Breast cancer in a patient with neurofibromatosis type 1: A case report and review of literature

Abstract

Neurofibromatosis 1 (NF1) represents a cluster of clinical features based on the National Institute of Health(NIH) diagnostic criteria. It is a multi-systemic disease with progressive features characterized by variable expression. NF1 is associated with an increased risk of malignancies including breast cancer. Presented was a 56 year old woman with a painless lump in the right breast in the past 15 months. Clinical evaluation revealed features of NF1 and an advanced right breast cancer. Histologic evaluation revealed an invasive ductal carcinoma and she was offered a right modified radical mastectomy. Due to clinical presentation with discrete lesions, NF1 may be diagnosed at presentation with malignancy. Clinicians are urged to be familiar with the subtle features of NF1 for early diagnosis that is largely clinical. Institution of early breast cancer surveillance in patients with NF1 is recommended for early diagnosis and improved outcomes.

Introduction

Neurofibromatosis 1 (NF1) also known as von Recklinghausen disease represents an aggregation of clinical features based on the National Institute of Health diagnostic criteria.^1,2 It is a multi-systemic genetic disease with progressive features characterized by full penetration but variable expression.^2,3 In 1972, the first report of the association between NF1 and breast cancer was published. ⁴ The estimated prevalence of NF1 is 1:3000. ⁴ However, the actual frequency is higher because some cases are not completely ascertained in individuals that are mildly affected. ⁵ NF1 is an autosomal dominant(AD) disorder that is associated with an increased risk of malignancy.^4,6,7 It is a risk factor for the development of breast malignancy, 27.7% of all breast carcinomas are said to harbor somatic mutations of the NF1 gene which are regarded as potential genomic driver in the development of breast cancer. ⁸ NF1 is caused by mutations in the NF1 gene, a classical tumor suppressor gene(TSG) that regulates Ras guanosine triphosphate(GTP) activity inhibiting GTPase activation that regulates cell proliferation and differentiation. The resultant effect is a multi-systemic neurocutaneous disorders.^4,8 Fifty(50%) percent of cases result from new mutations and are not hereditary.^1,2 NF1 gene is in the long arm of chromosome 17, where BRACA1 gene is also located. However, their interaction is not completely understood. ⁶ The diagnosis of NF1 is usually clinical. ¹ Most affected individuals present with multiple neurofibromas, café-au-lait spots, freckling in axillary and inguinal regions and lisch nodules. ⁴ Diagnosis of breast cancer is based on histology. The treatment for patients with breast cancer follows the standard of care protocol. ⁹ The prognosis of breast cancer depends on the stage of the disease. It is poor with advanced disease due to delayed diagnosis or challenges of diagnosis due to a high density of neurofibromas on the breast. ⁸ We present a 56 year old woman with an advanced breast cancer during which she was discovered to have NF1 for the first time. This was to highlight the challenges related to late diagnosis of NF1 a possible risk factor for breast cancer and emphasize the need for early surveillance and detection of breast cancer.

Case report

Presented is a 56 year old woman with a lump in the right breast of 15 months duration. The painless lump was insidious in onset initially of the size of a groundnut seed. It progressively increased in size and became adherent to the skin with the resemblance of an orange peel. This became associated with a lump in the right armpit. The contralateral breast was normal. There was no history of previous surgery or breast pathology nor was she managed for any gynecological malignancy. Age at menarche could not be recalled and was 5 years postmenopausal. There was no family history of breast cancer. At presentation she was noticed to have multiple tiny skin nodules more on the neck region. On further enquiry, she volunteered a similar history that involved her mother and elder sister attributed to be “birth marks” found in the family. She is a known hypertensive on control drugs.

On examination, she was not pale, anicteric and no pedal oedema but had right sided axillary lymphadenopathy. There were multiple dark brown nodules of varying sizes anteriorly and posteriorly mainly on the neck and chest region, Figure 1. Button-hole sign was positive. She also had bilateral axillary skin fold freckles, Figures 2(a) and (b). The breast was asymmetrical with the right larger than the left with peau d’ orange on the right breast. The mass was in the right lower quadrant of the breast and measured about 8 × 6 cm in the widest dimensions. The overlying skin was tethered to the mass and not attached to the chest wall. The nipple was retracted with expressible brownish discharge, Figure 3. There was a 4 × 3 cm discrete and hard medial axillary lymphadenopathy. Examination of the chest, abdomen and the limbs were unremarkable. A clinical diagnosis of an advanced right breast cancer(T₄N₁M₀) in a patient with NF1 was made.

Figure 1.

Clinical photographs showing neurofibromas.

Figure 2.

(a and b). (a) Bilateral axillary skin fold freckling(Blue arrows). (b) Right axillary skin fold freckles.

Figure 3.

Clinical photograph showing right breast cancer.

Work up included full blood count(FBC): PCV 33.3%, hemoglobin(Hb) 10.2 g/dl, white blood cell(WBC) count 5.3 × 10⁹/l, neutrophil 39%, eosinophil 1.4%, basophil 0.2%, monocytes 13.9%. Platelets 171 × 10⁹/l. Electrolytes/urea/creatinine- Na⁺ 145.6 mmol/l, K⁺ 4.9 mmol/l, cl⁻ 102 mmol/l, Hc₀₃^- 24 mmol/l, urea 93.5 mmol/l and creatinine 93.5umol/l. Urinalysis was normal. Breast ultrasound scan(USS) was reported as BIRADS IV right breast with solitary axillary lymph node. Chest X-ray showed hypertensive cardiovascular changes. Abdominal USS was reported as normal. ECHO cardiography reported features that was consistent with hypertensive heart disease. Trucut biopsy showed invasive ductal carcinoma and immunohistochemistry(IHC) was ER⁼, PR⁻ and Her2/neu positive(triple positive). A preoperative diagnosis of invasive carcinoma of the right breast was made in a patient with NF1.

She was offered a modified radical mastectomy including the biopsy of the skin nodule on the anterior chest wall. The postoperative period was uneventful. The histology of the skin nodule revealed a section that showed stratified squamous epithelium and spindle shape cells with wavy, slender nuclei with loose stroma in the dermis- neurofibroma, Figure 4(a) and (b). The mastectomy specimen revealed a section of tissue that showed a tumor composed of malignant epithelial cells disposed in nest, sheets, cords and trabeculae. Gland formation was less than 10% with a high mitotic index. The intervening stroma was desmoplastic- invasive ductal carcinoma(IDC), no specific type(NST), Figure 5. A definitive diagnosis of invasive ductal carcinoma(NST) with NF1 was made. She was commenced on adjuvant chemotherapy. Patient was counselled on the disease of neurofibromatosis 1 including the risk of the development of malignancies. Furthermore, the risk of cancer in the contralateral breast was emphasized and the need for breast screening highlighted including her sibling.

Figure 4.

(a and b) Neurofibroma. (a) H&E X 40, (b) H&E X100- Section of the skin that showed stratified squamous epithelium and spindle shape cells with wavy, slender nuclei with loose stroma in the dermis.

Figure 5.

Invasive ductal carcinoma, NST. H&E X100- Section of the breast tissue that showed a tumor composed of malignant epithelial cells disposed in nests, sheets, cords and trabeculae. Gland formation was less than 10% with a high mitotic index. The intervening stroma was desmoplastic.

Discussion

Neurofibromatosis 1 has been classified into 8 subtypes with NF1 being the most common accounting for more than 90% of all the cases. ³ It is known for variable expression; accordingly, a significant proportion remain undiagnosed due to presentation with discrete lesions. ² The index patient remained undiagnosed due to discrete lesions also found in her mother and elder sister believed to be birth marks prevalent in the family. It is one of the most prevalent conditions found in 1:3000-4000 births affecting sexes in the same frequency and found in all races.^2,8 NF1 patients are at a fourfold increased risk of developing cancer than in the general population. ⁸ In NF1, the incidence of breast cancer is 3.5 times more than in the general population. ⁶ When compared to healthy women, NF1 patients have an estimated two fold(18%) increase at risk of breast cancer with the most common rates found in women younger than 50 years in the general population.^4,10,11 A study by Swarez-Kelly LP et al., concluded that in NF1 patients, the mean age was 49.3 years at breast cancer diagnosis with a median of 46 years and an interquartile range of 38.3–58 years. ¹² In another study, most of the patients were < 50 years with 53% < 50 years old, 28% were between 35 and 44 years and 15% < 35 years old. ⁸ The lifetime risk of breast cancer is four-times higher than the cumulated risk for women with NF1 less than 50 years and this amounts to 8.4%. ¹³

NF1 gene is located on the second arm of chromosome 17 and is a suppressor gene. Neurofibromin a product of the gene is a negative regulator of the signal pathway RAS-MAPK(RAS/mitogen activated protein kinase) involved in the proliferation and differentiation of cell.^3,4 BRACA gene is also located within the long arm of chromosome 17². The proximity of both NF1 gene and BRACA 1 gene a breast cancer predisposition gene on chromosome 17 lends credence to the association of the two conditions.^4,8 This is a subject of further research. Patients lifestyle and environment in addition to genetic makeup constitute risk factors for breast cancer. ⁹

The consensus conference of the National Institute of Health(NIH), Bethsida(MD USA) defined in1988 seven main criteria of the diagnosis of NF 1. It is diagnosed when two of these signs are present in the same person:

1. First degree relative afflicted(Parent, sibling, child)

2. At least 6 café-au-lait macules; 1.5 cm after puberty and >0.5 cm prepubertal

3. Freckling in the axilla and inguinal region(CROWE sign)

4. At least 2 neurofibromas of any type or at least a plexiform neurofibroma

5. Optic nerve glioma

6. 2 lisch nodules(Iris hamartoma) and

7. Characteristic bone lesions- pseudoarthrosis, sphenoid wing dysplasia, thinning of long bone cortex.^2,3 The NF1 International consensus recommendation distinguish clinical and genetic characteristic in NF1 into two groups- Group A are individuals who do not have a parent diagnosed with NF1. They require 2 or more of the 7 diagnostic criteria. Group B are those who have parent meeting the diagnostic criteria of NF1. They need only one of the 7 diagnostic criteria. ⁹ Our patient belonged to group B. A history, physical examination and family history of NF1 are often sufficient to make a diagnosis. ⁹

The main symptoms are café-au-lait skin macule, neurofibroma, iris lisch nodules and axillary and inguinal freckling. ² The appearance of cutaneous signs is progressive and in adults the diagnosis of NF1 is usually clinical. ⁵ The detection of breast cancer in NF1 patients may be challenging for patients with large numerous skin neurofibromas that interfere with physical examination and in addition some patients are less likely to notice a lump in the breast. ⁶ Da Silva et al described a 54 year old woman with a delay in presentation on the assumption that the breast mass was part of the manifestation of NF1. ⁴ Detection of breast cancer on physical examination in the setting of numerous number of cutaneous lesions can be difficult as reported by Salemis NS et al. ¹⁴ Furthermore, the signs of malignancies could be masked by multiple cutaneous lesions and may be confusing to both the physicians and patients.^4,15 Khalil J et al reported breast cancer associated with NF1 in 3 patients in which the diagnosis of NF1 was made at birth in a patient and the other two made at 7 and 8 years and associated late diagnosis of breast cancer. The patient with NF1 diagnosed soon after birth detected the breast lesion following breast self-examination(BSE) in keeping with oncological surveillance. The late diagnosis in the other cases could be attributed to the non-observance of oncological surveillance. ¹⁶ Murayama Y et al reported 37 cases of breast cancer associated with NF1. ¹⁷ Most cases were diagnosed with advanced stage disease(IDC) an indication of lack of oncological surveillance. In a few cases of NF1, bilateral breast cancer have been reported. ⁶ It has been reported that patients with NF1 have a 4-11 fold higher risk of contralateral breast cancer.^1,8 Rarely men with NF1 have been reported to have breast cancer. ⁸ In our patient, the diagnosis of NF1 was made at the time of presentation with an advanced breast cancer. Multiple skin lesions noticed among some family members were regarded as birth marks prevalent in the family and did not prompt them to seek for medical attention. She had been attended to by physicians for other ailments but remained undiagnosed for NF1.

In the diagnosis of NF1, molecular genetic testing is rarely required and are used only in cases where diagnosis is difficult.^1,2,9 Dursun D et al reported a rare case about a woman and her daughter both with NF1, the mother had metachronous bilateral breast cancer observed during follow up. ¹⁸ The DNA repair gene expression, c.1246 C>T mutation were found to be similar in mother and daughter. The significance of this is that the daughter might also have breast cancer in future. In NF1 patients, the DNA repair gene expression may be used for screening to predict the possibility of the development of malignancy. ¹⁸ In the workup of patients, imaging modalities may be indicated for the evaluation of the breast and subsequently for surveillance. Studies have suggested that early mammography and breast MRI were helpful in surveillance in NF1 patients. ⁶ The National Comprehensive Cancer Networks recommendation includes an annual mammography beginning at the age 30 years including the consideration of contrast enhanced breast MRI between 30 and 50 years. ⁹ Diagnosis of breast cancer is by histology. Invasive ductal carcinoma, no specific type(IDC-NST), lobular carcinoma and metaplastic carcinoma were histological types reported. ⁸ Previous NF studies and the general population revealed the predominance of IDC in keeping with histology of our patient.^6,19 There are no extensive studies on the frequency of estrogen and progesterone receptor status in patients with NF1. ⁹ The receptor status of our patient was triple positive(ER⁺, PR⁺, Her2⁺).

von Recklinghausen disease has no cure and therapeutic methods specific for the disorder are not available. These patients require a lifetime supervision of physicians from various specialties that include dermatologist, neurologist, ophthalmologist, orthopedist(children) and oncologist. Furthermore, it is necessary to remember the increased risk of breast cancer in these patients in view of the increased associated mortality. ² NF1 patients should be instructed to report to a physician in case of observing any changes in the breasts. Oncological alertness is recommended in NF1 patients with screening with USS and MRI.^8,13 The overall mortality and breast cancer specific mortality is higher among women with NF1 especially those that present with more advanced disease.^1,8,20 NF1 associated breast cancer are associated with poor survival and unfavorable prognostic factors such as ER, PR negativity and Her2 amplifications.^6,8 The receptor status of our patient was triple positive a likely indicator of a favorable prognosis. Education and encouragement of patients to seek advice as soon as new symptoms appear is highly recommended. ⁹

Conclusion

Patients with NF1 may present with discrete lesions only to be diagnosed when they present with malignancy. Clinicians are urged to be familiar with this mode of presentation for early diagnosis that is largely clinical. It is desirable for early breast cancer surveillance to be instituted.