Invasive mammary carcinoma with neuroendocrine ...ijhbr.com/pdf/4 2014 42-46.pdf · Neuroendocrine differentiation of breast is a rare tumor ... Clinica Oncologica PO “G. Bernabeo,”

International J. of Healthcare and Biomedical Research, Volume: 2, Issue: 3 , April 2014 , Pages 42-46

42 www.ijhbr.com ISSN: 2319-7072

Case Report:

Invasive mammary carcinoma with neuroendocrine differentiation: a

diagnostic challenge

Dr. Gajender Singh, Dr. Pansi Gupta, Dr. S.K.Mathur, Dr. Sant Prakash Kataria, Dr. Sanjay Kumar

Name & Address of Institution: Department of Pathology, Pt B.D. Sharma PGIMS, Rohtak, Haryana, India

Corresponding author : Dr Pansi Gupta

Abstract :

Neuroendocrine differentiation has been reported in both in situ and infiltrating breast cancers. The prognostic

significance of neuroendocrine differentiation in mammary carcinoma is unclear. The spectrum ranges from

undifferentiated small cell carcinoma to ductal carcinoma in situ with neuroendocrine differentiation. Mucinous

carcinomas of the breast appear to have the greatest association with neuroendocrine differentiation. We add to the

literature a case of a morphologically composite mammary infiltrating ductal carcinoma with diffuse neuroendocrine

differentiation as demonstrated by immunohistochemical staining. We reported a case of 76 year old female

diagnosed as infiltrating ductal carcinoma in which there was a morphologically conventional-appearing infiltrating

ductal component admixed with nests of cells that resembled a carcinoid tumor and initially mimicked the

appearance of intraductal carcinoma. Immunohistochemical stains for synaptophysin and chromogranin

demonstrated diffuse, strong positivity uniformly throughout the tumor, even in the more conventional-appearing

areas. We concluded that this was an infiltrating ductal carcinoma with morphologic and immunohistochemical

evidence of neuroendocrine differentiation. The presence of neuroendocrine differentiation in a morphologically

composite tumor should be reported but that the tumor should essentially be classified according to existing schemes

of ductal and lobular carcinomas and variants. There is no evidence that neuroendocrine differentiation is

prognostically significant.

Keywords: Breast neoplasm; Neuroendocrine tumor

Introduction

Neuroendocrine differentiation of breast is a rare

tumor. They arise from cells able to produce peptide

and amines referred to as diffuse neuroendocrine

system. The significance of neuroendocrine

differentiation in carcinomas of the breast remains

unclear. The spectrum ranges from undifferentiated

small cell carcinoma to ductal carcinoma in situ with

neuroendocrine differentiation. Mucinous carcinomas

of the breast appear to have the greatest association

with neuroendocrine differentiation.1 It is likely that

neuroendocrine mammary carcinomas derive from

progressive neuroendocrine differentiation in a subset

of cancerous cells rather than from pre-existent

endocrine cells . Neuroendocrine differentiation can

be found in different histotypes of breast carcinoma,

including in situ and invasive ductal, lobular, colloid,

papillary breast cancer.2 Clayton et al. detected the

presence of argyrophilic and dense granules by

electron microscopy in different histotypes of

mammary breast cancer.3



Case report

A 76-year-old woman with no significant medical

history was found to have a palpable left breast mass

in the upper outer quadrant. A fine-needle aspiration

cytology was performed. Smears showed highly

necrotic ductal carcinoma. No cytologic features of

neuroendocrine differentiation were noted either

initially or upon review. Then patient underwent

modified radical mastectomy, specimed measured

15x15x6cm. On serial sectioning a growth measuring

2x1.5 cm was identified. Cut surface was greyish

white. Tumor was 0.2cm away from resected base

grossly. Representative microsections examined

showed infiltrating ductal carcinoma breast with

neuroendocrine differentiation. Focal areas of mucin

production was also seen. Overlying skin, nipple and

areola were free from tumor infiltration. Resected

base showed infiltration by tumor. Lymph nodes

isolated (8) showed reactive hyperplasia.

Special stains for the neuroendocrine markers

synaptophysin, chromogranin and neuro specific

enolase were performed and showed diffuse

positivity in both the nests and in the more

conventional invasive ductal carcinoma.

Morphologically transitional areas were also strongly

and diffusely positive for synaptophysin and

chromogranin. Positive and negative controls were

appropriate. Adjacent non-neoplastic breast was

negative. tion. Additional tests performed included

estrogen, progesterone, and HER-2/neu receptor

staining. The tumor was positive for estrogen

receptors and progesterone and HER-2/neu receptors.

Modified radical mastectomy was performed.

Discussion

Neoplasms with neuroendocrine differentiation do

not constitute a specific histopathological category of

female mammary carcinoma, but it is apparent that

there is a group of mammary carcinomas capable of

producing ectopic hormonal substances. The

recognition of these features is necessary for defining

their clinical characteristics. 4 Multiple studies have

been undertaken to identify a pre-existing population

of neuroendocrine cells in breast tissue. An early

study demonstrated the presence of chromogranin-

reactive endocrine cells in normal breast tissue as

well as in so-called argyrophilic or carcinoid tumors

of the breast. Other studies demonstrated dense-core

granules by electron microscopy.1 Pure carcinoid

tumors of the breast have been reported, as have

small cell carcinomas and composite tumors (ie,

tumors with more conventional-appearing types of

breast carcinomas admixed with or coexpressing

neuroendocrine carcinoma morphologically or

immunohistochemically).

Among composite tumors, the mucinous carcinoma is

the type most commonly associated with

neuroendocrine differentiation.1Neuroendocrine (NE)

was not recognized as a single entity until the last

WHO’s classification. This classification

differentiates between four different subtypes: (i)

small-cell carcinoma (SCC); (ii) large-cell

carcinoma; (iii) solid NE carcinoma; and (iv) atypical

carcinoid tumor. For simplification, this section

describes the solid neuroendocrine subtype (SN)

which represents a better prognosis group. (The SCC

subtype is described in the ‘poor prognosis, ER

positive’ section.) 5

Histologically the neuroendocrine component

resembles lung and gastrointestinal neuroendocrine

tumors. It is characterized by cellular monotony,

nuclear palisading, pseudorosette formation, loss of

cell cohesion, and abundant eosinophilic cytoplasm

and nuclei with stippled (‘salt and pepper’)

chromatin . Nevertheless these features per se are not



sensitive enough to rule in a diagnosis because they

are inconsistently present. A panel of the most

sensitive and specific IHC neuroendocrine markers

(chromogranin A or B and synaptophysin) are

known.6

Main reported morphological features in

neuroendocrine breast cancer are:

- production of mucin, retained into the cells

or secreted in extracellular milieu;

- presence of insular structures separated by

fibrovascular stroma;

- low nuclear grade and granulous cytosol.

There are no specific clinical features associated with

mammary carcinomas that exhibit structural or

histochemical evidence of endocrine differentiation,

so most of the lesions are palpable tumors or can be

detected by imaging.2

Histological grade is one of the most important

parameter in disease clinical development. High

grade neuroendocrine carcinomas show high

proliferation rate and poor prognosis. Low grade

neuroendocrine carcinomas with low proliferation

rate are be consider to have a better prognosis.

Another prognostic parameter is co-expression of

neuroendocrine and non-neuroendocrine proteins

such as glycoproteins and apocrine proteins. This

capability is present in well differentiated mammary

breast carcinomas while poor differentiated

carcinomas don’t show it .2

Sapino et al. has shown that mucin producing

carcinomas and pure apocrine carcinomas have a

better prognosis with a 5 years overall survival longer

than poor differentiated neuroendocrine carcinomas.8

Finally ER expression is an important prognostic

parameter in neuroendocrine breast carcinoma and

correlates to a long survival.2

Differential diagnosis should include direct invasion

of the breast by Merkel cell carcinoma, malignant

lymphoma (either primary or as a manifestation of

systemic disease), carcinoid tumor, and malignant

melanoma, which should be excluded by the exact

location and extension of the tumor and by

immunohistochemical stains, such as leukocyte

common antigen, neuroendocrine markers, S100

protein, and HMB-45, respectively. Modified radical

mastectomy with axillary lymph node dissection

seems to be the treatment of choice, with adjuvant

radiation, chemotherapy, or both, based on the

clinical stage and presence of metastasis.7

Conclusion

The presence of neuroendocrine differentiation in a

morphologically composite tumor should be reported

but that the tumor should essentially be classified

according to existing schemes of ductal and lobular

carcinomas and variants.

FIG 1: H&E VIEW OF BREAST TUMOR (10x)



FIG 2: H&E VIEW OF BREAST TUMOR (20x)

FIG 3: H&E VIEW OF NEUROENDOCRINE

DIFFERENTIATION (20x)

FIG 4:ER (20x)

FIG 5: PR (20x)

FIG 6: SYNAPTOPHYSIN (20x)

FIG 7: CHROMOGRANIN (20x)

FIG 8: NSE(20x)



References

1. David O, Bhattacharjee M. Diffuse Neuroendocrine Differentiation in a Morphologically Composite

Mammary Infiltrating Ductal Carcinoma. Arch Pathol Lab Med.2003;127:133-4.

2. Noccioli P, Grossi S, Tavoletta S, Scognamiglio MT, Natoli C, Cianchetti E et al. Neuroendocrine tumors

of the breast: our experience." Clinica Oncologica PO “G. Bernabeo,” Dipartimento di Neuroscienze,

Chieti, Italy.

3. Clayton F, Ordonez NG, Sibley RK, Hanssen G: Argyrophilic breast carcinomas. Evidence of

lactational differentiation. Am J Surg Pathol. 1982; 6: 323-33.

4. Filho OG, Miiji LNO, Vainchenker M, Gordan AN. Breast cancer with choriocarcinomatous and

neuroendocrine features. Sao Paulo Medical J. 2001;6: 154-5.

5. Yerushalmi, R, Hayes MM, Gelmon KA. Breast carcinoma—rare types: review of the literature. Annals of

oncology 2009;20:1763-70.

6. Angarita FA, Rodríguez JL, Meek E, Sánchez JO, Tawil M, Torregrosa L. Locally-advanced primary

neuroendocrine carcinoma of the breast: case report and review of the literature. World journal of surgical

oncology 2013;11(1):1-11.

7. Tanwani AK, Khalid A, Mudassara. Neuroendocrine Carcinoma of Breast. Ann. Pak. Inst. Med. Sci.

2008;4(3), 171-3.

8. Sapino A, Righi L, Cassoni P, Pietribiasi F, Bussolati G. Expression of the neuroendocrine phenotype in

carcinomas of the breast. Semin Diagn Pathol 2000;17:127-37.

46

Date of submission: 29 January 2014, Date of provisional acceptance: 12 Feb 2013

Date of Final acceptance: 22 March 2014 Date of Publication: 07 April 2014

Source of support: Nil; Conflict of interest: Nil

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Invasive mammary carcinoma with neuroendocrine ...ijhbr.com/pdf/4 2014 42-46.pdf · Neuroendocrine differentiation of breast is a rare tumor ... Clinica Oncologica PO “G. Bernabeo,”