＊1Division of Surgical Oncology, Cancer Research Institute, Kanazawa University, ＊2Department of Surgery, Ishikawa National Hospital, ＊3Department of Human Pathology, Kanazawa University Graduate School of Medicine, Japan.
Vol. 14 No. 4 October 2007
Case Report
Introduction
Small cell carcinoma usually occurs in the lung but can occur in a variety of other sites. It is aggressive and has similar histological appear-ance wherever it occurs. It is rare that the breast is the primary site of small cell carcinoma - to our knowledge, only 30 cases have been reported in
the English literature since Wade et al.1)reported
the first case in 1983. For this reason, there is little information on the treatment or prognosis of primary small cell carcinoma of the breast. Here, we report a case of primary small cell carcinoma of the breast and discuss its clinical and pathologi-cal features.
Case Report
A 44-year-old woman presented with a painless lump in the left breast. There was no nipple retrac-tion, dimpling, or palpable axillary lymph node. A physical examination revealed a well-defined, elastic firm, freely movable round tumor with a smooth surface measuring about 4×5 cm in the upper outer quadrant of her left breast. The mass appeared round with indistinct margins and small round calcifications on mammography (Category 4)(Fig 1A), and solid and hypoechoic with low heterogeneous echoes and a microlobulated contour on ultrasonography (Fig 1B). On chest CT, in addition to the mass, the ipsilateral axillary lymph node appeared enlarged (Fig 1C). On mammographic MRI, the mass gave a predominantly hyperintense heterogeneous signal on T2-weighted images, and a hypointense signal on T1-weighted images (Fig 1D, E). On dynamic MRI images, the mass appeared microlobulated and showed early intense enhancement (T2, N1, M0, stage IIB). The levels of the serum tumor markers CEA, CA15-3, NCC-ST439, NSE, and SCC were within normal limits.
Reprint requests to Hidekazu Kitakata, Department of Surgery, Ishikawa National Hospital, 150 Tezuka-machi, Kaga, Ishikawa, 922-0405, Japan.
Abbreviations:
NSE, neuron-specific enolase; TTF-1, thyroid transcription factor-1; LCA, leukocyte common antigen; ER, estrogen receptor; PR, progesterone receptor; EMA, epithelial membrane antigen Received December 5, 2006; accepted May 7, 2007
We report a rare case of primary small cell carcinoma of the breast. A 44-year-old woman was admitted to our hospital with a mass in her left breast. Fine-needle biopsy revealed small cell carcinoma with neu-roendocrine differentiation resembling small cell carcinoma of the lung. Systemic computed tomography (CT) and magnetic resonance imaging (MRI) revealed no primary site in the lung or any other organ. A modified radical mastectomy with removal of the axillary lymph node (Bt + Ax, R2) was performed. Histo-logical examination revealed that the tumor was composed of small round to oval cells with a large nuclear-cytoplasmic ratio. The tumor cells were positive for neuroendocrine differentiation markers such as synaptophysin, CD56, and neuron-specific enolase (NSE), but negative for thyroid transcription factor-1 (TTF-factor-1), leukocyte common antigen (LCA), estrogen receptor (ER), and progesterone receptor (PR). Interestingly, the tumor cells lacked immunoreactivity for epithelial markers, including cytokeratin AE1/3, CAM5.2, and epithelial membrane antigen (EMA). The patient was given adjuvant chemotherapy for axillary lymph node metastasis. There were no signs of recurrence 22 months after surgery.
Breast Cancer 14:414-419, 2007.
A Case of Primary Small Cell Carcinoma of the Breast
Hidekazu Kitakata＊1, 2, Kazuo Yasumoto＊1, Yoshiko Sudo＊3, Hiroshi Minato＊3, Yutaka Takahashi＊1
On fine needle biopsy, there were small round malignant cells with a large nuclear-cytoplasmic ratio, resembling pulmonary small cell carcinoma in appearance. The cells showed diffuse immuno-reactivity for synaptophysin, CD56, and NSE, indi-cating neuroendocrine differentiation.
To exclude a non-mammary primary site, the head and neck, chest, abdomen, and pelvis were
scanned by CT and MRI, but no other abnormali-ties were found. Isotopic bone scan results were also normal. Therefore, we concluded that the breast was the primar y site, and primary small cell carcinoma of the breast was diagnosed. The patient under went modified radical mastectomy with axillary lymph node dissection (Bt+Ax, R2).
The resected tumor measured 4.5×4.0 cm and
Fig 1．Primary small cell carcinoma of the breast. A: Mammogram: A round high-density
mass with an obscure margin in the upper outer quadrant of the left breast. B: Ultrasonogram: A hypoechoic lesion with heterogeneous echoes and microlobulated margins. C: CT image: A microlobulated mass in the left breast. D, E: Mammographic MRI scan: A microlobulated mass with hypointense signal on T1-weighted images (D), and predominantly hyperintense signal on T2-weighted images (E).
A
B
C
was white-gray with a relatively well-defined border on the cut surface (Fig 2A). Histological examination showed that the tumor was com-prised of small round or oval cells with hyperchro-matic nuclei, scant cytoplasm, inconspicuous
nucleoli, and a high mitotic figure (102per 10 high
power fields) (Fig 2B). The tumor showed a solid sheet-like growth pattern with occasional thin fibrovascular stroma. Papillotubular structures or intracytoplasmic lumina were not seen. Focal rosette-like structures and molding of tumor cells were observed, but peripheral nuclear palisading and/or a ribbon-like appearance was not obvious. There was no in situ component. Immunohisto-chemically, the tumor cells were positive for neuroendocrine differentiation markers, including synaptophysin, CD56, and NSE (Fig 2C, D), but were negative for chromogranin A. The cells were also negative for TTF-1, a marker of pulmonary carcinoma, cytokeratin AE1/3, CAM5.2, 34betaE12, keratin-wide, CK7, CK20, EMA, LCA, CD20,
CD79a, CD3,
α
SMA, p63, vimentin, S100,myo-genin, myeloperoxidase, ER, PR, or Her-2/neu.
The tumor was weakly positive for bcl-2.
Histological examination also showed axillary lymph node metastases to 1 of 9 level I lymph nodes and 1 of 6 level II lymph nodes. Therefore, the patient was given adjuvant chemotherapy, comprised of 3 courses of EC (epirubicin and cyclophosphamide), given at 3 week inter vals, followed by 3 courses of docetaxel, given at 3 week inter vals. The patient is alive and well 22 months after surgery with no signs of recurrence.
Discussion
Small cell carcinoma can occur in a variety of extrapulmonar y sites, including bowel, esopha-gus, pancreas, salivary gland, bladder, cervix, and
prostate1-5) and the incidence is described to be
about 2.5-4%. In par ticular, primar y small cell carcinoma of the breast is rare; to our knowledge,
only 30 cases have been reported6-22) in the
inter-national literature since Wade et al.6)reported the
first case in 1983. Primary small cell carcinoma of the breast can be diagnosed if the presence of a
Fig 2．Histological findings of primary small cell carcinoma of the breast. A: The resected tumor
was white-gray with a relatively well-defined margin on the cut surface. B: The tumor consisted of small round or oval cells with hyperchromatic nuclei and scant cytoplasm (HE stain, original magni-fication ×400). C, D: The tumor cells showed cytoplasmic reactivity for neuroendocrine differentia-tion indicators; synaptophysin (C) and NSE (D) (original magnificadifferentia-tion ×400).
A
B
D
C
non-mammary primary site can be ruled out clini-cally, or an in situ component is detected
histologi-cally, or both1, 17). In previous reports, 17 tumors
had in situ components and 9 did not. Especially, in cases where an in situ component is absent, it is essential to examine other par ts of the body thoroughly to confirm that the breast tumor has
not metastasized from elsewhere13, 17, 19). In our
case, an in situ component was not detected histologically, but the presence of a non-mammary primar y site was ruled out by systemic CT and MRI scans, making primary small cell carcinoma of the breast a reasonable diagnosis.
Histologically, primary small cell carcinoma of the breast is similar to those arising from other
sites9, 20). The tumor cells are small and round or
oval, and have a large nuclear-cytoplasmic ratio. The nuclei are hyperchromatic with inconspicu-ous or no nucleoli. There is usually a high mitotic count. A dimorphic pattern was obser ved in 6
cases8, 11, 14). Small cell carcinoma was present
together with invasive lobular carcinoma in 3 cases, invasive ductal carcinoma in 2 cases, and squamous cell carcinoma in 1 case.
Primary small cell carcinoma of the breast has
a varied immunohistochemical profile21). In our
patient, the tumor did not stain positively for any epithelial markers. However, all cases reported previously showed immunoreactivity for one or more epithelial markers; 14 of 15 cases (93%) were reactive for cytokeratin CAM5.2, 11 of 12 (92%) for AE1/3, and 11 of 13 (85%) for cytoker-atin 7. To our knowledge, this is the first report of small cell carcinoma of the breast which was neg-ative for epithelial markers. Although it is ver y unusual to see negative cytokeratin stains in the case of small cell carcinoma of the breast, given the negative results for lymphoid markers and CD99 (MIC2) and the histologic appearance, we think this tumor is best regarded as small cell carcinoma.
The tumor cells in our patient stained strongly for neuroendcrine markers. Small cell carcinomas of the breast reported previously showed no con-sistent pattern of immunoreactivity for neuro-endocrine markers. Twenty of 22 cases (91%) were reactive for NSE, 7 of 9 (78%) for CD56, and 11 of 19 (58%) for synaptophysin.
In our patient, the tumor showed immunoreac-tivity for bcl-2, but not for ER, PR or HER2/neu. In previous reports, all of 12 cases were reactive for bcl-2, 7 of 15 cases were reactive for ER and 6 of
15 cases were reactive for PR, while none of 14 cases were reactive for HER2/neu. A formal assessment of bcl-2 and HER2/neu immunoreac-tivity in primary small cell carcinoma of the breast has not been reported previously.
The histogenesis of small cell carcinoma of the breast remains unclear. While the precise cell of origin is not known for small cell lung carcinoma, there is likely a pluripotent bronchial precursor cell that can differentiate into each of the major histologic types of lung cancer, specifically adeno-carcinoma, squamous cell adeno-carcinoma, large cell
carcinoma, and small cell carcinoma23). The
pres-ence of neuroendocrine cells in normal breast
tissue has not been proved conclusively22). So
there is also likely to be a pluripotent precursor cell in the terminal duct lobular unit (TDLU) that can differentiate into ductal, lobular, or small cell carcinoma. This position is suppor ted by the dimorphic appearance of the tumor in previously
reported cases22).
The clinical findings of the published cases of primar y small cell carcinoma of the breast are summarized in Table 1. All but 1 of the 30 patients were women, and their age range was 41 to 71 years (mean, 55.8 years). The tumors measured between 1.3 and 27.0 cm (mean, 4.4 cm). Eighteen of 28 (64%) of the patients had a secondary tumor in the lymph nodes. At initial diagnosis, two patients had distant metastases, such as to the liver, bone, skin, or brain. These two patients died from the cancer.
Our patient received chemotherapy, consisting
of 400 mg/m2of cyclophosphamide and 40 mg/m2
of epirubicin, every 3 weeks. Because this disease is so rare, there is no standard chemotherapeutic regimen. In 7 of the above 30 cases, the tumor was treated like pulmonary small cell carcinoma; 2 patients received doxorubicin based chemother-apy and 5 patients received EP (etoposide and cis-platin). Of the 7 patients, 1 patient who received neoadjuvant chemotherapy with EP experienced
complete remission18), although 2 patients died
from the cancer7, 22). On the other hand, 4 patients
received CMF (cyclophosphamide, methotrexate and fluorouracil) or FEC (fluorouracil, epirubicine and cyclophosphamide), as for conventional breast cancer. One of these 4 patients suf fered
partial remission13), and 1 died from the cancer8).
It is difficult to determine which regimen is best because of the small number of cases. Fur ther studies including a larger number of patients are
Table 2．Clinical Characteristics and Outcome
T N
T1 (%) T2 (%) T3 (%) N(-) (%) N(+) (%)
alive without disease alive with disease dead of disease 6(75) 1(12) 1(12) 7(64) 2(18) 2(18) 2(50) 0(0) 2(50) 7(88) 0(0) 1(12) 6(43) 3(21) 5(36)
Table 1．Clinical Findings of Published Cases of Primary Small Cell Carcinoma of
the Breast sex female male 29 1 age 41-71 (55.8) size (cm) T0 T1 T2 T3 1.3 - 27.0 (4.4) 1 9 16 4 lymph node N(-) N(+) N.D.＊1 8 18 4 treatment surgery radical mastectomy lumpectomy, excision chemotherapy CAV, CAE EP CMF FEC radiotherapy hormonal treatment 29 19 10 4 18 11 2 5 3 1 outcome＊2
alive without disease alive with disease dead of disease
dead of unrelated disease
15 3 6 2＊3
range, mean (months) (6-48, 22.0)
(6-32, 16.3) (9-21, 13.7)
CAV: cyclophosphamide, doxorubicin and vincristin; CAE: cyclophosphamide, doxorubicin and etoposide; EP: etoposide and cisplatin; CMF: cyclophosphamide, methotrexate and fluorouracil; FEC: fluorouracil, epirubicin and cyclophosphamid; ＊1
: not done; ＊2
: Four cases with follow-up of less than 6 months were excluded.; ＊3
: brain hemorrhage, neurological disorder
needed to establish a standardized regimen for primary small cell carcinoma of the breast.
Our patient is alive 22 months after surgery. From earlier reports, it was generally thought that the prognosis of these tumors was as poor as that
of pulmonary small cell carcinoma6, 7, 22). In patients
with extensive or recurrent carcinoma, the clinical course was aggressive with an overall sur vival
span of 4.5 to 9.6 months4, 5). However, from more
recent reports, it seems that the prognosis is
bet-ter if the tumors are detected early9, 14)and if there
is no lymph node metastasis12). Actually, although
50% (2 of 4) of patients with T3 tumors died from the disease, 75% (6 of 8) of patients with T1 tumors were alive at the time of reporting without recurrence (Table 2). Furthermore, more than 50% of patients with lymph node metastasis at surgery experienced recurrence in lymph node or other organs, but 88% (7 of 8) of patients without lymph node metastasis at surgery remained alive without recurrence. From these findings, the prognosis seems to be related to the clinical stage and how early the tumors are detected.
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