CASE REPORT

Katarzyna Mączka-Piekarz, Joanna Mykała-Cieśla

Department of Internal Medicine and Oncological Chemotherapy — Andrzej Mielęcki Hospital of the Medical University of Silesia in Katowice, Poland

Breast cancer in a patient with neurofibromatosis type 1 — analysis of the clinical case

ABSTRACT

Neurofibromatosis type 1 (NF1), also called von Recklinghausen’s disease, is an autosomal dominant disorder, which is present in the population with a frequency of approx. 1:3000. One of the problems of medical care for patients with NF1 is a significantly increased risk of developing cancer (including breast cancer) compared to the general population. The NF1 gene product is a negative regulator of the RAS-MAPK pathway. Mutations in this gene may also be associated with some mutations in the BRCA1 gene. The aim of this study is to pay attention to the increased incidence of breast cancer in patients with NF1 and attempt to show the importance of constant oncological supervision in women with neurofibromatosis. The material for the analysis is the medical history of 41-year-old woman with NF1 and breast cancer diagnosed in 2012. In the control mammography performed in January 2012 the presence of atypical structure in the right breast, suspected of being malignant, was revealed. Needle aspiration biopsy indicated the presence of atypical cells. The tumour was removed. Pathological examination confirmed the malignant nature of the structure, and so the breast conserving therapy was extended and the right axillary lymph system was removed. The patient was qualified for adjuvant chemotherapy based on anthracyclines and radiotherapy.

Detection of breast cancer in patients with NF1 can be difficult because skin changes can mask symptoms of the tumour and the patient can treat new changes in the breast as a manifestation of NF1. Therefore, it is recommended to pay constant, increased oncological attention to patients with NF1.

Key words: NF1 gene, neurofibromatosis type 1, von Recklinghausen’s disease, breast cancer, phakomatoses

Oncol Clin Pract 2016; 12, 1: 33–36

Introduction

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is a relatively frequent autosomal dominant disorder characterised by full penetration but very variable expression [1]. Because of that, a significant proportion of cases with discrete lesions remain undiagnosed. It is accounted to a relatively numerous group of musculocutaneous diseases (phakomatoses) [2, 3]. The frequency of incidence of the disease is 1 per 3000 births [4–6]. It occurs with similar frequencies across both sexes and all races [4]. Half of the cases result from new mutations and are not hereditary [1, 2, 4].

The diagnosis of Von Recklinghausen disease is made based on strictly defined clinical criteria developed in 1987 by the National Institutes of Health and named the NF1 NIH Consensus Conference Criteria [1, 2, 5–7]. For the diagnosis, finding at least 2 of 7 included criteria is required (Table 1) [4, 6]. Molecular tests are used only in cases especially difficult to diagnose [1, 2].

Table 1. Diagnostic criteria for neurofibromatosis type 1

The main symptoms of the disease are café-au-lait skin maculae, neurofibromas, iris Lisch nodules (hamartoma changes), and axillary or inguinal freckling. Less frequently low height, microcephaly, scoliosis, and cognitive disorders are found [1, 3, 5, 8].

The NF1 gene is a suppressor gene located on the second arm of chromosome 17. The significant size of this gene (over 350 bp) is related to the high frequency of spontaneous mutations occurring in the neurofibromatosis [1, 8, 9]. The product of this gene — the neurofibromin peptide — is the negative regulator of the signal pathway RAS-MAPK (RAS/mitogen-activated protein kinase), engaged in proliferation and differentiation of cells. Neurofibromin contains the domain activating the GTPase enzyme responsible for the conversion of active form of RAS to the inactive form [4]. Neurofibromatosis type 1 is caused by the presence of an inactivating mutation in one of the NF1 gene alleles. Loss of heterozygosity by cells in their life cycle (Knudson two-hit hypothesis) results in the development of tumours [1, 8–10]. In light of subsequent reports concerning increased incidence of tumours in patients with NF1 [2, 10], more and more emphasis is brought to include these persons in extraordinary oncological supervision [1, 4, 5]. It is noteworthy that in the vicinity of the NF1 gene within the long arm of chromosome 17, the BRCA1 gene is also located. Bearing this in mind, it is probable that mutations in the NF1 gene can be connected to some mutations of the BRCA1 gene [6, 9–11]; however, further studies are necessary in this field. Neurofibromin is a peptide playing a very important role in cell functioning. Studies have shown that somatic mutations of the NF1 gene occur not only in relationship to the disease of neurofibromatosis but also in many other neoplasms [8].

In the group of patients with neurofibromatosis type 1, the risk of tumours of the nervous system tissues and other tissues is increased (Table 2) [1, 4–8, 12, 13]. Attention is drawn, among others, to the increased incidence of breast cancer, especially in the group of young women [5, 6, 9–14]. For patients with neurofibromatosis type 1, who are less than 50 years old, the lifetime risk of breast cancer is four-times higher than the cumulated risk for the general population, and it amounts to 8.4% [5, 15]. Furthermore, in this group of patients, higher mortality due to breast cancer is noted in comparison to the general population [13].

Table 2. Tumour types associated with neurofibromatosis type 1

Case presentation

A 41-year-old woman with Von Recklinghausen disease diagnosed 16 years ago was admitted to the Clinic in September 2012 for post-surgical systemic treatment of right breast cancer. She was under the constant control since 1998 of the Breast Diseases Outpatient Unit due to the increased risk of developing breast cancer in the course of neurofibromatosis type 1 and because of mammography showing a lump with features of fibrous dysplasia in both breasts (1993). During the control mammography conducted in January 2012, in the lower internal quadrant of the right breast, a spiculated mass of the nature of a radial scar (BI-RADS-4) was found. An ultrasonic examination in April 2012 confirmed the presence of pathological structure in the right breast of size 14 × 8 mm. Based on the conducted diagnostic imaging and the results of a smear test (atypical epithelial cells) the decision was made to remove the mass. The lump was dissected, and then, after confirming its cancerous nature by surgical biopsy, the procedure was extended and the right axillary lymph gland was also removed.

Results of the histopathological examination:

— tubular carcinoma G1;

— lump size: 7 mm;

— oestrogen receptor: ER negative (–);

— progesterone receptor: PR negative (–);

— HER2 receptor expression: negative result;

— Ki-67 proliferation index: 1%;

— lymph nodes 0/14;

— cancer stage in the TNM (tumour, nodus, metastases) classification: T1b N0 M0.

After analysis of the entire clinical view the patient was qualified for adjuvant treatment based on anthracyclines.

Imaging examinations (ultrasound and CT scanning) performed during the first hospitalisation showed a singular lumpy structure of size 56 × 47 × 51 mm, with smooth edges and quite well separated, located in the right iliac fossa, in direct contact with the iliac muscle and part of the fibres of the iliopsoas muscle that was insignificantly enhanced after administering the contrast medium. Finally, the structure was qualified as a lesion of radiological features of a benign lesion (probably the neurofibroma), and in the following control tests it was described as stable. The said lesion was moderately palpable and painless in the physical examination, while periodically the patient complained of idiopathic pain in right side of the lower abdomen and recurring numbness of the lower right limb.

After completing the chemotherapy, the patient was directed to the Department of Radiotherapy for complementary irradiation after breast-conserving surgery, and then she was included in the care of the Oncological Outpatient Clinic.

Von Recklinghausen disease was not finally confirmed in the patient until 1996 when this disease was diagnosed in the patient’s daughter (in her first year of life) based on the girl’s clinical symptoms and genetic tests supporting the diagnosis. Additionally, the case history indicated that similar symptoms were also present in the patient’s mother and her mother’s father (patient’s grandfather).

The clinical picture of our patient shows numerous changes, some of which is included in the criteria of classification of the Von Recklinghausen disease presented in Table 1:

— numerous café-au-lait maculae of variable size located on the skin of the entire body;

— numerous neurofibromas, especially in the lumbar region, paraspinally;

— Lisch nodules in the iris;

— lumpy lesion in the right ulnar nerve;

— lumpy lesion in the right lower abdomen, palpable in physical examination;

— short-sightedness of significant advancement (right eye: –14 D; left eye: –10 D), astigmatism and cataract of the left eye (head magnetic resonance imaging performed in 2011 did not show the presence of lumpy liaison in the optical nerve and eyeball);

— insignificant left-side reduction of hearing.

Discussion

Von Recklinghausen disease is an incurable disease; therapeutic methods specific for this disorder are lacking [1], and patients for their lifetime should be included in special supervision of physicians of various specialities including an ophthalmologist, neurologist, dermatologist, orthopaedist (children), and oncologist [1]. The natural history of neoplasms developing in these patients, which often differs from sporadic cases [7, 10], can lead to diagnostic mistakes, thus making the diagnosis and therapy longer and more complicated [7]. It is vital to remember about the increased risk of breast cancer in this group of patients, which is also associated with significantly increased mortality [5, 6, 9–15]. Detection of breast cancer in patients with NF1 can be more difficult and the diagnosis can sometimes be significantly delayed [6]. A patient can recognize lesions occurring in breasts as another manifestation of the original disease, and because of that may fail to report them to a physician [10, 14]. Skin changes of the neurofibroma type can additionally mask the symptoms of the breast tumour [9, 10].

Specific instructions that would clearly and unambiguously regulate the issue of maintaining oncological supervision over patients with diagnosed neurofibromatosis type 1 are lacking.

Co-occurrence of Von Recklinghausen disease with breast cancer is observed relatively rarely; however, the prognosis in such cases is significantly worse than for patients with breast cancer without the accompanying neurofibromatosis. That is why constant, increased oncological alertness in cases of patients with NF1 should be recommended [6, 9–11, 13, 14], while the patients themselves should be instructed to immediately report themselves to a physician in the case of observing any worrying changes in breasts.

Address for correspondence:

Lek. Katarzyna Mączka-Piekarz

Katedra i Klinika Chorób Wewnętrznych i Chemioterapii Onkologicznej

Samodzielny Publiczny Szpital Kliniczny im. A. Mielęckiego

Śląskiego Uniwersytetu Medycznego

ul. Reymonta 8, 40–027 Katowice, Poland

Phone: +48 608 457 963

e-mail: katarzyna.mp@10g.pl

Oncology in Clinical Practice

2016, Vol. 12, No. 1, –36

Translation: GROY Translations

Copyright © 2016 Via Medica

ISSN 2450–1654

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