Beyond skin deep: unraveling breast neurofibromatosis (a case report)

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BACKGROUND

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a multisystem genetic disorder with an estimated prevalence of approximately 1 in 3000 individuals worldwide [1–3]. It is characterized by café-au-lait macules, axillary freckling, Lisch nodules, and the development of multiple cutaneous and subcutaneous neurofibromas [1, 2]. Although neurofibromas typically arise from peripheral nerves, their occurrence within the breast parenchyma is uncommon [3].

Breast involvement in NF1 remains under-recognized and represents a diagnostic challenge due to overlapping imaging features with more common benign lesions, such as fibroadenomas and hamartomas, as well as malignant entities, including phyllodes tumors and breast carcinoma [4–6]. Although most breast lesions in NF1 patients are benign, the potential—albeit low—for malignant transformation necessitates a structured diagnostic approach integrating clinical assessment, multimodal imaging, and histopathological confirmation [2, 5, 7].

This case report describes the clinical presentation, imaging findings, diagnostic pathway, and management of a breast neurofibroma in a 55-year-old woman with NF1, with particular emphasis on radiological assessment and contemporary management strategies [8, 9].

CASE DESCRIPTION

Patient Information

A 55-year-old woman with a known history of NF1, diagnosed during childhood based on café-au-lait macules and multiple cutaneous neurofibromas (see Fig. 1), presented with a palpable mass in her left breast. The lesion had been self-detected approximately six months before and gradually increased in size, becoming intermittently uncomfortable.

 

Fig. 1. Skin of the abdomen of the patient with many cutaneous neurofibromas.

 

Anamnesis

The patient denied prior breast trauma, nipple discharge, or skin changes. She reported regular menstrual cycles and had no personal or family history of breast cancer.

On physical examination, a palpable, mobile nodule was identified in the upper outer quadrant of the left breast. The overlying skin and nipple-areolar complex appeared normal, without retraction or inflammatory changes.

Systemic Manifestations of Neurofibromatosis Type 1

In addition to multiple cutaneous neurofibromas and café-au-lait macules, no other systemic manifestations of NF1 were identified. Specifically, the patient had no evidence of central nervous system tumors, skeletal deformities, or visceral or ophthalmologic involvement beyond the cutaneous findings.

Diagnostic Assessment

Mammography

Mammography of the left breast revealed a poorly defined, round mass appearing laterally on the craniocaudal view and superiorly on the mediolateral-oblique projection, consistent with localization in the upper outer quadrant. The lesion was partially obscured by heterogeneously dense breast parenchyma (American College of Radiology density category C). No suspicious microcalcifications, architectural distortion, or skin thickening were observed (see Fig. 2).

 

Fig. 2. Mammography of the left breast in craniocaudal and mediolateral-oblique projections showing heterogeneously dense breast parenchyma (American College of Radiology density category C).

 

Based on the mammographic appearance and clinical context, the lesion was classified as BI-RADS 3 (probably benign).

Breast Ultrasound

Targeted breast ultrasound revealed an oval, well-circumscribed, heterogeneous hypoechoic mass corresponding to the palpable abnormality in the left breast. The lesion measured approximately 4 cm in maximum diameter and demonstrated parallel orientation, smooth margins, and no posterior acoustic shadowing or enhancement.

Color Doppler imaging showed minimal internal vascularity, without evidence of neovascularization. No associated ductal abnormalities or axillary lymphadenopathy were detected (see Fig. 3).

 

Fig. 3. Targeted breast ultrasound of the left breast showing an oval, well-circumscribed, heterogeneous hypoechoic mass with parallel orientation and smooth margins.

 

Based on sonographic findings, the lesion was also classified as BI-RADS 3 (probably benign).

Considering the patient’s history of NF1 and the imaging characteristics, neurofibroma was considered the leading diagnostic hypothesis, although histological verification was recommended [10, 11].

Percutaneous Biopsy

Given the progressive growth of the lesion and the underlying diagnosis of NF1, an ultrasound-guided core needle biopsy was performed before surgical intervention to exclude malignancy. Histopathological examination revealed a benign spindle-cell proliferation consistent with neurofibroma, without cytological atypia or increased mitotic activity. Immunohistochemical staining demonstrated diffuse positivity for S-100 protein, confirming the diagnosis of a benign peripheral nerve sheath tumor.

Differential Diagnosis

The differential diagnosis of breast masses in patients with NF1 includes:

• Fibroadenoma: common benign tumors, typically occurring in younger women [12, 13].
• Phyllodes tumor: rare fibroepithelial neoplasms that may demonstrate rapid growth and variable malignant potential [13].
• Hamartoma: benign mixed-tissue lesions with variable imaging appearance [12].
• Neurofibroma: benign peripheral nerve sheath tumors, particularly relevant in NF1 patients [1, 7, 13].
• Breast carcinoma: uncommon in NF1 but must always be excluded, given the reported increased risk in this population [6, 13, 14].
• Other benign lesions: including fat necrosis, adenosis, and cysts [12].

Intervention and Histopathological Findings

Following multidisciplinary discussion, the patient underwent surgical excision of the breast mass under general anesthesia. Lesion localization was guided by palpation and imaging findings. A well-defined mass was excised from the left breast parenchyma with clear surgical margins.

Microscopic examination confirmed the diagnosis of a breast neurofibroma, characterized by spindle-cell proliferation with wavy nuclei. Immunohistochemical staining for S-100 protein was positive, and no features of atypia or malignant transformation were identified.

Surgical Indication

Despite benign histology, surgical excision was recommended due to progressive lesion growth, patient-reported discomfort, potential cosmetic distortion, and the known—although low—risk of malignant peripheral nerve sheath tumor development in NF1 patients. After shared decision-making, the patient elected to proceed with surgical treatment.

Follow-Up and Outcomes

Postoperative recovery was uneventful. The patient reported complete resolution of discomfort and improvement in breast symmetry. Clinical follow-up examinations were scheduled at regular intervals to monitor for recurrence or the development of new lesions.

Given the increased risk of breast cancer in women with NF1, the patient was enrolled in a structured imaging surveillance program, including annual breast ultrasound and mammography, with consideration of contrast-enhanced magnetic resonance imaging (MRI) in accordance with National Comprehensive Cancer Network (NCCN) 2025 guidelines.

At one-year follow-up, the patient remained asymptomatic, and no recurrent or new breast lesions were identified on clinical examination or imaging studies. The patient was satisfied with the cosmetic outcome. Genetic counseling was recommended to address hereditary risk, long-term surveillance, and familial transmission of NF1.

DISCUSSION

NF1 is caused by pathogenic variants in the NF1 gene located on chromosome 17q11.2, encoding the tumor suppressor protein neurofibromin [15, 16]. Loss of neurofibromin function leads to dysregulation of the RAS/RAF/MEK/ERK signaling pathway, resulting in abnormal Schwann cell proliferation and neurofibroma development [15].

Although cutaneous neurofibromas are common, breast involvement is rare and may closely resemble other benign or malignant breast lesions on imaging [1, 12, 13]. In this case, mammography and ultrasound findings suggested a benign etiology but were not pathognomonic. Contrast-enhanced MRI could have provided additional tissue characterization and enhancement kinetics, potentially improving lesion characterization [9].

Women with NF1 have an increased lifetime risk of breast cancer, particularly before the age of 50 [6, 14], underscoring the importance of early and structured screening. Current NCCN 2025 guidelines recommend annual contrast-enhanced MRI between the ages of 30 and 50, with mammography introduced according to age and breast density [5].

Surgical excision remains the treatment of choice for symptomatic or enlarging breast neurofibromas [1, 13]. For patients with unresectable or plexiform neurofibromas, targeted therapy with MEK inhibitors has shown promising results, although data on breast-localized lesions are still limited [17].

CONCLUSION

Breast neurofibroma is a rare manifestation of NF1 that should be considered in the differential diagnosis of breast masses in NF1 patients. Accurate diagnosis relies on careful clinical assessment, multimodal imaging, and histopathological verification.

Adherence to contemporary surveillance guidelines and a multidisciplinary approach are essential for optimal management. Increased awareness of this uncommon presentation may facilitate timely diagnosis, appropriate intervention, and improved long-term outcomes for patients with NF1.

ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ

Вклад авторов. M. Balbino — проведение работы, работа с данными, написание черновика рукописи; M. Manuela — работа с данными, визуализация; M. Federica — проведение работы, пересмотр и редактирование текста рукописи; F.A. Carpagnano — руководство работой, пересмотр и редактирование текста рукописи; G. Guglielmi — определение концепции, руководство работой, пересмотр и редактирование текста рукописи. Все авторы одобрили рукопись (версию для публикации), а также согласились нести ответственность за все аспекты настоящей работы, гарантируя надлежащее рассмотрение и решение вопросов, связанных с точностью и добросовестностью любой её части.

Этическая экспертиза. Неприменимо.

Согласие на публикацию. Авторы получили письменное информированное добровольное согласие пациентки на публикацию персональных данных, в том числе фотографий, в научном журнале, включая его электронную версию.

Источники финансирования. Отсутствуют.

Раскрытие интересов. Авторы заявляют об отсутствии отношений, деятельности и интересов за последние три года, связанных с третьими лицами (коммерческими и некоммерческими организациями), интересы которых могут быть затронуты содержанием статьи.

Оригинальность. При проведении исследования и создании настоящей статьи авторы не использовали ранее полученные и опубликованные сведения (данные, текст, иллюстрации).

Доступ к данным. Редакционная политика в отношении совместного использования данных к настоящей работе не применима.

Генеративный искусственный интеллект. ChatGPT (GPT-4, OpenAI, https://openai.com), большую языковую модель, разработанную в США, использовали исключительно для языкового редактирования текста. Авторы самостоятельно проверили, отредактировали и утвердили окончательную версию рукописи и несут полную ответственность за её содержание. Инструменты искусственного интеллекта не использовали для подготовки текста, анализа данных, создания изображений или оформления списка литературы.

Рассмотрение и рецензирование. Настоящая работа подана в журнал в инициативном порядке и рассмотрена по обычной процедуре. В рецензировании участвовали внешний рецензент и член редакционной коллегии.

ADDITIONAL INFORMATION

Author contributions: M. Balbino: investigation, data curation, writing—original draft; M. Manuela: data curation, visualization; M. Federica: investigation, writing—review & editing; F.A. Carpagnano: supervision, writing—review & editing; G. Guglielmi: conceptualization, supervision, writing—review & editing. All the authors approved the version of the manuscript to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval: Not applicable.

Consent for publication: Written informed consent was obtained from the patient for the publication of personal data in a scientific journal and its online version.

Funding sources: No funding.

Disclosure of interests: The authors have no relationships, activities, or interests for the last three years related to for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality: We hereby confirm that no previously published material (including text, images, or data) has been used in this article.

Data availability statement: The editorial policy regarding data sharing does not apply to this work.

Generative AI: ChatGPT (GPT-4, OpenAI, https://openai.com), a large language model developed in the United States, was used solely to assist with language editing. The authors reviewed, revised, and approved all content and take full responsibility for the final version of the manuscript. No AI tools were used for drafting content, data analysis, images, or references.

Provenance and peer review: This article was submitted unsolicited and reviewed following the standard procedure. The peer-review process involved one external reviewer and a member of the Editorial Board.

About the authors

Marina Balbino

Foggia University School of Medicine

Email: marinabalbino93@gmail.com
ORCID iD: 0009-0009-2808-5708

MD

Italy, Foggia

Manuela Montatore

Foggia University School of Medicine

Email: manuela.montatore@unifg.it
ORCID iD: 0009-0002-1526-5047

MD

Italy, Foggia

Federica Masino

Foggia University School of Medicine

Email: federicamasino@gmail.com
ORCID iD: 0009-0004-4289-3289

MD

Italy, Foggia

Francesca A. Carpagnano

Dimiccoli Hospital

Email: c.francesca1991@gmail.com
ORCID iD: 0000-0001-7681-2898

MD

Italy, Barletta

Giuseppe Guglielmi

Foggia University School of Medicine; Dimiccoli Hospital; IRCCS Casa Sollievo della Sofferenza Hospital

Author for correspondence.
Email: giuseppe.guglielmi@unifg.it
ORCID iD: 0000-0002-4325-8330

MD, Professor

Italy, Foggia; Barletta; Foggia

References

Supplementary files