Breast neurofibromas in the context of Neurofibromatosis Type 1 (NF1)

1. Cause and Etiology

Neurofibromatosis Type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene on chromosome 17q11.2, which encodes neurofibromin, a tumor suppressor protein. Neurofibromin negatively regulates the RAS/MAPK signaling pathway, and its loss leads to increased cellular proliferation.

Breast neurofibromas in NF1 are:

Benign peripheral nerve sheath tumors involve the intradermal or subcutaneous nerves of the breast tissue.
Considered a cutaneous manifestation of systemic NF1.
May arise from terminal cutaneous branches of peripheral nerves within the breast.
Rare compared to other typical locations (e.g., trunk, limbs, face), but when present, usually occur in subareolar or subcutaneous tissue.

2. Pathophysiology

The formation of neurofibromas in the breast in NF1 follows the same mechanism as elsewhere:

Loss-of-function mutation in both alleles of the NF1 gene (germline and somatic "second hit") leads to:

Loss of neurofibromin function
Unregulated activation of RAS, promoting:

Schwann cell proliferation
Fibroblast and mast cell recruitment
Vascular proliferation and extracellular matrix deposition

Neurofibromas are composed of Schwann cells, fibroblasts, perineural cells, and axons embedded in a myxoid matrix.

In the breast, they may infiltrate the subcutaneous tissue or appear as nodular masses within or adjacent to glandular breast tissue.

3. Epidemiology

NF1 affects approximately 1 in 3,000 live births worldwide.
It exhibits autosomal dominant inheritance with complete penetrance but variable expressivity.
Breast neurofibromas are rare but likely under-reported:

Exact prevalence unknown, but studies suggest less than 5% of NF1 patients develop breast involvement.

Occurs more frequently in females, especially during puberty, pregnancy, or lactation, when hormonal changes may promote tumor growth.
Women with NF1 have an increased risk (4- to 5-fold) of developing breast cancer, especially before the age of 50.

4. Clinical Presentation

Breast neurofibromas in NF1 typically present as:

Painless, palpable subcutaneous nodules in the breast.
Soft, mobile, rubbery masses, often multiple and superficial.
May be confused with benign breast lesions (e.g., fibroadenomas).
Skin overlying the lesion may show café-au-lait macules or freckling.
Large or plexiform neurofibromas may cause:

Breast asymmetry or deformity
Pain, tenderness, or ulceration (rare)

In some cases, cosmetic disfigurement becomes a concern, especially in adolescents.

5. Imaging Features

a. Mammography

Well-defined, oval or lobulated soft-tissue densities in the subcutaneous region.
Often seen in the subareolar region.
Skin thickening or multiple cutaneous nodules may be apparent.
Can obscure deeper parenchymal structures, complicating cancer screening.

b. Ultrasound

Hypoechoic, well-circumscribed or mildly lobulated masses.
Posterior acoustic enhancement.
No calcifications or internal vascularity (unless complex).
Difficult to differentiate from fibroadenomas or lipomas.

c. MRI

T1: Iso- to hypointense relative to muscle
T2: Hyperintense, especially if myxoid matrix is abundant
Post-gadolinium: Heterogeneous enhancement
May show a "target sign" (central low signal surrounded by high T2 signal)
Useful in assessing:

Deep plexiform neurofibromas
Extent of infiltration
Surgical planning

d. PET/CT

Used to distinguish benign from malignant peripheral nerve sheath tumors (MPNSTs).
Neurofibromas show low to moderate FDG uptake, whereas MPNSTs demonstrate high SUV values.

6. Treatment

a. Observation

Asymptomatic and benign lesions may be monitored clinically.
Regular breast cancer screening is advised due to the increased risk in NF1 patients.

b. Surgical Excision

Indicated for:

Painful or growing masses
Suspicion of malignancy
Cosmetic deformity

Complete excision is usually curative.
Care is taken to preserve the underlying glandular tissue if breast conservation is desired.

c. Plastic Reconstruction

For extensive disfigurement or plexiform lesions.
May require oncoplastic surgery or reconstructive procedures.

d. Pharmacologic Trials (Experimental)

MEK inhibitors (e.g., selumetinib) have shown promise in reducing plexiform neurofibroma volume in children.
No established role yet for breast neurofibromas, but clinical trials are ongoing.

7. Prognosis

Breast neurofibromas are benign, and the prognosis is excellent after surgical excision.
The risk of transformation into MPNST is very low, especially in cutaneous or localized neurofibromas.
However, plexiform neurofibromas have a higher risk of malignant transformation (8–13% overall).
Cosmetic and psychological impact may be significant, especially in young women.
Increased risk of breast carcinoma:

Especially in NF1 women under 50
Often triple-negative, aggressive subtypes
Requires vigilant screening and sometimes early genetic counseling

Summary Table

Category	Description
Etiology	Germline NF1 mutation; autosomal dominant
Pathophysiology	Loss of neurofibromin → ↑RAS signaling → Schwann cell proliferation
Epidemiology	Rare in breast; <5% of NF1 patients
Clinical Features	Soft, mobile, painless nodules in subcutaneous breast tissue
Imaging	Oval/lobulated hypoechoic masses; MRI shows T2 hyperintensity
Treatment	Observation or surgical excision; MEK inhibitors (experimental)
Prognosis	Excellent; low risk of malignancy; increased breast cancer risk in NF1 women

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Case Study: 58-Year-Old Woman Undergoing Mammographic Screening
Breast Neurofibroma

History and Imaging

A 58-year-old woman presented for routine breast cancer screening.
She underwent mammography and digital breast tomosynthesis.

Quiz 1:

What is the most appropriate BI-RADS breast density classification?
(1) Fatty
(2) Scattered
(3) Heterogeneously dense
(4) Dense
Explanation: The breast parenchyma appears moderately dense with scattered areas of fibroglandular tissue that could obscure small lesions. This corresponds to BI-RADS Category C: Heterogeneously dense, which may lower the sensitivity of mammography.
Where is the most prominent finding most likely located?
(1) Pectoralis major muscle
(2) Lobule
(3) Skin
(4) Duct
(5) Fat
Explanation: Neurofibromas associated with NF1 frequently arise from cutaneous nerves, often presenting as superficial, well-defined nodules located in the skin or subcutaneous tissue. The imaging features and location suggest a cutaneous origin.
There are multiple well-circumscribed masses in both breasts.
(1) True
(2) False
Explanation: Patients with neurofibromatosis type 1 may present with multiple bilateral subcutaneous neurofibromas, which appear as well-defined, oval, or lobulated soft-tissue nodules on mammography and ultrasound.

Additional Image:
Below is a prior mammographic image of the patient.

Quiz 2:

Due to the variability of these lesions, malignancy is unlikely.
(1) True
(2) False

Explanation: The presence of multiple bilateral masses (e.g., more than three lesions across both breasts) is associated with a malignancy (interval cancer) rate of less than 1%, making the probability of breast cancer quite low in this context.
What is the best next step in the management of this patient?
(1) Stereotactic core needle biopsy
(2) Ultrasound
(3) 6-month follow-up mammography
(4) Clinical follow-up
(5) Breast MRI

Explanation: Targeted breast ultrasound is the most appropriate next step to further characterize the mammographic findings. It helps assess the internal composition (solid vs. cystic) and vascularity, which guides further management.
What is the most appropriate BI-RADS assessment?
(1) BI-RADS 0
(2) BI-RADS 1
(3) BI-RADS 2
(4) BI-RADS 3
(5) BI-RADS 4
(6) BI-RADS 5

Explanation: The imaging findings are benign, consistent with multiple bilateral neurofibromas. According to ACR BI-RADS guidelines, screening mammograms must be categorized as BI-RADS 0, 1, or 2. Since these are definitely benign, BI-RADS 2 is appropriate.
The patient has a known genetic condition. What is the most likely diagnosis?
(1) Multifocal primary breast cancer
(2) Neurofibromas in neurofibromatosis type 1
(3) Multiple fibroadenomas
(4) Multiple breast cysts
(5) Breast metastases

Explanation: The clinical and imaging presentation—multiple, well-circumscribed, bilateral cutaneous or subcutaneous masses in a patient with a genetic condition—is characteristic of neurofibromas in NF1.

Findings and Diagnosis

Findings

The breasts are heterogeneously dense, which may obscure small masses. No suspicious masses, calcifications, or other abnormalities are identified. Multiple round cutaneous nodules are observed bilaterally, with no significant change compared to prior studies. These findings are consistent with the patient's known history of neurofibromatosis.

Differential Diagnosis

Multifocal primary breast cancer
Multiple fibroadenomas
Multiple breast cysts
Breast metastases
Breast neurofibromas in neurofibromatosis type 1

Final Diagnosis:
Breast neurofibromas in neurofibromatosis type 1

Discussion

Breast Neurofibromas in Neurofibromatosis Type 1 (NF1)

Pathophysiology

Neurofibromas are benign peripheral nerve sheath tumors that arise from Schwann cells. They commonly occur in the head and neck region, limbs, and along the paraspinal areas. Breast involvement is rare but more frequently associated with neurofibromatosis type 1 (NF1), an autosomal dominant disorder caused by mutations in the NF1 tumor suppressor gene.

Epidemiology

NF1 affects approximately 1 in 2,000 individuals. While inherited in an autosomal dominant manner, up to 42% of cases result from de novo mutations, indicating a high spontaneous mutation rate.

Clinical Presentation

Patients with NF1 often present with multiple bilateral cutaneous neurofibromas, typically as nodular skin lesions. The diagnosis of NF1 requires at least two of the following clinical criteria:

Six or more café-au-lait macules
Two or more neurofibromas of any type or one plexiform neurofibroma
Axillary or inguinal freckling
Two or more Lisch nodules (iris hamartomas)
Optic glioma
Distinctive osseous lesions (e.g., sphenoid wing dysplasia or cortical thinning of long bones)
A first-degree relative with NF1 meeting the above criteria

Breast neurofibromas tend to occur near the nipple-areolar complex, but can also involve deeper tissues such as the pectoralis major or retroglandular fat.

Imaging Features

Mammography:
Localized neurofibromas may appear as well-circumscribed, oval masses. They are typically bilateral, superficial, and occasionally pedunculated. The presence of multiple cutaneous neurofibromas can obscure underlying breast parenchyma, reducing the sensitivity of mammography in detecting malignancy.

Ultrasound:
Neurofibromas usually appear as oval or round, well-defined masses in the subcutaneous tissue. They are often hypoechoic or anechoic and may demonstrate posterior acoustic enhancement. On ultrasound, they may resemble benign simple cysts or fibroadenomas.

Differential Diagnosis

Multifocal primary breast cancer
Multiple fibroadenomas
Multiple breast cysts
Breast metastases

Treatment

There is no definitive cure for NF1, but neurofibromas can be surgically excised for symptomatic relief or cosmetic reasons. Women with NF1 have a significantly increased risk of breast cancer, up to five times higher than the general population. Therefore, regular screening mammography is essential in this patient group.

References

Sharif S, Moran A, Huson SM, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. Int J Cancer. 2007;120(4):848-851. doi:10.1002/ijc.22272
Uusitalo E, Leppävirta J, Kallionpää RA, et al. Incidence and mortality of breast cancer in women with neurofibromatosis 1. Br J Cancer. 2017;116(3):444-447. doi:10.1038/bjc.2016.431
Luis NM, Moretti PN, Fusco DN, et al. Breast imaging in patients with neurofibromatosis type 1: mammographic and sonographic findings.AJR Am J Roentgenol. 2012;199(3):W310-W316. doi:10.2214/AJR.11.8055
Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register.Clin Genet. 2010;78(6):504-512. doi:10.1111/j.1399-0004.2010.01432.x
Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115:939-955. doi:10.1016/B978-0-444-52902-2.00053-3

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A 58-Year-Old Woman Undergoing Mammographic Screening, Breast Neurofibroma