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CORRESPONDENCE
Year : 2017  |  Volume : 13  |  Issue : 3  |  Page : 583-585

Neurofibromatosis and breast cancer: Do we need to revise the mammographic screening schedule in patients of neurofibromatosis?


1 Department of Pathology, PGIMER, Chandigarh, India
2 Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India
3 Department of Pediatrics, Grant Medical College, Mumbai, Maharashtra, India
4 Department of Pediatrics, Pt. JNM Medical College, Raipur, Chhattisgarh, India
5 Department of Pathology, Pushpanjali Crosslay Hospital, New Delhi, India
6 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Date of Web Publication31-Aug-2017

Correspondence Address:
Dinesh Pradhan
PGIMER, Sector 12, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.196761

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 > Abstract 


Neurofibromatosis type 1 (NF-1) is a neurocutaneous syndrome with autosomal dominant mode of inheritance and has a high propensity to develop benign and malignant nervous system tumors. Although uncommon, case reports describing the association of NF-1 and breast cancer are available in the literature. We illustrate one such case of NF-1, with no family history of the disorder and presenting with multifocal invasive carcinoma of the right breast, in an attempt to describe the association between these two entities. We also attempt to extensively review the current literature on the subject. Since patients with NF-1 are at an increased risk of developing breast cancer, we recommend strict adherence to careful clinical breast examination and annual screening mammographic examination starting at 40 years of age in all patients of NF-1.

Keywords: Breast cancer, mammography, neurofibromatosis


How to cite this article:
Pradhan D, Kaur N, Gami A, Hura KS, Garg G, Mohanty SK. Neurofibromatosis and breast cancer: Do we need to revise the mammographic screening schedule in patients of neurofibromatosis?. J Can Res Ther 2017;13:583-5

How to cite this URL:
Pradhan D, Kaur N, Gami A, Hura KS, Garg G, Mohanty SK. Neurofibromatosis and breast cancer: Do we need to revise the mammographic screening schedule in patients of neurofibromatosis?. J Can Res Ther [serial online] 2017 [cited 2020 Jun 4];13:583-5. Available from: http://www.cancerjournal.net/text.asp?2017/13/3/583/196761




 > Introduction Top


Neurofibromatosis type 1 (NF-1) or Von Recklinghausen disease is an autosomal dominant disorder with a high penetrance and wide variability in disease expression. It has an incidence of 1:3000–4000.[1] The characteristic common clinical features are subcutaneous nodules (neurofibromas), café-au-lait spots, axillary, inguinal freckling, and Lisch nodules with uncommon features being pseudoarthrosis, scoliosis, and parathyroid hyperplasia.[2] Patients can develop other benign and malignant tumors such as neurofibrosarcoma, optic gliomas, malignant schwannoma, pheochromocytoma, myelogenous leukemia, and rhabdomyosarcoma.[3] Few case reports describe the association of breast carcinoma with NF-1.[4] We describe a case of a 40-year-old female (with no history of NF-1 in the family) presenting with multifocal carcinoma in the right breast. We also present a comprehensive review of all the cases of breast cancer in patients of NF-1 that have been reported in the English literature till date.


 > Case Report Top


A 40-year-old female presented to the surgery outpatient department with a complaint of two progressively increasing swellings in the right breast. There was no history of loss of weight or appetite. She was a multiparous female with the first childbirth at 20 years of age. There was no other significant personal, menstrual, past, or family history. General physical examination revealed mild pallor with the presence of multiple, well-defined, discrete, soft, sessile nodules in the skin, diffusely scattered throughout the body, revealing varying colors. In addition, multiple (at least 8–9 in number), irregular-shaped, hyperpigmented macular skin patches were seen, the largest measuring 3.5 cm × 3.0 cm in the left lower back region [Figure 1]a and [Figure 1]b. The clinical features were consistent with NF-1. There was no evidence of plexiform neurofibroma anywhere in the body.
Figure 1: (a and b) Multiple neurofibromas seen throughout the body with the presence of multiple café-au-lait spots

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Local breast examination showed retracted right nipple with multiple, sessile subcutaneous nodules in the skin of right breast (including nipple-areolar complex). Similar nodules were also seen in the contralateral breast. In addition, at least two ill-defined, firm-to-hard lobulated masses were present in the upper outer and upper central quadrants of the right breast, measuring 3.5 cm × 3.0 cm and 4.0 cm × 3.0 cm, respectively [Figure 2]a and [Figure 2]b.
Figure 2: (a and b) Multiple neurofibromas seen in the nipple-areolar region of both the breasts. There is retracted right nipple and a skin discoloration in the upper inner quadrant of the right breast

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Bilateral mammogram was performed which confirmed the two high-density lobulated masses in the right breast and in the retro-areolar and upper outer quadrant location, the latter showing extensive clustered microcalcifications. Multiple enlarged lymph nodes (4 in number, the largest measuring 15 mm in the short-axis dimension) were seen. Lesions were categorized according to the Breast Imaging Reporting and Data System (BIRADS) with lesion in the upper outer quadrant as BIRADS-5 and the one in the retro-areolar quadrant as BIRADS-4/5 [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. Neurofibromas were seen as multiple, well-defined, sessile skin lesions outlined by air (showing well-defined margins) projecting over mammary tissue. Core biopsy was done from both the suspicious lesions in the right breast. The histologic examination of both the lesions revealed tumor cells arranged in the form of ducts or nests and surrounded by desmoplastic stroma, involving more than 60% of the area of the cores from the upper outer quadrant and 40% of the area of cores from the retro-areolar lesion. The tumor cells were moderately pleomorphic with vesicular nuclei, conspicuous nucleoli, and few mitotic figures [Figure 4]a and [Figure 4]b. Tumor cells were positive for estrogen and progesterone receptors, Her-2-neu was negative, and the overall features were consistent with invasive ductal carcinoma, histologic Grade 2. The patient underwent modified radical mastectomy with axillary lymph node dissection followed by postoperative chemotherapy. The patient is on 3-month follow-up with no obvious recurrence.
Figure 3: (a and b) Right breast shows two high-density masses in the upper outer quadrant and the central retroareolar quadrant. There is retracted right nipple with skin thickening in the central nipple-areolar region. There is a presence of clustered microcalcifications in the upper outer quadrant mass. Furthermore, multiple varying sized neurofibromas are seen in both the breasts. (c and d) Left breast shows dense parenchyma with multiple neurofibromas in the skin, predominantly in the nipple-areolar region

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Figure 4: Excision biopsy specimen of the right breast mass shows invasive ductal carcinoma with cells arranged in nests and small clusters having hyperchromatic nuclei and conspicuous nucleoli (a: H and E, ×200; b: H and E, ×400). Both the upper outer quadrant and central retroareolar quadrant masses revealed similar histopathologic features

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 > Discussion Top


Von Recklinghausen disease is the most common of the neurocutaneous syndromes with an autosomal dominant mode of inheritance.[1] Most of the cases are diagnosed in childhood with few patients remaining undiagnosed well into the adult life. About half of the patients have no family history of the disease, and the disease occurs as a result of spontaneous mutations.[5] These spontaneous mutations are frequent because of the large size of the gene which is located in the pericentromeric region of the chromosome 17q11.2. Various gene abnormalities such as chromosomal rearrangements, deletions, insertions, duplications, and base substitutions are seen in NF1 gene.[6]NF1 gene encodes for neurofibromin which acts as a tumor suppressor gene and also downregulates RAS proto-oncogene. Mutations in NF1 gene lead to 4–5-fold greater risk of malignancy compared to the general population.[7] Malignancy is the most common cause of death in NF1 patients reducing life expectancy by 10–15 years, and nervous system tumors are the most common malignancy in these patients.

The association of common non-neural malignancies such as breast carcinoma and NF-1 has also been reported. There are a few individual case reports and small case series describing the association of NF-1 and breast cancer. A thorough literature search revealed a wide age distribution of patients ranging from 18 years to 74 years. However, most of the cases of NF-1 with breast cancer were young patients.[7] There was a female preponderance in the reported cases. Most of the cases at presentation were either Stage II or Stage III with few progressing to Stage IV during treatment or on follow-up. Sharif et al. demonstrated a cumulative risk of 8.4% for developing breast cancer in NF-1 patients by the age of 50 years in a large cohort. Interestingly, they found a 5.8% risk in the fifth decade (40–49 years) and therefore advocated screening from 40 years of age.[7] Brasfield and Das Gupta[8] in their series of NF-1 and breast cancer reported death of all the cases and thus concluded that presence of underlying NF-1 in a breast cancer patient worsens the prognosis.

Presence of multiple skin nodules makes self-breast examination difficult for the patients of NF-1 and may obscure a small breast lump.[9] Even if the patient feels the lump, they usually ignore it considering it as a manifestation of their known disease spectrum. Consequently, most of these patients present at an advanced stage of the disease with large tumor size, at a high grade, and at times multifocal tumor with nodal metastases requiring aggressive postoperative radiotherapy and with dismal prognosis. There is also a high chance of radiation-induced secondary sarcomas in these patients. An aggressive postoperative follow-up for the early detection of secondary sarcomas is warranted in all such cases.[10]

Breast cancer 1 (BRCA1) and NF1 genes are located in proximity on chromosome 17, suggesting a possible interactive role of both genes in the pathogenesis of breast cancer. First molecular evidence of the involvement of NF1 gene in breast tumor was provided by Ogata et al. in 2001, who found defects in the expression of neurofibromin protein in breast cell lines with upregulation of RAS oncogene. This was later supported by Ceccaroni et al. in 2002, who reported concurrence of breast, ovarian, and gastrointestinal malignancies in the members of a family affected with NF-1. Later in 2005, loss of heterozygosity for NF1 gene was found in breast tumor cells.

There is an interesting association between NF-1 and the presence of neurofibromas in the nipple-areolar region. Female patients with NF-1 are more likely to develop neurofibromas of the nipple-areolar region,[6] and the breast mass may be difficult to detect by self-examination due to the simultaneous presence of neurofibromas. This makes mammography important in such cases. Mammography also plays an important role in detecting sarcomatous transformation in the NF-1 cases.

Knowledge of the association of NF-1 with breast cancer can help in the early diagnosis of breast malignancy by careful clinical breast examination, screening mammography, and further diagnostic evaluation in the case of a suspicious mass. This report attempts to generate awareness among the clinicians, radiologists, and pathologists regarding the increased risk of breast cancer in NF-1 patients and the need for mandatory early mammographic screening of these patients starting at 40 years of age.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Gokalp G, Hakyemez B, Kizilkaya E, Haholu A. Myxoid neurofibromas of the breast: Mammographical, sonographical and MRI appearances. Br J Radiol 2007;80:e234-7.  Back to cited text no. 1
    
2.
Riccardi VM. Neurofibromatosis: Phenotype, Natural History and Pathogenesis. 2nd ed. Baltimore: Johns Hopkins University Press; 1992.  Back to cited text no. 2
    
3.
Sørensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 1986;314:1010-5.  Back to cited text no. 3
    
4.
Teh BT, Birrell G, Farrell A, Leonard JH, Walters MK, Palmer JM, et al. Breast cancer in six women with neurofibromatosis type 1. Breast 1997;6:155-60.  Back to cited text no. 4
    
5.
Fortman BJ, Kuszyk BS, Urban BA, Fishman EK. Neurofibromatosis type 1: A diagnostic mimicker at CT. Radiographics 2001;21:601-12.  Back to cited text no. 5
    
6.
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. 6
    
7.
Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 2007;44:481-4.  Back to cited text no. 7
    
8.
Brasfield RD, Das Gupta TK. Von Recklinghausen's disease: A clinicopathological study. Ann Surg 1972;175:86-104.  Back to cited text no. 8
    
9.
Murayama Y, Yamamoto Y, Shimojima N, Takahara T, Kikuchi K, Iida S, et al. T1 Breast Cancer Associated with Von Recklinghausen's neurofibromatosis. Breast Cancer 1999;6:227-230.  Back to cited text no. 9
    
10.
Hasson DM, Khera SY, Meade TL, Dupont EL, Greenberg HM, Diaz NM, et al. Problems with the use of breast conservation therapy for breast cancer in a patient with neurofibromatosis type 1: A case report. Breast J 2008;14:188-92.  Back to cited text no. 10
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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