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CASE REPORT  
Year : 2013  |  Volume : 56  |  Issue : 2  |  Page : 166-168
Basal like carcinoma of breast in patient with neurofibromatosis I: An association or co-existence?


1 Department of Pathology, Jawaharlal Institute of Post-Graduate Medical Education and Research, Puducherry, India
2 Department of Surgical Oncology, Jawaharlal Institute of Post-Graduate Medical Education and Research, Puducherry, India

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Date of Web Publication23-Sep-2013
 

   Abstract 

Neurofibromatosis I (NF I), an autosomal dominant disorder is associated with increased risk of benign and malignant peripheral nerve sheath tumors and central nervous system tumors. There are only few case reports of breast carcinoma in known patients of NF I. We report a case of basal like carcinoma of the breast in a 69-year-old lady who had NF I. Considering the rare association of carcinomas with NF I and finding that both the NF I gene and a breast cancer pre-disposition gene, BRCA 1 are located in close proximity on chromosome 17q makes the association of these two conditions intriguing.

Keywords: Association, carcinoma breast, neurofibromatosis I

How to cite this article:
Jinkala SR, Rajesh NG, Ramkumar A. Basal like carcinoma of breast in patient with neurofibromatosis I: An association or co-existence?. Indian J Pathol Microbiol 2013;56:166-8

How to cite this URL:
Jinkala SR, Rajesh NG, Ramkumar A. Basal like carcinoma of breast in patient with neurofibromatosis I: An association or co-existence?. Indian J Pathol Microbiol [serial online] 2013 [cited 2014 Oct 25];56:166-8. Available from: http://www.ijpmonline.org/text.asp?2013/56/2/166/118682



   Introduction Top


Neurofibromatosis I (NF I), an autosomal dominant disorder, affects approximately 1 in 4000 individuals. It is associated with deletions, insertions or a mutation in the NF 1 gene, which is a tumor suppressor gene, located in the pericentromeric region of chromosome 17 and has a role in cell growth and differentiation. The overall risk of cancer was 2.7 times higher in NF 1 patients than the general population. [1] NF I is associated with increased risk of benign and malignant peripheral nerve sheath tumors (MPNST) and central nervous system tumors. [2]

Until date, there are many mutations, which have been implicated in hereditary breast carcinoma; the strongest association being with BRCA 1 and BRCA 2. We report this case due to the rarity of basal like breast carcinomas arising in NF 1.


   Case Report Top


A 69-year-old woman presented with a right breast lump of 3 months duration. She was a known case of NF I with multiple cutaneous neurofibromas over the bilateral breast and trunk with a positive paternal family history. Tru-cut biopsy from the breast lump was diagnosed as infiltrating ductal carcinoma. Subsequently, a modified radical mastectomy was carried out. There were multiple cutaneous nodules over the skin [Figure 1]a. Microscopy of the cutaneous nodules showed features of neurofibroma [Figure 1]b. The tumor in breast measured 4.5 cm × 3.5 cm × 3 cm (pT2). Histopathological examination of the tumor showed features of infiltrating ductal carcinoma. In our patient, nuclear atypia was score 3, tubule formation was score 3, but however mitotic activity was 4/10 hpf giving it a score of 1. Total Modified Scarff Bloom Richardson score was 7 and hence the tumor was diagnosed as Grade II infiltrating ductal carcinoma [Figure 1]c and [Figure 2]a. There was 40% necrosis in the primary tumor thus suggesting the possibility of necrosis of mitotically active area. The tumor cells were seen infiltrating the neurofibromatous nodules in the breast parenchyma. Paget disease of the nipple was also noticed [Figure 1]d. Extensive sampling of the axillary pad yielded only five lymph nodes of which two showed metastatic deposits. Mitotic activity was however higher (20/10 hpf) in the metastatic deposits in axillary lymph nodes. Surgical margins were free of tumor. Immunohistochemistry (IHC) was performed with monoclonal antibodies from DAKO antibodies, USA using Envision labeling system with the peroxidase-antiperoxidase method. IHC with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu) (score 1 by H scoring) was negative in the tumor [Figure 2]b. Her2/neu was however strongly positive (score 3) in the pagetoid infiltrate [Figure 3]a and duct cell carcinoma in situ (DCIS) foci [Figure 3]b. Subsequent IHC for high molecular weight cytokeratin (CK 5/6 and CK 14) in tumor cells revealed 90% positivity for CK 5/6 and negativity for CK 14. We studied the tumor for epidermal growth factor receptor 1 (EGFR1/Her1) and CD 117 mutations using IHC and found them to be negative. Ki 67 labeling index was low (1-2%) in the tumor. The final histopathologic diagnosis was basal like breast carcinoma with paget disease of the nipple and metastatsis in axillary lymph nodes (pT2 N1 MX).
Figure 1: (a) Modified radical mastectomy specimen of the right breast showing multiple cutaneous neurofibromas. (b) Photomicrograph from a cutaneous nodule showing features of neurofibroma; Inset showing entrapment of adnexal structures by neurofibroma (H and E, ×40, Inset ×40). (c) Infi ltrating ductal carcinoma, grade II (Modifi ed Scarff Bloom-Richardson score 7); Inset showing positivity of tumor cells for cytokeratin 5/6 (DAB, ×100, Inset ×400). (d) Paget disease of nipple showing infiltrati on of squamous epithelium by malignant single cells (H and E, ×100, Inset, ×400)

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Figure 2: (a) Infiltrating duct cell carcinoma, grade II (Modified Scarff Bloom-Richardson score 7) (H and E, ×200); Inset (b) human epidermal growth factor receptor 2 negativity in the primary tumor (DAB ×400)

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Figure 3: (a) Paget disease of nipple showing 3+ human epidermal growth factor receptor 2 (Her2/neu) positivity (DAB ×200); Inset (b) Foci of DCIS showing 3+ Her2/neu positivity (DAB ×400)

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   Discussion Top


NF 1 represents a major risk factor in the development of several malignancies, particularly MPNST, optic gliomas, other gliomas, rhabdomyosarcoma, astrocytoma and leukemias. [3] The average life expectancy of patients with NF 1 is probably reduced by 10-15 years and malignancy is the most common cause of death. [4] There are only a few cases in the literature describing epithelial malignancies like infiltrating ductal carcinoma of the breast in association with NF I.

It has been speculated that the presence of multiple cutaneous and subcutaneous neurofibromas may obscure the palpation of a breast mass and thus result in delayed clinical detection. [5] Patients with NF I should undergo more rigorous clinical and mammographic examinations to determine the presence or absence of breast malignancies.

Studies suggest that loss of heterozygosity in the tumor supports the role of NF 1 gene in the etiology in some cases of breast cancer. [6] Basal like breast carcinomas are positively associated with BRCA1 mutations. [7] The finding that both the NF I gene and breast cancer predisposition gene, BRCA 1 are located in close proximity on chromosome 17q makes the association of these two conditions intriguing. [3] The diagnosis of Basal like breast carcinoma is hampered by lack of standard definition using IHC markers. We defined basal like breast cancer as infiltrating tumor cells negative for ER, PR and Her2/neu and expressing CK 5/6, or CK 14 or EGFR 1 or CD 117. We include HER1 and c-kit in the panel because HER1 and c-kit are highly expressed in basal-like breast carcinoma and rarely expressed in non-basal-like breast carcinoma; furthermore, the association of HER1 and c-kit expression may have an important application in patients for whom an EGFR-targeted and c-kit-targeted therapy might be a treatment option. Using this panel is compatible with the gene expression profile of basal-like carcinomas, with a sensitivity of 76% and specificity of 100%. [8]

Mutations for EGFR and CD 117 have been reported in basal like breast carcinomas and this subtype is associated with high proliferative activity. [7] However, we found that these mutations were negative in our patient and the tumor had low proliferative activity. Her2/neu expression has been found to be associated with 100% of Paget disease and DCIS focus even when primary tumor is negative. [9]

Basal like phenotype of breast carcinoma is a recently described entity and its co-existence with NF 1 needs to be evaluated further for molecular mutations.

 
   References Top

1.Maheshwari UM, Sahu SS, Borkar DB, Paul B. An unusual presentation of neurofibromatosis with breast carcinoma. Bombay Hosp J 2009;51:380-1.  Back to cited text no. 1
    
2.Korf BR. Malignancy in neurofibromatosis type 1. Oncologist 2000;5:477-85.  Back to cited text no. 2
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3.Bongiorno MR, Doukaki S, Aricò M. Neurofibromatosis of the nipple-areolar area: A case series. J Med Case Rep 2010;4:22.  Back to cited text no. 3
    
4.Murat A, Kansiz F, Kabakus N, Kazez A, Ozercan R. Neurofibroma of the breast in a boy with neurofibromatosis type 1. Clin Imaging 2004;28:415-7.  Back to cited text no. 4
[PUBMED]    
5.Millman SL, Mercado CL. An unusual presentation of neurofibromatosis of the breast. Breast J 2004;10:45-7.  Back to cited text no. 5
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6.Güran S, Safali M. A case of neurofibromatosis and breast cancer: Loss of heterozygosity of NF1 in breast cancer. Cancer Genet Cytogenet 2005;156:86-8.  Back to cited text no. 6
    
7.Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, et al. Triple-negative breast cancer: Distinguishing between basal and nonbasal subtypes. Clin Cancer Res 2009;15:2302-10.  Back to cited text no. 7
[PUBMED]    
8.Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367-74.  Back to cited text no. 8
[PUBMED]    
9.Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: Ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009;14:320-68.  Back to cited text no. 9
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Correspondence Address:
Nachiappa Ganesh Rajesh
Department of Pathology, Jawaharlal Institute of Post-Graduate Medical Education and Research, Puducherry
India
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DOI: 10.4103/0377-4929.118682

PMID: 24056659

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