Breast cancer and neurofibromatosis type 1: a diagnostic challenge in patients with a high number of neurofibromas

Although digital mammography is the gold standard for screening for early stage breast cancer, in this paper we highlight the challenge in interpreting images of a large breast carcinoma in an NF1 patient due to the high number of skin neurofibromas. Physical examination of this patient was also somewhat impaired because of the amount of cutaneous lesions. The difficultly in detecting breast cancer in NF1 individuals with numerous skin neurofibromas has been reported previously [4,9,10]. NF1 can obscure or delay the identification of breast lesions not only because skin neurofibromas can mask the signs of a malignant lesion, but also because patients and physicians may mistakenly consider a breast mass to be a manifestation of the primary disease [11].

The first report of an association between NF1 and breast cancer was published in 1972 [12]. Several other clinical cases of NF1 patients with breast cancer were subsequently presented in the literature [4,9-11,13-17]. Because breast cancer is a common tumor in the general female population, the exact relationship between NF1 and breast cancer has been debated. To date, the study with the largest cohort of NF1 individuals (n = 448) that investigated the prevalence of breast cancer, as well as other types of cancer, showed that the risk of breast cancer was significantly higher in NF1 patients younger than 50 years of age than in the general population [5]. Sharif et al. [6] identified 14 cases of breast cancer within a cohort of 304 NF1 women older than 20 years, which represented a 3.5-fold risk of breast cancer in association with NF1. The same study calculated a 4.9-fold risk of developing breast cancer up to age of 50, representing an 8.4% cumulative risk of developing breast cancer compared with the risk in the general population of 2%. In a cohort of 126 patients, Madanikia et al. [7], in a retrospective study with 506 NF1 patients, identified four cases of breast cancer, and found a trend for an almost 3-fold increase in the risk of breast cancer in women with NF1 who were <50 years old compared with age-matched unadjusted incidence rates.

The data showing a high prevalence and a possible earlier onset of breast cancer in NF1 individuals have important implications on screening [5]. Breast cancer screening guidelines have been delineated for the general population and for women with known genetic risk factors for breast cancer (i.e. BRCA1 and PTEN syndromes) to decrease mortality through early diagnosis; however, there are currently no such guidelines for NF1 patients [7].

A study of over 1,000 NF1 individuals found an incidence of breast cancer mortality in NF1 females of approximately 3.5-fold that of the general population [18]. This finding suggests that not only is there an increased risk and earlier onset of breast cancer in women with NF1, but also a worse prognosis associated with the disease. As occurred in our patient, most of the cases of breast cancer in NF1 individuals are diagnosed at an advanced stage with a T score greater than 2 [9,13]. Therefore, the worse prognosis of breast cancer in NF1 may not be a characteristic of the disease itself, but may result from late-stage diagnosis due to the presence of skin neurofibromas, which hinder its identification, or due to the delay in seeking medical care by patients who think the breast mass is a neurofibroma. The most common histopathological type of breast cancer in NF1, as well as in the general population, is infiltrating ductal carcinoma [7], as observed in our case.

The scientific data support a real association between breast cancer and NF1. With regard to this, various authors have suggested different mechanisms supporting the relationship between NF1 and breast cancer. One of the implicated oncogenic events in breast cancer is the overexpression of Ras, which occurs in up to 60% of all cases and exerts several effects including perturbed cytoskeletal structure, decreased cell survival and increased apoptosis [19]. Neurofibromin, the protein product of NF1 gene, which is located on chromosome 17q11.2, functions as a negative regulator of the Ras pathway, interacting with Ras and converting active Ras-GTP to its inactive form, Ras-GDP. The NF1 gene acts in accordance with the Knudson two-hit hypothesis: in NF1-related tumors, biallelic inactivation of the NF1 gene results in complete loss of functional neurofibromin activity [13]. In addition to upregulation of Ras, absence of neurofibromin expression has been observed in breast cell lines [20], suggesting overlapping etiologies [13]. However, it is not known whether the lack of neurofibromin is a primary or a secondary event in breast cancer tumorigenesis. Interestingly, around 30% of sporadic breast cancers in humans lack at least one copy of NF1 gene [15].

Mutations of the tumor suppressor genes BRCA1 and BRCA2 are known to be associated with different patterns of hereditary breast and ovarian cancer [13]. Because BRCA1, like NF1, is located on human chromosome 17q, it has been suggested that an interaction could exist between these two genes [6]. While it is probable that some individuals reported in the literature carried mutations in both BRCA1 and NF1 genes, there is a scarcity of reports of germline mutations in both genes in the same individual. To the best of our knowledge, Campos et al. [13] were the only group to report a family with individuals with diagnosis of NF1 and breast cancer who were carriers of both BRCA1 and NF1 mutations. They concluded that the concurrence of NF1 and breast cancer was probably due to the simultaneous existence of two cancer-predisposing conditions.