Small Cell Carcinoma
FREDERICK C. KOERNER
Carcinomas that resemble small cell carcinoma (SCC, oat cell carcinoma) of the lung can occur in many extrapulmonary sites,1 including the mammary gland, which gives rise to this type of carcinoma on rare occasions. In 1992, Papotti et al.2 reported the first well-established cases of mammary neuroendocrine carcinoma displaying features similar to those of pulmonary SCC. Since the time of this publication, approximately 50 additional cases have been described.3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26
The diagnosis of primary mammary SCC can be made only if a nonmammary site is excluded as a source of metastasis to the breast or an in situ component is demonstrated histologically. Several reports fail to meet these criteria, and a few others do not provide sufficient details to substantiate the diagnosis of mammary SCC.3,27,28,29,30,31,32,33,34 For example, one report described a 52-year-old woman with a large mammary tumor, clinically involved axillary lymph nodes (ALNs), and metastases in the liver and bones.31 A modified Grimelius staining was negative for argyrophilic granules, but scattered neurosecretory granules were detected by electron microscopy. In situ carcinoma was not identified, and an autopsy was not performed to exclude the presence of a nonmammary primary site. Another report documents a 68-year-old woman with a 4-cm tumor that was classified as a SCC.33 The tumor was negative with the Grimelius stain but was immunoreactive for chromogranin and neuron-specific enolase (NSE) and weakly immunoreactive for cytokeratin (CK). An in situ component was not detected. The patient died 21 months after diagnosis with widespread metastases, and a nonmammary primary site could not be excluded.
At times, pathologists have used the diagnosis of “small cell carcinoma” to describe a mammary carcinoma composed of small cells rather than to identify a carcinoma showing specific neuroendocrine attributes. For example, several papers described “small cell carcinoma” of the male breast.35,36,37 On the basis of the illustrations and histologic descriptions provided, most of these appear to be examples of other types of carcinoma, possibly infiltrating lobular carcinoma. This confusion may have arisen because for a short time certain pathologists used the diagnosis of “small cell carcinoma” to refer to an invasive mammary carcinoma showing features of invasive lobular carcinoma but lacking an in situ component.35 Contemporary usage classifies such carcinomas as invasive lobular carcinomas. Along similar lines, Fiorella et al.38 described the cytologic features of a group of well-differentiated invasive ductal carcinoma, which the authors termed “small cell duct carcinoma.” These carcinomas probably do not represent genuine SCC of the neuroendocrine type.
CLINICAL PRESENTATION
The age of patients with mammary SCC ranges from 2911 to 81 years15 with a mean of 53 years. A family history of breast carcinoma or evidence of breast cancer (BRCA)-associated carcinoma was only rarely mentioned in reports of mammary SCC. One patient had solid non-small cell ductal carcinoma in situ (DCIS) in her contralateral breast.27 With the exception of one possible case,10 all patients have been women. Jundt et al.10 described a 52-year-old man with small cell (oat cell) carcinoma in the breast and ALNs. The histologic appearance was that of an oat cell carcinoma and the tumor cells were immunoreactive for NSE. Electron microscopy revealed desmosomes and cytoplasmic granules with neuroendocrine features. In situ carcinoma was not detected, but a nonmammary primary site was not evident by clinical evaluation.
SCC arises in all regions of the breast. It typically forms a single mass, but one patient had two masses in different quadrants of the same breast.9 Another patient had multiple superficial nodules on the breast, a solitary breast mass, and matted ALNs.15 Mammograms of SCC revealed welldefined or irregular masses with borders often described as microlobulated.2,8,10,13,14,18,21,24 Sonography showed the masses to be solid, exhibiting low homogeneous echoes and mild posterior acoustic enhancement.8,13,14,21 Magnetic resonance imaging (MRI) displayed early enhancement of the masses,8,13,14,21,39 a hyperintense heterogeneous signal on T2-weighted images, and a hypointense signal on T1-weighted images.13,39 In one case,39 the tumor was isointense with normal tissue, and the images showed segmental non-mass-like enhancement. Positron emission tomogram-computerized tomogram (PET-CT) scans showed that the carcinomas demonstrate marked avidity for fluorodeoxyglucose.5,24 The tumor doubling time based on imaging studies in one case was 12 days.12 The pattern of enhancement on CT and MRI scans may be indicative of extensive DCIS.39
GROSS PATHOLOGY
The macroscopic appearance of SCC does not differ substantially from that of commonplace breast carcinomas. SCC has ranged from 13 to 14.5 cm7 in greatest dimension; the average size was 4.1 cm. Pathologists usually described the tumors as firm and irregular. A “fleshy” consistency, a lobulated or nodular structure, and a mucoid quality were noted in individual cases.40 The neoplastic tissue appears white, gray, or tan or variations of these colors, and shades of yellow or pink have been noted in a few cases. One group of observers5 described a SCC as “pink to pale fawn.”
MICROSCOPIC PATHOLOGY
The histologic characteristics of mammary SCC resemble those of SCC arising in other organs. The noninvasive component usually consists of small cells with scant cytoplasm and hyperchromatic nuclei. These cells may constitute the entire noninvasive neoplastic population (Fig. 21.1A, B) as they did in the four cases described by Papotti et al.2 and five of the nine cases reported by Shin et al.,19 or the small cells may represent only one component of an in situ carcinoma with mixed features. For example, Figure 21.2 illustrates a DCIS in which SCC coexists with large malignant cells showing traces of squamous metaplasia. The small tumor cells were CK-positive (CAM5.2) and variably stained with 34βE12, whereas the large tumor cells were negative for CAM5.2 and strongly stained with 34βE12. Figure 21.3A, B illustrates an intraductal carcinoma composed of cells with poorly differentiated nuclear grade merging with others showing features of SCC.
The invasive component typically consists of patternless sheets and clusters of cells that often contain zones of coagulative necrosis and foci of hemorrhage (Figs. 21.1C, D and 21.4A, B). Regions sometimes display architectural patterns of a neuroendocrine nature: organoid groups, trabeculae, or rosette-like structures surrounded by delicate blood vessels and stroma (Fig. 21.4C, D). The neoplastic cells appear small and round, polygonal, or spindly. They contain round to oval nuclei, homogeneous dark chromatin, inconspicuous nucleoli, and scant eosinophilic cytoplasm. The nuclear-tocytoplasmic ratio is high. Nuclear molding can be seen, but it usually does not appear as prominent in tissue sections as it does in cytologic specimens.19 Mitotic figures abound in most examples, and mitotic counts as high as 10 per highpower field have been recorded.13 Disruption of nuclei occasionally leads to deposition of the nuclear material around blood vessels (the “Azzopardi” effect).7,10 Vascular invasion often appears prominent. Staining with the Grimelius method produces variable results,6,22,
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