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Primary mammary small-cell carcinoma: A case report and review of the literature

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2009; 30(01): 31-34

DOI: DOI: 10.4103/0971-5851.56334

Author : Haji, Altaf Gauhar; Sharma, Shekhar; Vijaykumar, D K; Mukherjee, Poulome; Babu, R; Chitrathara, K:

Abstract

Only a few cases of primary small-cell carcinoma of the breast have been documented in the current medical literature. A confident diagnosis can only be made if a nonmammary site is excluded or if an in-situ component can be demonstrated histologically. These criteria have been met only in a very few of the published cases, including this case report. We describe a case of a 68-year-old lady with left breast lump, which was diagnosed as breast cancer on fine-needle aspiration and core biopsy. Metastatic workup was negative for disease elsewhere, and she received 3 cycles of neoadjuvant chemotherapy followed by surgery (modified radical mastectomy). However, the disease behaved very aggressively in the postoperative period. There is a lack of consensus regarding the management of the primary tumor. Present surgical treatment options are similar to those in cases of invasive ductal breast cancer, as appropriate for the size and stage of the lesion. A review of current literature on his rare entity is also presented.

Keywords

Small cell carcinoma - mammary - neuroendocrine tumor


Publication History

Article published online:
19 November 2021

© 2009. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Only a few cases of primary small-cell carcinoma of the breast have been documented in the current medical literature. A confident diagnosis can only be made if a nonmammary site is excluded or if an in-situ component can be demonstrated histologically. These criteria have been met only in a very few of the published cases, including this case report. We describe a case of a 68-year-old lady with left breast lump, which was diagnosed as breast cancer on fine-needle aspiration and core biopsy. Metastatic workup was negative for disease elsewhere, and she received 3 cycles of neoadjuvant chemotherapy followed by surgery (modified radical mastectomy). However, the disease behaved very aggressively in the postoperative period. There is a lack of consensus regarding the management of the primary tumor. Present surgical treatment options are similar to those in cases of invasive ductal breast cancer, as appropriate for the size and stage of the lesion. A review of current literature on his rare entity is also presented.

Keywords: Small cell carcinoma, mammary, neuroendocrine tumor

INTRODUCTION

Small-cell carcinoma, although most commonly encountered in the lung, can occur in many extrapulmonary sites, including the salivary glands, upper respiratory mucosa, intestinal tract, pancreas, urinary tract and other organs.[] Despite a histologically undifferentiated appearance, these tumors are notable for variable expression of neuroendocrine (NE) markers.[]

Primary mammary small-cell carcinoma (PMSCC) is an uncommon entity and has been documented infrequently in the current medical literature.[–] The diagnosis of PMSCC can be made with confidence only if a nonmammary site is excluded clinically and radiologically or if an in-situ component can be demonstrated histologically.[] These criteria have not been met in all of the published descriptions of this rare neoplasm. It is important to differentiate between small-cell carcinoma originating primarily in breast and metastatic disease to the breast.

CASE REPORT

A 68-year-old woman presented with a left breast lump that had gradually increased in size over the last 3 months. She had no other significant local or systemic symptoms or any other significant medical history. Physical examination revealed a 5.8 × 4.3 cm lump in the upper outer quadrant of left breast with multiple significantly enlarged left axillary nodes. Fine-needle aspiration and core biopsy were suggestive of infiltrating ductal carcinoma (IDC). Metastatic workup [including computed tomography (CT) chest, ultrasound abdomen and bone scans] excluded any obvious metastatic focus, and she was then started on Docetaxel and Epirubicin as a part of neoadjuvant chemotherapy protocol, with good clinical response (>50% reduction in the sum of two dimensions) after 6 cycles of chemotherapy. She then underwent modified radical mastectomy.

The gross primary tumor size at the time of surgery was 2.8 × 2.2 cm, with 13 lymph nodes dissected out during axillary dissection. In the final histopathology report, the resection margins were free of tumor and 1 (out of 13) lymph node showed metastatic tumor. Routine immunohistochemistry for Estrogen receptor (ER), Progesterone receptor (PR) and Her-2neu was reported as negative.

Microscopically, the majority of cells were small with scanty cytoplasm and hyperchromatic nuclei, admixed with occasional nucleoli arranged in nests with a focal cribriform pattern and trabeculae separated by desmoplastic stroma. Mitosis was scanty and necrosis was absent [Figures ​[Figures11 and ​and2].2]. No lymphovascular or perineural invasion was seen. Two areas of in-situ component were also noted showing cells of similar morphology. Immunohistochemistry was negative for neuron-specific enolase, chromogranin and synaptophysin, while it was positive for cytokeratin.


| Figure 1  Low-power view of primary mammary cell carcinoma —H and E stain, (magnification ×100): Photomicrograph of the lesion inthe breast showing monomorphic small cells with scanty cytoplasm arranged in cribriform and trabecular pattern

| Figure 2  High-power view of primary mammary cell carcinoma — H and E stain, (magnification ×200): High-power magnification photomicrograph showing small cells with prominent hyperchromatic nuclei with evenly distributed chromatin, scanty cytoplasm and occasional mitosis


A thorough evaluation to search for the extra-mammary primary site was carried out, including a CT scan of the abdomen, cervical smear and a review of the CT scan chest in the postoperative period. Surprisingly, this time the abdominal scan showed several metastatic liver deposits, mainly in segments V and VI. Results of other investigations were normal. The patient died as a result of the disease a month after surgery.

Discussions with pathologist and review of the initial core biopsy and comparison with final histopathology were done, which revealed similar morphology of the cells. Possible reason for initial diagnosis of IDC, postulated during this discussion and review, was the first reported FNAC, clinical history and nature and site of biopsy.

DISCUSSION

Few cases of PMSCC have been described in the available literature, which consists largely of case reports; [–]and 4 series: One each with nine,[] seven,[] three[] and four patients.[] The absence of a primary small-cell carcinoma elsewhere and the presence of an in-situ component favor the diagnosis of a primary small-cell lesion originating in the breast.[]

Table 1 presents the clinico-pathological findings of all published cases of primary mammary small-cell carcinoma.

Table 1

Clinico-pathological findings of published cases of primary mammary small-cell carcinoma. (This table lists out the details of 33 cases of primary mammary small-cell carcinoma published in English literature to date.) LN = Lymph node status (positive/ total number);IS = In-situ component; VI = Vascular invasion; ER: Estrogen receptor status; Pos = Positive; Neg: Negative; NS = Not specified; MRM = Modified radical mastectomy;RM = Radical mastectomy; TE = Tumorectomy; NACT = Neoadjuvant chemotherapy; CT = Chemotherapy; RT = Radiotherapy; F-U = Follow-up; DOD = Dead of disease;NED = No evidence of disease; AWD = Alive with disease; *= Present in 7 cases; ? = Not known or not reported; + = Involved; NA = Not available; Surg@ = Surgery done but exact details not known; BCS = Breast-conserving surgery a= Associated with Paget's disease, reported as an addendum to the initial series of 9 cases

Clinical presentation

There are no notable differences in presentation when compared with other types of breast cancers. The average (mean) age at presentation of the reported patients [Table 1] is 57.6 years (range, 41-75 years). Patients often present with a palpable mass (mean size of 3.5 cm; range, 0.5-10.5 cm), which usually appears circumscribed on mammography and ultrasound examination.

Histology

These tumors exhibit features similar to those of NE tumors of the gastrointestinal tract or lung. Although they exhibit NE markers in more than 50% of the cell population, there is no consistent immunoreactivity, and the diagnosis should not be excluded only on the basis of negative reactivity for selected NE markers.[] Thus, at present, the demonstration of an NE immunoprofile is supportive but not essential for the diagnosis of PMSCC.[,]

In our patient, the tumor had histological characteristics of a small-cell carcinoma, including 'small' (approximately the sum of diameters of three lymphocytes) nuclei with scant cytoplasm; finely granular, evenly distributed chromatin; absent or inconspicuous nucleoli; and frequent mitoses. The observations of variable immunoreactivity provide an explanation for the negative immunoreactivity for synaptophysin, neuron-specific enolase and chromogranin in our case.

Molecular biology

It is generally agreed that tumors of the breast with endocrine features do not arise from preexisting endocrine cells.[] The immunoprofile suggests that small-cell carcinoma of the breast may represent a type of 'metaplasia.' Hoang et al.,[] reported identical molecular alterations at multiple chromosomal regions in 2 cases of PMSCC using laser-capture micro-dissection followed by loss-of-heterozygosity (LOH) analysis. Further research is necessary to analyze the molecular pathology of PMSCC.

Imaging

The existence of a primary lesion is controversial and should only be considered after a thorough evaluation has been performed to rule out an occult primary tumor elsewhere. A thorough history-taking and detailed clinical evaluation followed by radiological investigations (CT chest and CT abdomen at the minimum) are recommended before a diagnosis of primary mammary small-cell carcinoma can be made.[] This is in contrast to invasive epithelial breast cancer, where a metastatic workup is recommended only for locally advanced cases; and that too includes only a chest X-ray, USG abdomen and bone scan.

Treatment

The recognition of a presumptive origin of PMSCC is extremely important because of the different clinical management of a primary versus a metastatic tumor[,] (see present consensus below).

Surgical options, used in the reported 34 cases, vary widely from no surgery (1 case); plain tumor excision (9 cases); breast-conserving surgery (1 case); modified radical mastectomy (12 cases) to even radical mastectomy (4 cases). Details of surgery are in fact not available for 7 cases.

There are no recommendations or guidelines for chemotherapy or radiotherapy for PMSCC. This lack of consensus is quite apparent on review of treatment schedules used in the reported cases.

In the largest series reported, Shin et al.,[] treated 7 patients with chemotherapy, although the authors do not provide any further details of the chemotherapy that these patients received. Yamamoto et al.,[] treated 3 patients with adjuvant chemotherapy (cyclophosphamide, adriamycin and fluorouracil ‒ CAF). Papotti et al.,[] treated 1 out of their 4 patients with adjuvant Streptozocin initially; and later, with CAF for recurrence. Sridhar et al.,[] used cisplatin and adriamycin-based chemotherapy; Francois et al.,[] used a combination of cyclophosphamide, adriamycin and etoposide; Wade et al.,[] used etoposide initially, followed by cyclophosphamide, adriamycin and vincristine for recurrence; while Mariscal et al.,[] used cisplatin and etoposide. Jundt et al.,[] used adjuvant chemotherapy but have not reported on the details.

Similarly, adjuvant radiotherapy is reported only in 8 out of 34 cases, with minimal or no details regarding the fields, portals, dosage, fractions, etc. Thus, there is paucity of clear recommendations regarding management of these rare tumors. The present consensus is that a patient with PMSCC should be treated in a manner similar to that used to treat invasive epithelial breast carcinoma, as appropriate for the size and stage of the lesion; although there is no definitive evidence that this approach is superior to, or more effective than, other approaches.

Prognosis

Historically these tumors are considered highly malignant with a very poor prognosis. It was generally thought that the prognosis of these tumors was as poor as their counterpart in the lung.[,] This, however, may not be a true representation of the natural history of the disease. Available literature seems to suggest that the prognosis may not be as grave as believed, especially for tumors detected earlier and those without lymph node metastasis. With a mean follow-up period of nearly 2 years (mean follow-up period, 23.9 months; range, 1-84 months), literature shows a mortality of 20.5% (7 out of 34 cases).

CONCLUSION

PMSCC is extremely rare, and historically it is considered to be a highly aggressive tumor. The initial diagnostic tools (mammography, fine-needle aspiration cytology and core biopsy) may not detect this malignant tumor in many instances. Most of the cases are treated according to conventional clinical and pathological criteria, similar to those for the treatment of other invasive breast cancers. It is important to rule out extra-mammary primary sites, as PMSCC is treated as an invasive epithelial breast cancer. The prognosis remains unclear, although more recent data suggest that the prognosis for relatively early-stage small-cell carcinoma may be more favorable than historically believed.

Acknowledgments

Authors gratefully acknowledge the contribution of MS Radha through secretarial assistance.

Footnotes

Source of Support: Nil

Conflict of Interest: None declared.

  • References
Author Ref.no Age TNM Size(cm) LN IS VI ER Treatment F-U Status
Jundt 2 52 TxN1M0 NS NS NS NS NS CT/RT 14 DOD
Shin 3 43 T1NxM0 1.3 NA NS NS NS TE/RT 30 NED
44 T1N0M0 2 0/21 NS * Pos TE/CT/RT 27 NED
46 T2N1M0 3.4 2/26 NS * Pos TE/CT 11 AWD
50 T2NxM0 2.2 + / ? NS * Pos TE/CT/HT 35 NED
51 T1N0M0 1.5 0/10 NS * Pos TE/RT 25 NED
57 T2N0M0 2.5 0/19 NS * Pos MRM/CT 10 NED
62 T2N1M0 5 2/17 NS * Pos NACT/MRM 32 AWD
64 T1N0M0 1.8 0/15 NS * Pos TE/CT 10 NED
70 T2NxM0 4 + / ? NS * Pos TE/CT/RT 3 NED
67a T1NxM0 2 + / ? Yes NS Neg TE/? ? ?
Jochems 4 71 T2N0M0 3 0/10 No No Pos MRM/HT 12 NED
Chua 5 45 T2N0M0 4.5 NS NS NS Neg TE <1> NED
Yamasaki 6 41 T2N0M0 4.5 0/5 Yes Yes Neg MRM/CT 16 NED
Francois 7 68 T2N0M0 4 0/20 No Yes Neg MRM/RT 21 DOD
Fukunaga 8 56 T4NxMx 10.5 1/11 Yes Yes Neg RM 48 NED
Wade 9 52 T4N1M1 10 25/25 No Yes Ns MRM/CT 9 DOD
Sridhar 10 58 T1N1M0 2 1/9 NS NS NS BCS/CT/RT 18 NED
Mariscal 11 53 T2N2M0 5 + / ? NS NS NS NACT/MRM 6 NED
Yamamoto 12 53 T3N2M0 6.5 + / ? NS NS NA Surg@ 34 NED
75 T2N1M0 2.5 + / ? NS NS NA Surg@ 43 NED
58 T2N0M0 2.3 NS NS NS NA Surg@ 23 NED
65 T1N0M0 0.7 NS NS NS NA Surg@ 28 NED
70 T3N0M0 6.6 NS NS NS NA Surg@ 24 NED
50 T3N0M0 6.0 NS NS NS NA surg@ 34 NED
50 T1N0M0 0.5 NS NS NS NA surg@ 35 NED
Jablon 13 72 T2N0M0 2.5 0/14 NS NS Pos MRM 84 NED
71 T1N0M0 2 0/21 NS NS Pos MRM 60 NED
54 T1N0M0 1.3 0 / ? NS NS Neg MRM 15 NED
Papotti 14 64 T1N0M0 2 0/10 Yes Yes Neg RM 44 NED
41 T2N3M0 3.5 7/14 Yes Yes Neg RM/CT 15 DOD
50 T2N1M0 3 3/18 Yes Yes Neg RM/CT 14 DOD
69 T3N1M0 5 3/10 Yes Yes Pos MRM/HT 9 DOD
Present 68 T3N1M0 5.8 1/13 No Yes Pos MRM 1 DOD
  1.  Ibrahim NBN, Briggs JC, Corbishley CM. Extrapulmonary oat cell carcinoma. Cancer 1984;54:1645-61.
  2.  Jundt G, Schulz A, Heitz P, Osborn M. Small cell neuroendocrine (oat cell) carcinoma of the male breast: Immunocytochemical and ultrastructural investigations. Virchows Arch A Pathol Pathol Anat 1984;404:213-21.
  3.  Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell carcinoma of the breast: A clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 2000;24:1231-8.
  4.  Jochems L, Tjalma WA. Primary small cell neuroendocrine tumor of the breast. Eur J Obstet Gynecol Reprod Biol 2004;115:213-33.
  5.  Chua RS, Torno RB, Vuletine JC. Fine needle aspiration cytology of small cell neuroendocrine carcinoma of the breast: A case report. Acta Cytol 1997;41:1341-4.
  6.  Yamasaki T, Shimazaki H, Aia S, Tamai S, Tamaki K, Hiraide H, et al. Primary small cell (oat cell) carcinoma of the breast: Report of a case and review of literature. Pathol Int 2000;50:914-8.
  7.  Francois A, Chatikhine VA, Chevallier B, Ren GS, Berry M, Chevrier A, et al. Neuroendocrine primary small cell carcinoma of the breast: Report of a case and review of the literature. Am J Clin Oncol 1995;18:133-8.
  8.  Fukunaga M, Ushigome S. Small cell (oat cell) carcinoma of the breast. Pathol Int 1998;48:744-8.
  9.  Wade PM Jr, Mills SE, Read M, Cloud W, Lambert MJ 3 rd , Smith RE. Small cell neuroendocrine (oat cell) carcinoma of the breast. Cancer 1983;52:121-5.
  10.  Sridhar P, Matey P, Aluwihare N. Primary carcinoma of breast with small-cell differentiation. Breast 2004;13:149-51.
  11.  Mariscal A, Balliu E, Dνaz R, Casas JD, Gallart AM. Primary oat cell carcinoma of the breast: Imaging features. Am J Radiol 2004;183:1169-71.
  12.  Yamamoto J, Ohshima K, Nabeshima K, Ikeda S, Iwasaki H, Kikuchi M. Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. Oncol Rep 2004;11:825-31.
  13.  Jablon LK, Somers RG, Kim PY. Carcinoid tumor of the breast: Treatment with breast conservation in three patients. Ann Surg Oncol 1998;5:261-4.
  14.  Papotti M, Gherardi G, Eusebi V, Pagani A, Bussolati G. Primary oat cell (neuroendocrine) carcinoma of the breast: Report of four cases. Virchows Arch A Pathol Pathol Anat 1992;420:103-8.
  15.  Rosen PP. Mammary carcinomas with endocrine features. In: Rosen′s Breast Pathology. Philadelphia, PA: Lippincott-Raven; 1997. p. 431-6.
  16.  Hoang MP, Maitra A, Gazdar AF, Albores-Saavedra J. Primary mammary small-cell carcinoma: A molecular analysis of 2 cases. Hum Pathol 2001;32:753-7.
  17.  Upalakalin JN, Collins LC, Tawa N, Parangi S. Carcinoid tumors in the breast. Am J Surg 2006;191:799-805.

| Figure 1  Low-power view of primary mammary cell carcinoma —H and E stain, (magnification ×100): Photomicrograph of the lesion inthe breast showing monomorphic small cells with scanty cytoplasm arranged in cribriform and trabecular pattern

| Figure 2  High-power view of primary mammary cell carcinoma — H and E stain, (magnification ×200): High-power magnification photomicrograph showing small cells with prominent hyperchromatic nuclei with evenly distributed chromatin, scanty cytoplasm and occasional mitosis

  1.  Ibrahim NBN, Briggs JC, Corbishley CM. Extrapulmonary oat cell carcinoma. Cancer 1984;54:1645-61.
  2.  Jundt G, Schulz A, Heitz P, Osborn M. Small cell neuroendocrine (oat cell) carcinoma of the male breast: Immunocytochemical and ultrastructural investigations. Virchows Arch A Pathol Pathol Anat 1984;404:213-21.
  3.  Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell carcinoma of the breast: A clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 2000;24:1231-8.
  4.  Jochems L, Tjalma WA. Primary small cell neuroendocrine tumor of the breast. Eur J Obstet Gynecol Reprod Biol 2004;115:213-33.
  5.  Chua RS, Torno RB, Vuletine JC. Fine needle aspiration cytology of small cell neuroendocrine carcinoma of the breast: A case report. Acta Cytol 1997;41:1341-4.
  6.  Yamasaki T, Shimazaki H, Aia S, Tamai S, Tamaki K, Hiraide H, et al. Primary small cell (oat cell) carcinoma of the breast: Report of a case and review of literature. Pathol Int 2000;50:914-8.
  7.  Francois A, Chatikhine VA, Chevallier B, Ren GS, Berry M, Chevrier A, et al. Neuroendocrine primary small cell carcinoma of the breast: Report of a case and review of the literature. Am J Clin Oncol 1995;18:133-8.
  8.  Fukunaga M, Ushigome S. Small cell (oat cell) carcinoma of the breast. Pathol Int 1998;48:744-8.
  9.  Wade PM Jr, Mills SE, Read M, Cloud W, Lambert MJ 3 rd , Smith RE. Small cell neuroendocrine (oat cell) carcinoma of the breast. Cancer 1983;52:121-5.
  10.  Sridhar P, Matey P, Aluwihare N. Primary carcinoma of breast with small-cell differentiation. Breast 2004;13:149-51.
  11.  Mariscal A, Balliu E, Dνaz R, Casas JD, Gallart AM. Primary oat cell carcinoma of the breast: Imaging features. Am J Radiol 2004;183:1169-71.
  12.  Yamamoto J, Ohshima K, Nabeshima K, Ikeda S, Iwasaki H, Kikuchi M. Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. Oncol Rep 2004;11:825-31.
  13.  Jablon LK, Somers RG, Kim PY. Carcinoid tumor of the breast: Treatment with breast conservation in three patients. Ann Surg Oncol 1998;5:261-4.
  14.  Papotti M, Gherardi G, Eusebi V, Pagani A, Bussolati G. Primary oat cell (neuroendocrine) carcinoma of the breast: Report of four cases. Virchows Arch A Pathol Pathol Anat 1992;420:103-8.
  15.  Rosen PP. Mammary carcinomas with endocrine features. In: Rosen′s Breast Pathology. Philadelphia, PA: Lippincott-Raven; 1997. p. 431-6.
  16.  Hoang MP, Maitra A, Gazdar AF, Albores-Saavedra J. Primary mammary small-cell carcinoma: A molecular analysis of 2 cases. Hum Pathol 2001;32:753-7.
  17.  Upalakalin JN, Collins LC, Tawa N, Parangi S. Carcinoid tumors in the breast. Am J Surg 2006;191:799-805.

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