tumors located at the extremities and an alveolar histology [35]. Most commonly, a disseminated tumor is evident at diagnosis, as in our 2 patients. Bone marrow involvement often precedes the development of breast metastasis (5/7 times for Howarth et al. [35], 1/2 in our cases). Finally, only 1 case of malignant mesothelioma
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metastasizing in the breast is mentioned in the literature
PI. In conclusion, metastatic cancer must be confirmed by appropriate histopathologic and immunohistochemical examination, in order to preclude unnecessary mastectomy and to provide a suitable treatment.
REFERENCES
17. 18.
19. 20.
1. Toombs BD, Kalisher L: Metastatic disease to the breast: clinical,
pathological and radiographic features. AJR 129:673476, 1977. 2. Amichetti M, Perani B, Boi S: Metastases to the breast from extramammary malignancies. Oncology 47:257-260, 1990. 3. McIntosh IH, Hooper AA, Millis RR, Greening WP: Metastatic carcinoma within the breast. Clin Oncol 2:393401, 1976. 4. Alexander HR, Turnbull AD, Rosen PP: Isolated breast metastases from gastrointestinal carcinomas: report of two cases. J Surg Oncol 42:264-266, 1989. 5 . Jochimsen PR, Brown RC: Metastatic melanoma in the breast masquerading as fibroadenoma. JAMA 236:2779-2780, 1976. 6. Baranzelli MC, Demaille MC, Lesoin A, Granier AM: Breast metastases of solid tumors in children and adolescents. Breast Dis Senol 1:208-2 12, 198511986. 7. Nayer M, Chandra M, Agganval R, Chander S: Carcinoma cervix presenting as primary breast malignancy. Indian J Pathol Microbiol 30:283-286, 1987. 8. McCrea ES, Johnston C, Haney PJ: Metastases to the breast. AJR 141:685-690, 1983. 9. Hadju SI, Urban JA: Cancers metastatic to the breast. Cancer 29:1691-1696, 1972. 10. Bohman LG, Basset W, Gold RH, Voet R: Breast metastases from extramammary malignancies. Radiology 144:309-3 12, 1982. 11. Barker JNWN, Girling AC: A case of metastatic malignant melanoma masquerading as disseminated mammary carcinoma. Histopathology 14:219-221, 1989. 12. Pressman PI: Malignant melanoma and the breast. Cancer 31:784788, 1973. 13. Donegan WL, Spratt JS: Metastatic neoplasms to the breast from other primary cancers. In Donegan WL, Spratt JS (eds). “Cancer of the Breast.” Third edition. Philadelphia: WB Saunders, 1988, p 644. 14. Kelly C, Henderson D, Corris P: Breast lumps: rare presentation of oat cell carcinoma of lung. J Clin Pathol 41:171-172, 1988. 15. Palgon NM, Novetsky AD, Fogler RJ, Lichter SM: Lung carcinoma presenting as a breast tumor. NY State J Med 83: 11881189, 1983. 16. Ahlman H, Larsson I, Gronstad K, Tisell LE, Dahlstrom A: A case of midgut carcinoid with breast metastasis and cellular
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
32. 33. 34. 35.
localization of serotonin and substance P. J Surg Oncol 31:170173, 1986. Chodoff RJ: Solitary breast metastasis from carcioid of the ileum. Am J Surg 1092314-815, 1965. Di Palma S , Andreola S , Lombardi L, Colombo C: Ileal carcinoid metastatic to the breast. Report of a case. Tumori 74:321-327, 1988. Haagensen CO: “Diseases of the Breast.” 2nd Ed. Philadelphia: WB Saunders, 1971, pp 498-499. Hawley PR: A case of secondary carcinoid tumors in both breasts following excision of primary carcinoid tumor of the duodenum. Br J Surg 53:818-820, 1966. Kashlan RB, Powell RW, Nolting SF: Carcinoid and other tumors metastatic to the breast. J Surg Oncol 20:25-30, 1982. Oleksowicz L, Morris JC, Phelps RG, Bruckner HW: Pulmonary carcinoid presenting as multiple subcutaneous nodules. Tumori 76:4&47, 1990. Schiirch W, Lamoureux E, Lefebvre R, Fauteux JP: Solitary breast metastasis: First manifestation of an occult carcinoid of the ileum. Virchows Arch Pathol Anat Histol 386:117-124, 1980. Turner M, Gallager DS: Occult appendiceal carcinoid. Arch Pathol 88:188-190, 1969. Zetzel L: Case records of the Massachusetts General Hospital. N Engl J Med 256:703-707, 1957. Hanist TJ, Kalisher L: Breast metastasis: an unusual manifestation of a malignant carcinoid tumor. Cancer 40:3102-3106, 1977. Taxy JB, Tischler AS, Insalaco SJ, Battifora H: “Carcinoid’ tumor of the breast. A variant of conventional breast cancer? Hum Pathol 12:17&179, 1981. Keshgegian AA, Wheeler JE: Estrogen receptor protein in malignant carcinoid tumor. A report of 2 cases. Cancer 45:293-296, 1980. Krishnan EU, Phillips AK, Randell A, Taylor B, Garg SK: Bilateral metastatic inflammatory carcinoma in the breast from primary ovanan cancer. Obstet Gynecol 55943-963, 1980. Laifer S , Buscema J, Parmley TH, Rosenshein NB: Ovarian cancer metastatic to the breast. Gynecol Oncol 24:97-102, 1986. Hardy SC, Benson EA: Solitary breast metastasis from a hypernephroma. J Surg Oncol 13:365-366, 1987. Moldwin RM, Orihuela E: Breast masses associated with adenocarcinoma of the prostate. Cancer 63:2229-2233, 1989. Sayler WR, Sayler DC: Metastases of prostatic carcinoma to the breast. J Urol 109:671-675, 1973. Baranzelli MC, Granier AM, Cornillot M, Demaille MC: Cinq cas de metastases mammaires chez I’enfant. Arch Anat Cytol Pathol 3458-61, 1986. Howarth CB, Caces JN, Pratt CH: Breast metastases in children with rhabdomyosarcoma. Cancer 46:2520-2524, 1980.
Metastases to the Breast: Differential Diagnosis From Primary Breast Carcinoma BEATRICE VERGIER, MD, MONIQUE TROJANI, MD, ISABELLE DE MASCAREL, M D , JEAN-MICHEL COINDRE, MD, AND ALAIN LE TREUT, MD From the Departments of Pathology (B.V., M.T., I.D.M., I.-M.C.) and Radiology (A.L.J.), Fondation Bergonig, Bordeaux, France
Eight patients with breast metastases from primary tumors other than breast carcinoma were studied: 3 malignant melanomas, 2 rhabdomyosarcomas, 1 malignant mesothelioma, 1 appendiceal carcinoid, and 1 epidennoid cervical carcinoma. All had mammographic, histopathologic, and immunohistochemical examinations. The main problem was differential diagnosis from primary breast carcinoma. History of extramammary primary tumor was helpful but breast metastasis was the first clinical feature in 2 cases. Patients had noticed palpable, round, rapid growth masses which were mammographically benign. Pathologic diagnosis was difficult and immunohistochemical studies necessary, whenever the proliferation had histologic features of primary breast carcinoma or when no primary tumor was known. However, some histologic features were of value for diagnosis of metastasis: atypical histologic features for a primary breast carcinoma, a well-circumscribed tumor with multiple satellite foci, the absence of an intraductal component, and the presence of many lymphatic emboli. In adults, the most frequent types of tumors metastasizing in the breast are malignant melanoma and neuroendocrine-like tumors, especially small cell carcinoma and carcinoid. In children, rhabdomyosarcoma is the most common. Accurate diagnosis of breast metastasis is important to avoid unnecessary mastectomy and to implement an appropriate systemic therapy. KEYWORDS:breast carcinoid, melanoma, rhabdomyosarcoma, mesothelioma, squamous carcinoma
INTRODUCTION
MATERIALS AND METHODS
Breast metastases from non-mammary malignant neoplasms are rare, accounting for approximately 2% of breast tumors [ l ] . Apart from leukemia, lymphoma and contralateral breast carcinoma, malignant melanoma, lung carcinoma, and carcinoid tumor are the most commonly reported primary tumors. Clinical and pathologic features of 8 new cases, excluding contralateral breast carcinoma and the leukemia-lymphoma group, are the subject of this report which attempts to establish differential criteria from primary carcinoma.
We studied 8 pathologically-proven cases of breast metastasis from primary tumors other than breast carcinoma, over a period of 10 years. All patients were women. Mammography was performed in every case. Pathologic proof was obtained by tumorectomy in 6
0 1991 Wiley-Liss, Inc.
Accepted for publication June 13, 1991. Address reprint requests to Dr. Monique Trojani, Department of Pathology, Fondation Bergonie, 180 rue de Saint-Genks, 33076 Bordeaux Cedex, France.
Metastases to the Breast
113
Microscopic and Immunohistochemical Findings All tumors, particularly malignant mesotheliomas, were rather sharply demarcated from the surrounding breast tissue but were not encapsulated. They had prominent periductal and perilobular distribution, except in the carcinoid where malignant tumor cells infiltrated between the acini. However, there was no in situ change in the breast ducts or lobules. Calcifications were never seen. Necrosis was not uncommon and noticeable in metastases from melanomas, squamous carcinoma, and embryonal rhabdomyosarcomas. Surrounding breast parenchyma showed no signs of hyperplasia or atypia. Lymphatic invasion was seen in carcinoid metastasis. In the majority of cases, pathologic diagnosis of metastatic tumor was obvious when the proliferation looked like the RESULTS primary source, e.g., in 2 of the 3 melanomas, the Primary tumors in the 8 cases were as follows: 3 epidermoid carcinoma and the rhabdomyosarcomas . Immalignant melanomas, 2 rhabdomyosarcomas, 1 malig- munohistochemical studies enabled us to confirm the nant mesothelioma, 1 carcinoid of the appendix, and 1 diagnosis in the last 3 cases. The first was an achromic melanoma presenting as an anaplastic tumor. This tumor epidermoid cervical carcinoma. expressed S 100 protein but not cytokeratin and vimentin Clinical and Mammographic Findings immunoreactivity . The second case concerned the carciBreast metastasis appeared on the average 4 years after noid with cytologic features and an infiltration pattern discovery of the primary lesion in 6 cases and was compatible with primary breast carcinoma; however, the synchronous with the primary neoplasm in 2 patients notion of primary carcinoid of the appendix required (Table I). When breast metastasis was discovered, the special stains (Fig. 2). Tumor cells stained very positive mean age was 41 years (range 16-69). One patient (case with Grimelius, Masson-Fontana, and chromogranin A 2) was 7 months pregnant and had presented a primary (Fig. 3). The last case was a malignant mesothelioma; melanoma during a first pregnancy. In the 3 cases of this patient had a history of primary breast carcinoma 20 melanoma and 1 case of cervical carcinoma, the breast years previously and now complained of constipation, lesion was the first and only metastasis. In 3 other cases, abdominal pain, ascites, and a breast nodule. Microscopmetastatic disease was present elsewhere 1 or 2 years ically the tumor consisted of a mixture of epithelial before, and in the last 2, breast metastasis was concom- tubulopapillary and sarcomatous components (Fig. 4). itant with metastatic disease. Symptoms were similar to Epithelial cells and a few spindle cells stained positively those of primary mammary carcinoma. All 8 patients had for cytokeratin and to a lesser extent for EMA and noticed palpable rounded breast masses, firm in consis- vimentin. So we encountered 2 completely different and tency, usually freely mobile without skin tethering. difficult scenarios: a known extramammary primary Rapid growth suggested malignancy. The masses were tumor, with breast metastasis having the histologic solitary in 6 cases, multiple in 1 rhabdomyosarcoma features of primary breast carcinoma; and a lesion case, and bilateral in the second. Axillary adenopathy microscopically quite unusual for primary breast carciwas present in this latter case and 2 other cases had node noma in spite of an unknown primary tumor. involvement proven by axillary node dissection. The DISCUSSION right breast was involved in 5 patients, the left breast in Breast metastases are uncommon, with about 300 2, and both breasts in 1 patient. Tumors were located in the upper outer quadrant in 4 patients. Mammography cases reported in the literature [2]. McIntosh et al. even was positive in all cases. Mammographically , metastases suggests that dual primaries are more common than 1 were round with slightly irregular margins. They were primary tumor metastasizing to the breast [3]. Women 1.2-10 cm in diameter, with a mean size of 4 cm. are affected 5-6 times more frequently than men with an Microcalcifications were never seen but spiculation was average age at diagnosis of 48 vs. 61 years [1,4]. The present in one case (Fig. 1). Prognosis was poor; 5 younger age of women suggests that after the fourth patients died within 2 years or less. Two women, those decade, the breast is not a favorite site for metastasis, with embryonal rhabdomyosarcoma and carcinoid are in because there are large areas of fibrous tissue and a good general condition, respectively, 7 and 15 months relatively poor blood supply [5]. The role of hormonal after discovery of their primary malignancy. The last status as a predisposing factor is debatable. Indeed, Baranzelli et al. explain the high occurrence of breast patient has been lost to follow-up.
patients, fine needle aspiration cytology then mastectomy in 1, and biopsy of associated skin nodule in the other. Axillary node dissection was associated in 3 cases. Tumor specimens were fixed in Bouin’s fluid and special stainings were performed on paraffin sections: Grimelius, Masson-Fontana, and immunohistochemical stains using the peroxydase-antiperoxydase technique with monoclonal and polyclonal antibodies: cytokeratin : KL 1 (Immunotech, Marseille, France), epithelial membrane antigen: (EMA) (Dako, Dakopatts, Copenhagen, Denmark), vimentin (Dako), leukocyte common antigen (Dako), desmin (Euro-diagnostics BV, Apeldoorn, Holland), S 100 protein (Dako), chromogranin A (Immunotech), HMB 45 (Enzo, New-York).
114
Vergier et al.
TABLE I. Clinical Details of Eight Patients With Metastases to the Breast From Non-Breast Primary Tumors*
Age 29
Primary site
Time since diagnosis of primary tumor
Tumor nodules
Side and size (mm)
Axillary node dissection
Survival from breast metastasis
2 years
Solitary
ND
?
4 years
Multiple
5 years
Solitary
Right ? Right 65 Left 100 Bilateral
Synchronous
42
Malignant melanoma (finger) Malignant melanoma (armpit) Malignant melanoma (subungual) Embryonal rhabdomyosarcoma (elbow) Alveolar rhabdomyosarcoma (maxillary sinus) Malignant mesothelioma (peritoneal) Appendiceal carcinoid
1 year
Solitary
69
Epidermoid
10 years
Solitary
32 61 18
16 59
2 years Synchronous
Multiple Solitary Solitary
Right 50 Right 12 Right 15 Left 15
N S 3
12 months
ND
5 months
ND ND
Alive after 7 months 28 months
ND
4 months
N+l
Alive after 15 months 12 months
N-
*Abbreviations: ND, not done; N+: nodal involvement.
Fig. 1. Mammography of epidermoid carcinoma metastatic to the breast (case 8).
Fig. 2. Tumor cells of carcinoid metastasis infiltrating between acini. Much lymphatic invasion is present (case 7).
metastasis in pubescent girls by the greater vascularity of the breast due to hormonal impregnation during puberty [6]. Moreover, breast metastasis during pregnancy or lactation, as observed in 1 of our patients, is found in the literature [ 71. Finally, breast metastasis of prostatic adenocarcinoma is more frequent when men receive estrogens [ 11. The major problem for establishing such a diagnosis is to differentiate primary and metastatic mammary neoplasms. The easiest situation is the occurrence of metastases on average 1-9 years after a known nonbreast primary malignancy [8]. The breast is often the first metastatic site (18/29 cases of McIntosh et al.’s clinical
report [ 3 ] ) . It is the first sign of malignant disease in 2 5 4 0 % of patients [ 1,4,9]. The clinical features are not very helpful because they are often those -of malignant disease with rapid growth and a 1-3 cm solitary nodule [8-lo]. In about half of the cases, tumors are adherent to the skin and superficially located, but nipple retraction or discharge is not observed [9]. The tumor is usually palpable in the upper outer quadrant and is bilateral in up to 8-25% of patients [ 1,2]. Axillary node involvement is frequently encountered (25-58%) [ 11. Even if clinical features are not specific, the mammographic pattern must suggest such a diagnosis. The mass is well-defined, tends to be of the same size as when palpated, and is generally
Metastases to the Breast
Fig. 3. Tumor cells strongly stained with chromogranin A (case 7).
not associated with spiculations or microcalcifications (except in a metastasis of ovarian carcinoma) [lo]. Therefore, differential diagnosis on mammograms could prove difficult because this pattern is found both in benign lesions like fibroadenoma and in certain malignant neoplasms, particularly medullary carcinoma and intracystic carcinoma [3,5]. Microscopically, breast metastasis is suspected on the basis of several factors: 1. Atypical histologic features for a primary breast carcinoma (as in our 2 rhabdomyosarcoma cases). 2. A well-circumscribed but non-encapsulated tumor with periductal and/or perilobular distribution [9]. 3. An absence of associated in situ carcinoma [ 111. 4. Multiple microscopic foci of tumor in addition to the grossly evident masses [4]. 5 . Many lymphatic tumor emboli [4]. Immunohistochemical studies could be helpful in cases mimicking primary carcinoma, for instance positivity of chromogranin A in carcinoid tumor. In adults, the most frequent types of tumors which metastasize to the breast are malignant melanoma and neuroendocrine-like tumors, especially small cell carcinoma and carcinoid tumor. In most cases, intramammary malignant melanoma corresponds to metastasis of cutaneous tumor, even with superficial invasion [ 1 11. However, a few primary cases have been described [ 121. Metastatic melanoma to the breast was indicative of very poor prognosis with less than 1 year survival [ 131. Lung carcinoma is the second most common primary neoplasm responsible, accounting for almost a third of cases. Within this group, the small cell type represents about 80% of cases [14]. All other histologic types of lung carcinoma have been described, even clear cell carcinoma [15]. The third primary neoplasm incriminated is carcinoid with about 12 cases
115
Fig. 4. Metastasis of mesothelium showed epithelial tubulopapillary and sarcomatous components (case 6).
reported (our patient included): 7 of the ileum, 1 of the ileocecal area, 1 of the duodenum, 2 of the appendix, and 2 of the lung [ 16261. The existence of primary carcinoid tumors of the breast is debatable [27], they would always be argyrophilic and never argentaffnic as was our appendiceal carcinoid case [lo]. Positivity of estrogen receptors is not helpful, because this would be observed in both primary mammary and gastrointestinal carcinoids [28]. However, the diagnosis of primary breast carcinoid tumor remains one of exclusion, requiring that no other primary carcinoid tumor should be demonstrated elsewhere. Prognosis of metastatic carcinoid seems to be favorable, with 6 year survival reported [ 181. Other common breast metastatic cancers are ovarian cancer [2,29,301, renal carcinoma [3 11, and epidermoid cervical carcinoma [7] in decreasing order of frequency. In men, the most common primary neoplasm observed is adenocarcinoma of the prostate [32]. Indeed, Sayler and Sayler examined the breast tissue of 46 patients who died of metastasis of prostatic carcinoma; they found microscopic disease in 11 patients (24%), none of whom had clinical evidence of breast disease [33]. In children and adolescents, breast metastases other than hematologic diseases are rarely found. They are most often linked to rhabdomyosarcoma. Other primary tumors described are Ewing’s sarcoma, neuroblastoma, synovial sarcoma, and yolk sac tumor [6,34,35]. Breast metastasis of a rhabdomyosarcoma usually occurs in adolescent females (older than the median age for rhabdomyosarcoma), with primary tumors located at the extremities and an alveolar histology [35]. Most commonly, a disseminated tumor is evident at diagnosis, as in our 2 patients. Bone marrow involvement often precedes the development of breast metastasis (5/7 times for Howarth et al. [35], 1/2 in our cases). Finally, only 1 case of malignant mesothelioma
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metastasizing in the breast is mentioned in the literature
PI. In conclusion, metastatic cancer must be confirmed by appropriate histopathologic and immunohistochemical examination, in order to preclude unnecessary mastectomy and to provide a suitable treatment.
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