Neuroendocrine Tumor of the Breast

By Valdes, Edna K; Feldman, Sheldon M; Krassilnik, Nina

Mammary carcinoid is an uncommon neoplasm. It accounts for approximately 5 per cent of all breast carcinomas. It is well-known that neuroendocrine elements can be demonstrated in ductal and lobular carcinoma. However, it is still controversial whether mammary carcinoid tumors should be considered a distinct clinical entity or be treated as a variant of conventional breast carcinoma. Differentiating these lesions from benign lesions such as epithelial hyperplasia and papillomas can be challenging at times. We present a case of neuroendocrine tumor of the breast.

THE PATIENT IS A 41-year-old female with a history of right breast ductal carcinoma in situ for which she underwent lumpectomy and postoperative radiation therapy approximately 3 years earlier. She was doing well on tamoxifen. A screening mammogram revealed new indeterminate calcifications in the lateral aspect of the right breast posterior to the previous lumpectomy site. Sonography of the right breast identified five separate solid nodules with irregular margins as follows: 1.7 cm in the 9:00 position 5 cm from the nipple with an adjacent 7 mm nodule; 1.2 cm nodule in the 9:30 location 6 cm from the nipple; and two adjacent solid nodules measuring 1.6 cm and 1.3 cm, respectively, in the 9:30 location 4 cm from the nipple. Sonographic-guided needle biopsy of four of these nodules as well as a core biopsy of one of these nodules revealed ductal carcinoma with neuroendocrine features (Fig. 1). The tumor was estrogen receptor positive, progesterone receptor negative, and Her-2 negative.

On physical examination, no abnormality was noted other than echymotic region secondary to the needle biopsies. Metastatic evaluation did not demonstrate any distant disease. She underwent right mastectomy, right axillary sentinel node biopsy, right deep inferior epigastric perforator flap reconstruction, and left mastopexy. Pathology revealed a 1.5-cm multifocal carcinoid (carcinoma with neuroendocrine differentiation) of the breast with an intraductal component (Figs. 2 and 3). The sentinel lymph nodes were negative.

The patient recently completed four cycles of adriamycin and cytoxan.

Discussion

Mammary carcinoid is an uncommon neoplasm.1, 2 It accounts for approximately 5 per cent of all breast carcinomas.2, 3 In 1947, Vogler5 found argyrophilic “clear” cells in the human breast ducts and considered them to be of endocrine nature. In 1963, Feyrter and Hartmann4 described two breast carcinomas with carcinoid growth pattern and thus suggested a degree of (neuro) endocrine differentiation. However it was not until 1977, when Cubilla and Woodruff6 stated that the granules in the tumor cells were of the neurosecretory type and named these tumors “carcinoids.” In 1982, Azzapardi7 presented 14 cases of carcinoid tumors in which he showed that argyrophilic breast tumors form a spectrum with wide range of morphological and histochemical appearances and a variable prognosis.

Since Cubilla and Woodruff6 first described primary breast carcinoids, many researchers have attempted to further define these tumors by microscopy and immunohistochemical staining methods. To date there is still no universal definition of a breast carcinoid tumor. Diagnosis based on mammographic or sonographic appearance of these tumors is not possible.7

It is well-known that neuroendocrine elements can be demonstrated in ductal and lobular carcinoma. However, it is still controversial whether mammary carcinoid tumors should be considered a distinct clinical entity or be treated as a variant of conventional breast carcinoma.1 Endocrine breast carcinomas usually contain estrogen receptors, sometimes at very high levels. A surprisingly high number of male breast carcinomas (20%) show evidence of endocrine differentiation compared with 5 per cent in women.4

The following categories encompass the majority of mammary endocrine tumors: low-grade insular duct carcinoma (type A), which occurs most frequently; cellular mucinous carcinoma (type B), which allegedly have better prognosis4, 8; lobular carcinoma, alveolar type (type F); small cell undifferentiated carcinoma (type G), which is the most distinctive and the least common type.

FIG. 1. Ultrasound-guided fine-needle aspiration specimen showing malignant cells (Wright-Giemsa, original magnification 400).

FIG. 2. Surgical pathology showing carcinoma with neuroendocrine differentiation (hematoxilin-eosin, original magnification 400).

Most endocrine tumors of the breast, except small cell carcinomas, are well differentiated and consist of densely cellular, solid nests and trabeculae of cells separated by delicate fibrovascular stroma. The tumor cells occasionally form rosette- like structures and display peripheral nuclear palisading reminiscent of carcinoid tumors.9 Because of the mild cytologic atypia of carcinoid cells, differentiating these lesions from benign lesions such as epithelial hyperplasia and papillomas can be challenging on fine-needle aspiration specimen.4 Two histopathological features are used to identify these tumors: argyrophilia and ultrastructural “neurosecretory” granules.3 Features that can help in differentiation of these lesions include peripheral palisading of the nuclei, pseudorosette formation, accumulation of intracellular mucin, and demonstration of endocrine features by silver precipitation or immunohistochemical methods.4

FIG. 3. Neuroendocrine differentiation of the tumor cells is confirmed by staining for synaptophysin (immunoperoxidase, original magnification 400).

The principal differential diagnosis of mammary carcinoid include lobular carcinoma, mammary non-Hodgkin’s lymphoma, and carcinoid tumor metastatic to the breast. The cytological features of metastatic carcinoid are similar to that of breast carcinoid. Therefore, to differentiate these two entities, medical history and clinical investigation to rule out carcinoid tumor elsewhere is of utmost importance.2

Although no carcinoid syndrome has been reported, an increased production of parathyroid hormone, norepinephrine, adrenocorticotrophic hormone, calcitonin, human chorionic gonadotropin, chromogranin, bombesin, gastrin, B-endorphins, serotonin, and substance P have been reported in argyrophil breast tumors.2, 3, 10 Nodal or distant metastases have been reported in about 18 per cent of all the cases and only when the tumor was 2.5 cm or larger and with ten or more mitoses/10 HPF.3 Metastases have been reported to bone, liver, lungs, and brain.10 There is some data in the literature supporting the use of anthracyclines in the treatment of neuroendocrine differentiated breast carcinoma. Because this tumor is felt to be less aggressive, surgical resection of metastatic disease can lead to a lasting disease-free survival.11

The overall prognosis of mammary carcinoma with carcinoid features is generally considered to be comparable to that of conventional breast carcinomas2 and seems to correlate well with their size and degree of anaplasia.12 However, the small cell subtype is reportedly a very aggressive tumor with poor prognosis for which no clear management has been agreed upon. Stage, tumor size, and lymph node status are the prognostic factors. In most series, patients were treated with modified radical mastectomy, various chemotherapeutic regimens and adjuvant radiation therapy to the chest wall and draining lymph nodes, with mode and total dose as in primary breast cancer. The commonly used chemotherapeutic agents are VP16 and cisplatin. Neoadjuvant chemotherapy has also resulted in decreased tumor size. However, no long-term follow-up studies are available.13, 14

Conclusion

The concept of endocrine differentiation of breast cancers is well-established.4 Although mammary carcinoids often demonstrate an innocent histologic and cytologic appearance, they probably carry a similar prognosis to that of conventional breast carcinomas2 and seem to correlate well with their size and degree of anaplasia,12 whereas the small cell subtype is reportedly a very aggressive tumor with poor prognosis for which no clear management has been agreed upon.13, 14 Diagnosis cannot be established based on mammographic or sonographic appearance of these tumors.7 Therefore, the treatment approach should be decided upon accordingly.2, 15 Although very rare, carcinoid tumor has been reported to metastasize to the breast. Therefore, the possibility of metastasis to the breast from a primary in the lung or even in the gastrointestinal tract should always be kept in mind and ruled out.16

REFERENCES

1. wee A, Nilsson B, Chong SM, Raju GC. Bilateral carcinoid tumor of the breast. Report of a case with diagnosis by fine needle aspiration cytology. Acta Cytol 1992;36:55-9.

2. Ni K, Bibbo M. Fine needle aspiration of mammary carcinoma with features of a carcinoid tumor. A case report with immunohistochemical and ultrastructural studies. Acta Cytol 1994; 38:73-8.

3. Giacchi R, Sebastiani M, Lungarotti F. The so-called “carcinoid” tumors of the breast. Ital J Surg Sci 1986;16:249-53.

4. Maluf HM, Koerner FC. Carcinomas of the breast with endocrine differentiation: a review. Virchows Arch 1994;425: 449-57.

5. Nesland JM, Memoli VA, Holm R, et al. Breast carcinomas with neuroendocrine differentiation. Ultrastruct Pathol 1985;8: \225-40.

6. Kaneko H, Sumida T, Sekiya M, et al. A breast carcinoid tumor with special reference to ultrastructural study. Acta Pathol Jpn 1982;32:327-32.

7. Hartgrink HH, Lagaay MB, Spaander PJ, et al. A series of carcinoid tumors of the breast. Eur J Surg Oncol 1995;21:609-12.

8. Fisher ER, Palekar AS, Collaborators NSABP. Solid and mucinous varieties of so-called mammary carcinoid tumors. Am J Clin Pathol 1979;72:909-16.

9. Sapino A, Righi L, Cassoni P, et al. Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol 2000;17:127-37.

10. Dubilier LD, Stoeckinger JM. Carcinoid tumor of the breast. J Ky Med Assoc 1982;80:147-9.

11. Berruti A, Saini A, Leonardo E, et al. Management of neuroendocrine differentiated breast carcinoma. Breast 2004;13: 527- 9.

12. Forouhar FA. Morphologic study of carcinoid-like tumors and their relation to true carcinoids, using tumors of the breast as a model. Tumori 1983;69:171-6.

13. Sridhar P, Matey P, Aluwihare N. Primary carcinoma of breast with small-cell differentiation. Breast 2004;13:149-51.

14. Stein ME, Gershuny A, Abdach L, Quigley MM. Primary small- cell carcinoma of the breast. Clin Oncol (R Coll Radiol) 17:202-2.

15. Van Laarhoven HAJ, Gratama S, Wereldsma JCJ. Neuro-endocrine carcinoid tumours of the breast: a variant of carcinoma with neuroendocrine differentiation. J Surg Oncol 1991;46: 125-32.

16. Pereda E, Ibanez T, Ereno C, et al. Well differentiated neuroendocrine carcinoma of the breast. Arch Anat Cytol Path 1995;43:164-6.

EDNA K. VALUES, M.D., SHELDON M. FELDMAN, M.D., F.A.C.S., NINA KRASSILNIK, M.D.

From the Louis Venet Comprehensive Breast Service, Beth Israel Medical Center, New York, New York

Address correspondence and reprint requests to Edna K. Valdes, M.D., Phillips Ambulatory Care Center, 10 East Union Square, Suite 4E, New York, NY 10003.

Copyright The Southeastern Surgical Congress Feb 2006