Primary SCNC of the breast is a rare tumour with less than 30 cases reported in the literature. Most cases are found in women, as is the case with breast carcinoma of the usual type. Only one case occurring in a 52 year old man has been reported in the literature.8
The reported age of incidence varies from 40 to 70 years, with a higher incidence in women greater than 60 years. There is considerable similarity between the morphological and histochemical features of these tumours and pulmonary small cell carcinomas.4–6,8
The histogenesis is still unclear, because the presence of neuroendocrine cells in normal breast has not been proved conclusively.9,10
It has been suggested that SCNC is a variant of metaplastic carcinoma arising from usual lobular or ductal carcinoma.4
This position is strengthened by the dimorphic appearance of the tumour in a large number of reported cases.4,11
However, some believe that SCNC is a distinct type of breast carcinoma different from the usual types of carcinoma, with variable degrees of neuroendocrine differentiation and carrying a worse prognosis.1,6
The presence of an intraductal component with a morphological and immunohistochemical profile similar to the invasive component, as in one of our cases (case 2), lends support to the hypothesis of a primary small cell carcinoma in its own right. Primary SCNC also occurs, as already stated, in many other sites where neuroendocrine cells are normally absent or not readily identifiable, including the ovary and prostate.
The prognostic relevance of neuroendocrine differentiation in breast carcinoma is a subject of debate. Although most studies reported an appreciably worse prognosis,1,5,6
a few did not.4,9
This discrepancy may result from non-separation of pure neuroendocrine carcinoma from carcinoma of the usual type with areas of neuroendocrine differentiation.6,11
There is no mention of the degree of differentiation in some of the reported cases.6,11
In addition, the neuroendocrine component in most of the tumours of the usual type falls into the moderately to well differentiated World Health Organisation (WHO) category. Most of the reported pure SCNC cases show an appreciably worse prognosis. Using the WHO criteria, all our cases fall into the poorly differentiated SCNC category. A uniform standard for diagnosis of neuroendocrine carcinoma as is the case with mucinous carcinoma should be set, and the degree of differentiation according to the current WHO classification of neuroendocrine carcinoma should be clearly stated for reasonable comparison.
Take home messages
- We report three rare cases of small cell neuroendocrine carcinoma of the breast
- The morphological and immunohistochemical patterns of this tumour are similar to its pulmonary counterpart
- Expression of neuroendocrine markers is inconsistent, so morphology is the mainstay of diagnosis
- Size is a very important prognostic factor in this tumour, as in breast carcinomas of the usual type
- The prognosis may not be as poor as previously thought, particularly for early stage disease
“Positive neuroendocrine markers will give strong support to the diagnosis, and this should be carefully searched for”
Size is an important prognostic factor in breast carcinoma in general.4,9
Shin et al
found that patients with a mean tumour size of 5.2 cm did appreciably worse than those with a mean tumour size of 2.6 cm. The second woman (case 2) in our series with a tumour size of 1.7 cm died within 20 months of diagnosis. The woman with a 1.0 cm tumour (case 1) is alive and free of disease 48 months after diagnosis.
The immunoprofile of epithelial markers in our series is similar to most reported cases.1,4,5,8,11
All the tumours showed at least focal positivity for CAM 5.2 and CK7 and were negative for CK20. This is also consistent with the immunoprofile of breast carcinoma of usual types.12
In contrast, Merkel cell carcinomas are positive for CK20 and negative for CK7, whereas SCNCs of the lung are negative for both markers.13
This may be useful in differentiating between these tumours.
The expression of neuroendocrine markers by SCNC is inconsistent.9,14,15
This is not surprising in view of the fact that these tumours are poorly differentiated. Some have argued that the diagnosis of these tumours rests on routine haematoxylin and eosin morphology,14,15
and negative expression of neuroendocrine markers should not be used as an exclusion criterion. However, positive neuroendocrine markers will give strong support to the diagnosis, and this should be carefully searched for. All our cases showed diffuse positivity for neurone specific enolase (fig 2) and PGP9.5, weak to moderate staining for chromogranin (fig 3), and two were positive focally for synaptophysin, which as pointed out above supports the diagnosis.
Figure 2 Section showing positive staining for neurone specific enolase in the invasive component.
Figure 3 Section showing positive staining for chromogranin in the invasive component.
Positive expression of oestrogen and progesterone receptors in SCNC of the lung and a few other sites has been reported. Thus, their expression in SCNC is not definite proof of mammary origin. Oestrogen and progesterone receptors were expressed in 67% and 56% of cases reported by Shin et al. All three of our cases were negative for oestrogen and progesterone receptors and HER2.
In summary, SCNC is a distinct type of primary breast tumour. The prognosis may not be as poor as previously portrayed, especially for early stage disease.