Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases in humans and is associated with various benign and malignant tumors, including breast cancer. However, an increased risk of breast cancer in NF1 patients has not been widely recognized or accepted. Here, we report two cases of breast cancer in NF1 patients and review the literature on the association between NF1 and breast cancer.
Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is one of the most common autosomal dominant diseases in humans, and its incidence and prevalence have been reported to be approximately 1 in 2,700 and 1 in 4,600, respectively [
Here, we report two cases of breast cancer in NF1 patients and review the literature on the association between NF1 and breast cancer.
A 25-year-old woman with a palpable lump in her right breast was referred to our department. She had been diagnosed with NF1 at the age of 17 years. Two of her aunts had cancer; one had breast cancer and the other had ovarian cancer. However, there was no family history of neurofibromatosis.
On US, an ill-defined hypoechoic mass with microcalcifications and irregular duct changes, extending to the subareolar area, was noted in her right breast. Additionally, several lesions believed to be metastatic lymph nodes were observed in the ipsilateral axilla (Figures
Ultrasonography shows an ill-defined hypoechoic mass with microcalcifications and irregular duct changes in the right breast. The mass with irregular duct changes extends to the subareolar area (a). Metastatic lymph node is seen in the ipsilateral axilla (b). Mammography shows fine pleomorphic microcalcifications with segmental distribution in the lower outer portion of the right breast. And mild skin thickening (arrows in c) and metastatic lymph node are also noted (c). Magnetic resonance imaging shows that lesion exhibits nonmass enhancement lesion with heterogeneous internal enhancement pattern and occupies most of the right breast, except the lower inner portion (d).
She underwent US-guided core needle biopsy in the lower outer portion of her right breast and of the pathological lymph nodes in the right axilla. She was diagnosed with ductal carcinoma in situ in the breast and metastatic lymphadenopathy in the right axilla. She underwent modified radical mastectomy and axillary lymph node dissection, and the final diagnosis was invasive ductal carcinoma with axillary metastasis (T2N3M0; estrogen receptor positive; progesterone receptor positive; human epidermal growth factor receptor 2 negative; Ki-67 10–20%). We analyzed DNA from peripheral blood in order to evaluate the presence of mutations in the
A 47-year-old woman with NF1 visited our department for a palpable lump in her left breast. On MMG, an irregular hyperdense mass with microlobulated margin was noted in her left breast, and pathologic lymph nodes were noted in her left axilla (Figure
Left mediolateral oblique mammography shows an irregular hyperdense mass with indistinct margin (thin arrow) and axillary lymphadenopathy (arrowhead). Additionally, skin undulation is seen, indicating presence of cutaneous neurofibromas (thick arrow). Ultrasonography shows a large, hypoechoic, irregular mass with angular margin in the left breast (b) and multiple metastatic lymph nodes in the left axilla (c). PET-CT shows hepatic metastasis (d).
She underwent US-guided core needle biopsy of the irregular mass in the left breast and was diagnosed with invasive ductal carcinoma. Additionally, during the staging workup, she was diagnosed with hepatic metastasis on PET-CT (Figure
Here, we reported two cases of NF1 associated with breast cancer. NF1 is a complex neuroectodermal disorder characterized by autosomal dominant inheritance, high penetrance, and wide variability in expression. The disease is caused by mutations in the
The
Neurofibromin, the protein product of the
The first report of an association between NF1 and breast cancer was published in 1972 [
Summary of previously reported NF1 patients with breast cancer.
Author | Age (yr) | Family history of breast cancer | Gene mutation | Stage | Molecular subtype | Characteristics |
---|---|---|---|---|---|---|
Brasfield and Das Gupta [ |
5 patients | |||||
McMillan and Edwards [ |
27 | NA | NA | NA | NA | |
Hiraide et al. [ |
32 | NA | NA | NA | NA | |
el-Zawahry et al. [ |
2 patients | |||||
Vilar Sanchis and Vazquez Albaladejo [ |
1 patient | |||||
Hollo way et al. [ |
68 | NA | NA | IIA | NA | Male |
Nakamura et al. [ |
49 | NA | NA | NA | NA | |
Murayama et al. [ |
66 | NA | NA | IIA | NA | |
Ceccaroni et al. [ |
66 | Daughter |
NA | NA | NA | |
Satgé et al. [ |
23 | 4 aunts | NA | NA | NA | |
Güran and Safali [ |
23 |
Mother |
NA | NA | NA | |
52 |
Daughter |
NA | NA | NA | ||
Posada and Chakmakjian [ |
74 | No | NA | IIA | NA | |
Kawawa et al. [ |
66 | No | NA | IIB | Luminal | Paget’ disease |
Natsiopoulos et al. [ |
60 | No | NA | IIB | Metaplastic carcinoma | |
Hasson et al. [ |
49 | No | NA | IB | Luminal | |
Invernizzi et al. [ |
60 | NA | NA | IA | Luminal | |
Alamsamimi et al. [ |
51 | Sister | NA | IIA | Luminal | Synchronous bilateral breast cancer |
Salemis et al. [ |
59 | No | NA | IIB | Luminal | |
Bhargava et al. [ |
58 | NA | NA | NA | NA | |
Takeuchi et al. [ |
76 | NA | NA | IIA | NA | Metachronous contralateral breast cancer |
Zhou et al. [ |
48 | NA | NA | IA | Luminal | |
Campos et al. [ |
35 |
Mother | NA | NA | Nonluminal | |
40 |
Daughter | BRCA1 | IV | NA | ||
Cheuk et al. [ |
42 | NA | NA | NA | NA | |
Jinkala et al. [ |
69 | NA | NA | NA | NA | |
Nogimori et al. [ |
1 patient | |||||
Vivas et al. [ |
53 | NA | NA | IV | HER2 | Metaplastic carcinoma |
Lakshmaiah et al. [ |
55 | No | NA | IIB | Luminal | Male |
Chaudhry et al. [ |
46 | No | NA | IIIA | HER2 | Metaplastic carcinoma |
Da Silva et al. [ |
54 | No | NA | IA | HER2 | |
Jeon et al. [ |
21 |
No | No | IIB | Luminal | |
30 |
No | NA | IIA | Luminal | Metachronous contralateral breast cancer | |
Khalil et al. [ |
39 | NA | NA | IIIA | Luminal | |
Zöller et al. [ |
2 breast cancers in 70 NF1 patients (2.8%) | |||||
Walker et al. [ |
5 breast cancers in 448 NF1 patients (1.1%) | |||||
Sharif et al. [ |
14 breast cancers in 304 NF1 patients (4.6%) | |||||
Madanikia et al. [ |
4 breast cancers in 126 NF1 patients (3.2%) | |||||
Wang et al. [ |
15 breast cancers in 76 NF1 patients (19.7%) | |||||
Seminog and Goldacre [ |
52 breast cancers in 3855 NF1 patients (1.3%) |
NF1: neurofibromatosis type 1; NA: not assessable; luminal: estrogen receptor (ER) or progesterone receptor (PR) positive; nonluminal: ER and PR negative; HER2: ER and PR negative and human epidermal growth factor receptor 2 (HER2) positive.
Sharif et al. retrospectively evaluated the risk of developing breast cancer among 304 women aged 20 years or older who were diagnosed with NF1 over a period of 30 years [
Murayama et al. reported 37 cases of breast cancer associated with NF1, and most of the cases were diagnosed at an advanced stage [
All the above-mentioned articles have similar findings that NF1 increases the risk of developing breast cancer and that NF1 patients with breast cancer have a poor prognosis.
Breast cancer screening guidelines have been well established for the general population and for high-risk women, to decrease mortality through early diagnosis. However, currently, there are no such guidelines for NF1 patients, and guidelines similar to those for Cowden syndrome, which is a genetic disorder associated with breast cancer, should be developed [
The patients and physicians should be aware of the high possibility of breast cancer in individuals with NF1. For early diagnosis, the current guidelines used to screen women in the general population appear to be insufficient to screen NF1 patients. The findings of the above-mentioned reports and other published data justify the requirement of specific screening programs for NF1 patients, similar to the programs for Cowden syndrome patients. Further studies are needed to clarify the relationship between NF1 and breast cancer, especially at the genetic level, and to establish specific screening guidelines for the early diagnosis of breast cancer in NF1 patients.
The authors declare that there is no conflict of interests regarding the publication of this paper.