Fig 1a Fig 1b Fig 2a Fig 2b History: 52 year old female presents with a palpable mass. A two part diagnosis must be given to be considered a correct answer. Fig 5a Fig 5b Fig 3 Fig 4

Fig 1a Fig 1b Fig 2a Fig 2b History: 52 year old female presents with a palpable mass. A two part diagnosis must be given to be considered a correct answer. Fig 5a Fig 5b Fig 3 Fig 4

Mammographic Findings: Fig 1b Fig 2b Mammographic Findings: Mediolateral oblique and craniocaudal views of both breasts demonstrate multiple circumscribed masses of varying sizes located in the subcutaneous tissue, compatible with patient’s known history of neurofibromatosis type 1 (NF 1). There is a spiculate mass (solid arrow) with surrounding area of architectural distortion in the left upper outer quadrant (Fig 1b, 2b) spanning approximately over a distance of 1cm. The architectural distortion is better demonstrated on the mediolateral oblique spot compression view (Fig 3). Adjacent to the architectural distortion, there are multiple discontinuous clusters of pleomorphic and linear calcifications, segmental in distribution (open arrows). They extend anteriorly towards the nipple (Fig 3,4) and are compatible with Ductal carcinoma in situ (DCIS). Fig 3

Diagnosis: Neurofibromatosis type-1 with left upper outer quadrant IDC with DCIS

CASE HISTORY Fig 6a 52 year old African American female, no family history of malignancies. No siblings with NF 1. She has four children, one son with NF 1. The patient initially presented with flank pain and weight loss. However, at that time, routine CBC showed anemia. She was placed on iron supplements and a colonoscopy and EGD were performed that revealed multiple gastric lesions, which revealed poorly differentiated adenocarcinoma. CT scan showed multiple lesions in the liver (Fig 6a, solid arrow ) & bones (Fig 6b, open arrow ) which revealed poorly differentiated metastatic adenocarcinoma of breast origin. Patient was started on chemotherapy. Fig 6b

Fig 7a After two months of chemotherapy she presented with blurry vision and frontal headache. Brain MRI (Fig 7a, 7b) revealed multiple brain metastases. After discussion of treatment options, patient decided to undergo whole brain radiation therapy. Patient is currently on chemotherapy for breast cancer. Fig 7b

Sonographic Findings: Single ultrasound image (Fig 5a) of the left breast at 2 o’clock position reveals a parallel oriented, mixed echogenic lesion with lobulated margins superficial in location. Doppler ultrasound interrogation (Fig 5b) demonstrates significantly increased blood flow centrally and along the periphery. The patient underwent ultrasound guided core biopsy of lobulated mass in the left breast 2 o’ clock position. The pathology report stated invasive ductal carcinoma, grade 3 with component of DCIS. It was positive for ER/PR and Her-2/neu negative cancer. Fig 5a Fig 5b

High power histology slide (Fig 6b): Fig 6a Pathology Findings: Low power histology slide ( Fig 6a): demonstrates extensive desmoplastic reaction surrounding nests or columns of monotypic invasive ductal carcinoma: grade III. Fig 6b High power histology slide (Fig 6b): Demonstrates columns of monotypic invasive ductal carcinoma: grade III. Multiple mitotic figures are noted (solid arrow).

Pathology slide of gastric ca to be inserted The adenocarcinoma in the stomach is histologically dissimilar from the patient's breast carcinoma.

NF 1 is an autosomal dominant disorder that is localized at the long arm of chromosome 17, affecting 1 in 4000 individuals. A recent study from UK to assess the risk of breast cancer in 304 women with NF 1 reveals a fivefold risk of breast cancer in women with NF 1 aged < 50 years (1). Few cases have been reported in the literature of NF1 associated with breast cancer and the role of NF1 gene in breast cancer development (2). Loss of heterozygosity in the NF1 gene, observed in the tumor, suggests an important role of the NF1 gene in the breast cancer etiology. The NF1 gene has also a portion similar to genes that encode guanosine-triphosphate-activating proteins, which inactivate the ras proto-oncogene. This hypothesized downregulation of ras may result in unsuppressed cell proliferation. A research group from Italy conducted a linkage analysis study of 5 family members to establish an association between NF1 and BRCA 1 loci on chromosome 17. Both BRCA1 and NF1 genes are located on the long arm of chromosome 17. The results of linkage analysis and mutation performed on five members of the NF 1/breast/ovarian cancer family show that the three individuals affected by both NF 1 and carcinomas share a common haplotype including the NF 1 and BRCA1 loci on chromosome 17 and a BRCA1 mutation. Therefore, the concurrence of NF 1 and hereditary breast/ovarian cancer in this family is likely due to the presence of two linked mutations at the NF 1 and BRCA 1 loci (4). BRCA1 mutations might increase the risk for other tumors namely, prostate, large bowel, gastric and squamous cell cutaneous carcinomas (4). In NF 1 patients, identifying Paget’s disease or infiltration of DCIS may be difficult, and the detection of breast cancer may be delayed because of presence of numerous NF skin tumours hinders the detection of breast lumps (3).

NF 1 is an autosomal dominant disorder that is localized at the long arm of chromosome 17, affecting 1 in 4000 individuals. Few cases have been reported in the literature of NF 1 associated with breast cancer and the role of NF1 gene in breast cancer development (2). Loss of heterozygosity in the NF1 gene, observed in the tumor, suggests an important role of the NF1 gene in the breast cancer etiology. Predisposition of tumor genesis in NF 1 might be explained by overexpression of p21-ras a tumor suppressor gene called neurofibromin (5). A research group from Italy conducted a linkage analysis study of 5 family members to establish an association between NF1 and BRCA1 loci on chromosome 17. Both BRCA1 and NF1 genes are located on the long arm of chromosome 17. The results of linkage analysis and mutation performed on five members of the NF 1/breast/ovarian cancer family show that the three individuals affected by both NF 1 and carcinomas share a common haplotype including the NF 1 and BRCA1 loci on chromosome 17 and a BRCA1 mutation. Therefore, the concurrence of NF 1 and hereditary breast/ovarian cancer in this family is likely due to the presence of two linked mutations at the NF 1 and BRCA 1 loci (4). BRCA1 mutations might increase the risk for other tumors namely, prostate, large bowel, gastric and squamous cell cutaneous carcinomas (4). A recent study from UK to assess the risk of breast cancer in 304 women with NF 1 reveals a fivefold risk of breast cancer in women with NF 1 aged < 50 years (1). In NF 1 patients, identifying Paget’s disease or infiltration of DCIS may be difficult, and the detection of breast cancer may be delayed because of presence of numerous NF skin tumors hinders the detection of breast lumps (3).

NF 1 is a major risk factor for the development of several malignancies including Malignant peripheral nerve sheath tumors, optic gliomas and leukemias (4).

References: (1) Sharif S, Moran A 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 Aug;44(8):481-4 (2) Sefik Guran et al: A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer. Cancer Genetics and Cytogenetics 156 (2005) 86-88. (3) Yoko Kawawa et al: Paget’s disease of the breast in a woman with Neurofibromatosis. Clinical Imaging 31 (2007) 127-130. (4) Marcello C et al: BRCA1-Related Malignancies in a Family Presenting with von Recklinghausen’s Disease. Gynecologic Oncology 86, (2002) 375-78.