Context.-Carcinoid tumor metastatic to the breast is uncommon and can closely mimic a mammary carcinoma. The differentiation of metastatic carcinoid tumor from primary breast tumor is important, however, owing to different clinical management and prognosis.
Objective.-The purpose of this study was to describe 2 patients with bilateral metastatic carcinoid tumors to the breast with different clinical manifestations.
Design.-We examined the radiological, clinical, cytologie, histologic, immunohistochemical, and ultrastructural features of these 2 cases.
Results.-In case 1, the tumor presented initially as a stellate mass on mammogram and was diagnosed as grade II infiltrating ductal carcinoma. It was only after the discovery of small intestinal, liver, ovarian, and contralateral breast masses, as well as careful morphologic and immunohistochemical evaluations, that the true nature of the tumor was realized. In case 2, the tumor initially presented as a small intestinal tumor with liver metastases and bilateral breast masses. The breast masses were diagnosed accurately as metastatic carcinoid tumor by morphologic and immunohistochemical evaluations.
Conclusions.-Metastatic carcinoid tumor to the breast is uncommon, but poses a diagnostic challenge in that morphologically it can closely mimic a primary breast tumor. Careful attention to clinical features and the use of auxiliary immunohistochemical studies can help in arriving at the correct diagnosis.
(Arch Pathol Lab Med. 2004;128:292-297)
Metastatic tumors to the breast are rare and represent about 1% to 2% of all breast tumors.1,2 The most common tumors that metastasize to the breast include those of bronchus and lung, prostate, hematopoietic system, and melanoma.3,4 While adenocarcinomas from the gastrointestinal tract are rare sources of metastatic lesions, carcinoid tumors of the small bowel have been found to be a relatively more frequent source of breast metastases, with fewer than 30 cases described in the literature.
To our knowledge, only 3 cases of bilateral metastatic carcinoid tumor have been described in the English literature to date.5-7 Metastatic carcinoid tumors are easily mistaken for primary breast carcinoma, and this confusion has serious consequences for the patients involved. In this report, we describe 2 cases of bilateral metastatic carcinoid tumors to the breast with different clinical presentations and discuss some of the pitfalls involved in their diagnoses. The use of ancillary techniques, such as immunohistochemical and ultrastructural studies, together with a careful history, should allow one to distinguish primary breast carcinoma from metastatic carcinoid and better guide clinicians in the management of these patients.
REPORT OF CASES
A 60-year-old woman with no family history of breast carcinoma presented with a palpable mass of the left breast. Mammography revealed a stellate mass measuring 0.96 × 0.7 × 0.86 cm in the upper inner quadrant, approximately 2 cm from the nipple, which was highly suggestive of carcinoma. Fine-needle aspiration (FNA) was performed, and a diagnosis of ductal carcinoma was rendered. The patient underwent lumpectomy, and the tumor was interpreted as infiltrating ductal carcinoma grade II, with extensive areas of solid ductal carcinoma in situ (DCIS) with intermediate nuclear grade. Estrogen and progesterone receptors were negative and HER-2/neu was strongly positive by immunohistochemistry. (All reagents used for immunohistochemistry were from Dako Corporation, Carpinteria, Calif.) The resection margins were positive, and subsequent re-excision with axillary dissection was performed. Residual tumor was identified, and 30 axillary lymph nodes were dissected to reveal 1 node containing micrometastasis. The patient was treated with adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide for 4 cycles; she handled the treatment well. Additional workup for evaluation of abnormal alkaline phosphatase levels included complete abdominal and pelvic computed tomography with contrast, which revealed 2 heterogeneous masses in the liver, measuring 3.5 and 1.5 cm in diameter. These masses were thought to represent metastatic disease. A solid 5 × 4-cm right adnexal mass, suggestive of pedunculated fibroid tumor, was also identified. Fine-needle aspiration of the liver masses was interpreted as metastatic carcinoid. Search for primary carcinoid rumor demonstrated 2 obstructive masses in the ileum, measuring 1.3 and 1.5 cm in diameter. The patient's preoperative 24-hour urinary 5-hydroxyindolacetic acid (5-HIAA) level was found to be markedly elevated at 80 mg/24 h (417 µmol/d). Partial resection of the ileum revealed primary carcinoid tumor with angiolymphatic invasion and metastatic carcinoid in 1 regional lymph node. Resection of the enlarged ovary showed benign fibrothecoma, as well as metastatic carcinoid to the surface of the ovary. The patient's postoperative 24-hour urinary 5-HIAA level returned to normal, at 4 mg/24 h (22 µmol/d). At this point, the patient was thought to have 2 different primary tumors, both of which were adequately treated. The patient was doing well clinically until 2 years later, when she presented with a contralateral breast mass. Core needle biopsy showed metastatic carcinoid, and the morphologic findings were substantiated with immunohistochemical stains. The initial breast lumpectomy was reevaluated carefully to demonstrate presence of morphologic features suggestive of neuroendocrine origin. Additional immunostains were performed to substantiate the metastatic nature of this tumor.
A 55-year-old African American woman presented with a history of dyspepsia, early satiety, abdominal pain, and an 8.1-kg weight loss in the past several months. Computed tomographic scan showed an air-fluid level in the small bowel and multiple hepatic lesions. Upper gastrointestinal series showed a partially obstructing lesion in the mid jejunum. Fine-needle aspiration of the hepatic lesion showed tumor with morphologic features consistent with metastatic carcinoid. The patient's 24-hour urinary 5-HIAA level was elevated at 18 mg/24 h (95 µmol/d). She underwent segmental resection of the small bowel, which revealed an obstructive lesion in jejunum, measuring 1.5 × 1.5 × 1.0 cm. The mass was infiltrating throughout the bowel wall into peritoneum with loop-to-loop intestinal adhesions. Histologically, the tumor was consistent with carcinoid. Fourteen regional lymph nodes and omentum were negative for metastatic carcinoid. The patient was minimally symptomatic and was treated medically with subcutaneous octreotide. Twenty-six months later, bilateral spiculated masses were noted on a yearly screening mammogram (Figure 1, a). In the right breast, the lesion was situated in the upper outer quadrant and measured 1.5 cm in diameter. The left breast contained 2 new noncalcified 5-mm masses. Fine-needle aspiration was performed on the right breast mass. The definitive diagnosis could not be achieved, and the differential diagnoses included well-differentiated ductal carcinoma versus metastatic carcinoid. Core needle biopsies of both breast lesions were performed to disclose metastatic carcinoid to both breasts.
Fine-needle aspiration of the left breast mass showed noncohesive sheets and clusters of cells with an enlarged nuclear-cytoplasmic ratio, coarse chromatin, and peripherally positioned nuclei with granular cytoplasm (Figure 1, b). Left breast lumpectomy showed a mass composed of cords of infiltrating tumor cells with marked desmoplastic reaction. Tumor cells exhibited mild pleomorphism, peripherally positioned round to oval nuclei with coarse chromatin and small inconspicuous nucleoli, moderate amounts of eosinophilic cytoplasm, and fewer than 5 mitoses per 10 high-power fields. Infiltrating tumor was associated with what appeared to be distended ducts filled with similar cells and was interpreted as solid grade II DCIS (Figure 1, c). Some cribriforming was identified within solid DCIS. Tumor was negative for estrogen receptor and progesterone receptor and positive for HER-2/neu (2-3+) by immunohistochemistry. A single axillary lymph node contained subcapsular micrometastases.
Fine-needle aspiration biopsy of the liver lesion showed clusters of bland cells with coarse chromatin and ample eosinophilic cytoplasm, showing an organoid pattern. Cells were strongly positive for synaptophysin and were negative for cytokeratin (CK) 7 and CK20, confirming the neuroendocrine origin of this tumor.
The small bowel tumor showed all of the morphologic features of carcinoid that are readily identifiable on hematoxylin-eosin-stained slides, including organoid pattern, coarse "salt-and-pepper" chromatin, rosette formation, and presence of red neuroendocrine granules in the cytoplasm (Figure 2). One mesenteric lymph node was positive. The same tumor cells were identified on the surface of the left ovary, which was enlarged by a benign fibroma-thecoma tumor.
Core biopsy of the right breast showed an infiltrating pattern in the tumor, as well as marked desmoplastic reaction. No DCIS-like areas were noted. Cells exhibited neuroendocrine features, including the presence of cytoplasmic eosinophilic granules, organoid pattern, and characteristic coarse chromatin.
In the wake of the discovery of the small bowel carcinoid tumor, the tumor diagnosed as invasive breast carcinoma in the initial lumpectomy specimen was reevaluated and showed morphology identical to the carcinoid tumor. Trabeculae of carcinoid tumor cells and the surrounding marked desmoplastic response were found to closely mimic invasive ductal carcinoma. Areas of what was thought to be solid DCIS were reinterpreted as cell nests in the carcinoid tumor, and the punch-out cribriform spaces that were reminiscent of cribriform DCIS were in fact rosettes formed by carcinoid tumor.
Positive immunohistochemical staining for synaptophysin and chromogranin confirmed the neuroendocrine nature of this tumor (Figure 1, d). Cytokeratin 7 reactivity was negative, which argues against primary breast carcinoma. Myoepithelial stains (smooth muscle actin and calponin) were negative around the nests that mimicked solid low-grade DCIS. One lymph node showed metastasis with the same immunohistochemical profile as the primary tumor (chromogranin, synaptophysin, and cytokeratin positive; CK7 and CK20 negative) (Figure 1, e). Only 1 morphologically different focus in the breast tumor was actually confirmed to be DCIS by immunohistochemistry (CK7 positive, chromogranin negative) (Figure 3). Therefore, the evidence for this tumor to be primary breast tumor-either of ductal or neuroendocrine origin-was lacking, and both breast lesions were considered to be metastatic carcinoid to the breast, presumably from a small intestinal primary.
The first lesion discovered in this patient was a liver lesion detected by FNA. It showed organoid clusters of cells with coarse chromatin, eosinophilic cytoplasm, and peripherally positioned nuclei. Immunohistochemical stains for chromogranin confirmed the neuroendocrine nature of this tumor. The search for primary tumor revealed an obstructing lesion in the mid jejunum, measuring 1.5 × 1.5 × 1.0 cm, which showed identical morphologic features to the liver lesion and was considered the primary tumor.
Fine-needle aspiration of the breast masses revealed features of malignant tumor; cells were mostly single or in small clusters and had an increased nuclear-cytoplasmic ratio, coarse chromatin, peripherally positioned nuclei, and pale slightly granular cytoplasm. Core biopsies of both breast lesions showed identical features. Clusters, ribbons, and trabeculae of neuroendocrine-like cells were surrounded by marked desmoplastic reaction. No evidence of DCIS was seen in either biopsy. Cells showed coarse chromatin, and characteristic neuroendocrine granules were again present within the cytoplasm (Figure 4). Results of immunohistochemical stains were identical to those of the primary jejunal tumor.
Carcinoids are tumors that are typically slow-growing neoplasms derived from the enterochromaffin cells of a variety of organ systems, most commonly the gastrointestinal or respiratory tract.8 Carcinoid syndrome occurs in approximately 5% of patients and consists of episodes of flushing, diarrhea, and abdominal pain.9 Carcinoid tumors are potentially malignant, generally being associated with regional lymph node and liver metastases. Morphologic features cannot predict the metastatic potential of typical carcinoids, and it is not uncommon for a tumor with vary bland morphology, no mitotic activity, or necrosis to produce distant metastases. The most common sites of distant metastases are liver, lung, and the peritoneum, whereas bone, skin, and the nervous system are rarely involved.8
Metastases to the breast from extramammary tumors are relatively uncommon, with the lung, prostate, lymphoma, and melanoma being the most frequent types.10 While adenocarcinomas from the gastrointestinal tract are rare sources of metastatic lesions, carcinoid tumors of the small bowel have been found to be a somewhat more frequent source of breast metastases; fewer than 25 cases have been described in the literature to date.11-14
Distinguishing carcinoid tumor to the breast from primary breast carcinoma is difficult both clinically and morphologically. In our study, case 1 clinically presented as a solitary spiculated lesion detected on mammography and was virtually indistinguishable from primary invasive breast carcinoma. However, some of the described metastatic carcinoids to the breast presented clinically as solid or multiple well-circumscribed lesions and could be clinically interpreted as fibroadenomas, medullary carcinoma, or mucinous carcinoma.4,15,16
Morphologic distinction was difficult both on FNA and lumpectomy specimens. The FNA of case 1 was interpreted as ductal carcinoma owing to high cellularity of the smear, single cells, and small clusters of cells with coarse chromatin and a somewhat increased nuclear-cytoplasmic ratio. Features such as plasmacytoid appearance, salt-and-pepper chromatin, and even the presence of bluish granules17-20 on Giemsa stain were overlooked and should have raised a possibility of neuroendocrine origin. In the review by Fishman et al,24 8 of 13 patients with metastatic carcinoid to the breast were initially considered to have primary breast carcinoma and were treated with mastectomy. Identical to our case 1, the diagnosis of metastatic carcinoid was made only after reviewing the lumpectomy/mastectomy specimen once the patient was diagnosed with primary carcinoid tumor elsewhere.
Morphologic distinction between primary invasive ductal carcinoma and primary breast carcinoid is difficult owing to several overlapping features and the reported frequency of neuroendocrine cells from 3% to 25%1 in female mammary carcinomas. Many of the tumors that contain neuroendocrine granules have been described as infiltrating ductal carcinomas with varying degrees of differentiation. Some of those tumors have organoid growth patterns that resemble carcinoid tumors that arise in other organs, therefore Cubilla and Woodruff22 introduced the term primary carcinoid of the breast in 1977. However, no neuroendocrine granules were ever detected in normal human fetal or adult breast tissue by immunohistochemistry or electron microscopy; therefore, the concept of primary breast carcinoid has now largely been discredited, and the term mammary carcinoma with endocrine features is favored. Only by the presence of DCIS with neuroendocrine expression it is possible to confirm the mammary origin of those carcinomas.23 However, organoid nests of carcinoid tumor with rosettelike structures can mimic the pattern of solid or cribriform DCIS. It has been noted that the pattern of neuroendocrine DCIS is either solid papillary or organoid, whereas conventional cribriform and comedo intraductal carcinomas are typically nonendocrine.24 Additional immunohistochemical stains may help in distinguishing the two. In particular, the use of smooth muscle actin or calponin can be helpful, since in any DCIS the basal layer of myoepithelial cells still persists, confirming the ductal origin of the lesion. On the contrary, such a layer of myoepithelial cells is absent in the case of metastatic carcinoid exhibiting organoid pattern and mimicking DCIS. Carcinomas of mammary origin will strongly express CK7 and will not express CK20, whereas in neuroendocrine tumors in general, both CK7 and CK20 will be negative. In our case 1, 2 morphologic patterns were observed. The "infiltrating" pattern consisted of rows and trabeculae of tumor cells surrounded by intense desmoplastic reaction.
Oval and round islands of the same type of cells with occasional "punched-out" spaces reminiscent of the solid and cribriform pattern of DCIS were also present. Only 1 area of cribriform DCIS, which contained cells that exhibit more pleomorphism and no neuroendocrine features, was observed. This is the only focus that strongly expressed CK7 and was negative for both synaptophysin and chromogranin, and positive for smooth actin muscle and calponin in the single layer of the myoepithelial cells at the base of the expanded duct, thus confirming the true mammary origin. The rest of the solid DCIS-like areas exhibited the reverse pattern, with no CK7, calponin, or smooth muscle actin expression and strong synaptophysin and chromogranin staining. This staining pattern could represent collision of 2 tumors, genuine mammary DCIS and metastatic carcinoid tumor. The other unusual feature of case 1 was the presence of regional lymph node metastases both in axillary lymph node and in mesenteric lymph node. This finding raises a possibility of multiple primary tumors with the regional lymph node metastases. However, in the presence of gastrointestinal carcinoid it is clinically more likely for the bilateral breast tumors to be of metastatic origin, despite the local regional lymph node metastases. In this case, the breast tumor also did not stain for estrogen receptor, which is unusual for primary neuroendocrine tumors in the breast.25,26 The presence of carcinoid syndrome would also be seen more commonly in metastatic carcinoid tumor than in primary neuroendocrine tumor of breast27; but as we saw in both our cases, these symptoms may not be identified. In fact, it is not unusual for metastatic gastrointestinal carcinoid tumor to present initially as a solitary breast mass,14 which could make clinical distinction extremely difficult.
The clinical course of case 2 took a different turn, and a diagnosis of metastatic bilateral carcinoid to the breast was facilitated by the presence of previously resected carcinoid tumor of the small bowel. The pattern in both breast core biopsies was infiltrative, and tumor cells exhibited clear presence of neuroendocrine granules even on hematoxylin-eosin-stained slides. Studies on our 2 patients demonstrated that carcinoid tumors can metastasize in both breasts, either as a late manifestation of already recognized disease or as a presenting lesion. Certainly the diagnosis is much easier with the existence of primary carcinoid tumor; however, in the review study of Fishman et al,21 8 of 13 patients with metastatic carcinoid to the breast were initially considered to have primary breast carcinoma, even cases with a medical record of carcinoid tumor.
Without a history of previously resected carcinoid tumor, diagnosis of metastatic carcinoid is difficult. We presented 2 cases with virtually identical morphologic findings, yet the initial diagnoses of the breast lesions were different owing to different clinical presentations. Our case confirms the difficulty of the diagnosis due to histologie similarities that may exist between carcinoid tumor and primary breast ductal carcinoma.
Even though metastases to the breast from other sites are relatively rare, special attention should be dedicated to breast lesions with morphologic features of neuroendocrine tumors. A search for evidence of DCIS with additional special staining, especially smooth muscle actin, calponin, and CK7 is recommended (Table). In cases of breast lesions with neuroendocrine features but negative staining for estrogen receptor, CK7, smooth muscle actin, and calponin, meticulous clinical evaluation and search for other sites of possible primary carcinoid is justified.
We thank Brenda C. Furlong for technical help in performing electron microscopy analysis and obtaining photographs.
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Marina B. Mosunjac, MD; Ruby Kochhar, MD; Mario I. Mosunjac, MD; Stephen K. Lau, MD
Accepted for publication October 22, 2003.
From the Departments of Pathology and Laboratory Medicine (Drs M. B. Mosunjac, M. I. Mosunjac, and Lau) and Hematology and Oncology (Dr Kochhar), Emory University, Grady Memorial Hospital, Atlanta, Ga.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Stephen K. Lau, MD, Department of Pathology, Grady Memorial Hospital, 80 Jesse Hill Jr Dr SE, Atlanta, GA 30303 (e-mail: email@example.com).
Copyright College of American Pathologists Mar 2004
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