Late diagnosis of neurofibromatosis type 1 masquerading as thyroid cancer metastasis for six years: The pivotal role of multimodal MRI in a patient with anaplastic thyroid carcinoma

Abstract

Neurofibromatosis type 1 (NF1) is a hereditary tumor predisposition syndrome associated with multiple benign and malignant neoplasms. We report the case of a 55-year-old man with a history of thyroid carcinoma diagnosed 6 years earlier, who was referred for MRI evaluation of a slowly progressive right submandibular mass and a left fronto-temporal brain lesion that had long been considered metastatic disease. Multimodal MRI demonstrated imaging features inconsistent with aggressive metastases. The brain lesion showed no diffusion restriction or hyperperfusion, while MR spectroscopy revealed a prominent myo-inositol peak suggestive of a low-grade glial tumor. The submandibular lesion was well circumscribed and markedly hyperintense on T2-weighted imaging, favoring a neurofibroma. These radiological findings prompted targeted physical examination, which revealed multiple café-au-lait macules, axillary freckling, and diffuse cutaneous neurofibromas, leading to the diagnosis of NF1 according to revised international criteria. This case highlights the important role of multimodal MRI in challenging anchoring bias in oncologic patients and emphasizes the value of correlating imaging findings with clinical examination to identify previously unrecognized genetic syndromes.

Introduction

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common neurocutaneous syndrome caused by germline mutations in the NF1 tumor suppressor gene. This gene encodes neurofibromin, an important negative regulator of the RAS-MAPK signaling pathway [1]. NF1 is associated with an increased risk of multiple benign and malignant tumors, including tumors of the peripheral nervous system, gliomas, gastrointestinal stromal tumors, pheochromocytomas, and several other neoplasms [2].

The association between NF1 and thyroid carcinoma remains uncommon and poorly documented in the literature. In oncologic imaging, diagnostic anchoring may lead clinicians to attribute newly detected lesions to metastatic disease despite discordant radiological features. We report a patient with a previous history of thyroid carcinoma in whom multimodal MRI findings prompted reconsideration of presumed metastatic lesions and ultimately led to the delayed diagnosis of neurofibromatosis type 1. This case highlights the value of advanced MRI techniques in challenging diagnostic bias and guiding more accurate clinical reasoning.

Case presentation

A 55-year-old man was referred for MRI evaluation of 2 slowly progressive lesions: a right submandibular mass and a left fronto-temporal brain lesion previously detected on computed tomography. The patient had a history of thyroid carcinoma diagnosed 6 years earlier and treated with total thyroidectomy followed by radioiodine therapy according to the available medical records. During follow-up, both lesions had been considered metastatic disease because of the oncologic context, although no histopathological confirmation had been obtained.

Brain MRI demonstrated a large left fronto-temporal lesion measuring 66 × 45 × 37 mm with extension toward the cerebral peduncle. The lesion appeared isointense on T1-weighted imaging and heterogeneously hyperintense on T2-weighted and FLAIR sequences. Susceptibility-weighted imaging demonstrated internal signal voids compatible with microhemorrhages. Postcontrast T1-weighted images showed peripheral ring enhancement without significant surrounding edema (Fig. 1).

Fig. 1.

Brain MRI morphological sequences. (A) Axial FLAIR, (B) Postcontrast T1-weighted images show a large left fronto-temporal mass with ring enhancement and no significant perilesional edema and (C) SWI sequence reveals internal signal voids (arrow) consistent with microhemorrhages.

Diffusion-weighted imaging showed no diffusion restriction, with elevated ADC values relative to normal brain parenchyma (Fig. 2). Arterial spin labeling perfusion imaging demonstrated no significant hyperperfusion. MR spectroscopy performed with a short echo time (TE 35 ms) demonstrated a choline/NAA ratio of 1.35 and a choline/creatine ratio of 2.02, with a prominent myo-inositol peak at 3.56 ppm.

Fig. 2.

DWI and ADC evaluation. (A) Axial DWI (b = 1000) and (B) ADC map show no restricted diffusion within the mass, contradicting the diagnosis of a highly cellular anaplastic metastasis.

Cervical MRI revealed a well-circumscribed ovoid lesion within the right submandibular region. The lesion was hypointense on T1-weighted imaging and markedly hyperintense on T2-weighted imaging, without infiltrative margins or associated cervical lymphadenopathy (Fig. 3). Multiple additional nodular lesions with similar signal characteristics were identified within the subcutaneous soft tissues. Incidental left-convex scoliosis was also noted.

Fig. 3.

Neurofibromas. 3D FLAIR weighted images showing a well-circumscribed, markedly hyperintense lesion (brown arrow, A and B) within the right submandibular gland.

The discordance between the indolent clinical course and the imaging characteristics of the lesions prompted reconsideration of the presumed metastatic diagnosis. The combination of multiple T2-hyperintense soft tissue lesions and the spectroscopic profile of the brain lesion raised suspicion for neurofibromatosis type 1.

Targeted physical examination subsequently revealed multiple café-au-lait macules larger than 15 mm, diffuse cutaneous neurofibromas involving the trunk and forehead, and axillary freckling (Fig. 4). Based on the revised 2021 international diagnostic criteria, a diagnosis of neurofibromatosis type 1 was established.

Fig. 4.

Clinical Stigmata. (A and B) Multiple café-au-lait macules and (B and C) diffuse cutaneous neurofibromas on the patient's trunk and forehead confirmed the NF1 diagnosis upon retrospective examination.

Discussion

This case illustrates how multimodal MRI can help prevent diagnostic anchoring in oncologic patients by identifying imaging features inconsistent with metastatic disease. Cognitive biases, particularly anchoring bias, are a recognized source of diagnostic error in clinical decision-making and may lead to premature closure in complex oncologic contexts [3,4].

The brain lesion demonstrated several imaging findings atypical for aggressive metastatic disease. Although peripheral enhancement and internal hemorrhagic components could initially suggest metastasis, the absence of diffusion restriction and lack of hyperperfusion argued against a highly cellular or highly vascular tumor. In addition, MR spectroscopy revealed a prominent myo-inositol peak, a metabolic pattern more commonly associated with low-grade glial tumors than with metastatic lesions [5,6]. These imaging features collectively supported a more indolent biological process.

The cervical lesion also demonstrated characteristics more suggestive of a benign peripheral nerve sheath tumor than metastatic lymphadenopathy. The lesion was well circumscribed, markedly hyperintense on T2-weighted imaging, and showed slow evolution over time. Such imaging features are consistent with neurofibromas described in neurofibromatosis type 1 [2,7]. The presence of multiple similar subcutaneous lesions further supported a systemic neurocutaneous disorder rather than metastatic dissemination.

These radiological findings prompted targeted clinical re-evaluation, which revealed previously unrecognized cutaneous stigmata of neurofibromatosis type 1. This highlights the importance of integrating imaging interpretation with clinical examination, particularly when imaging findings are discordant with the expected evolution of an aggressive malignancy [8].

Neurofibromatosis type 1 is a rasopathy caused by mutations in the NF1 tumor suppressor gene, leading to dysregulation of the RAS-MAPK signaling pathway and a predisposition to multiple tumor types [1,2]. Although associations between NF1 and thyroid malignancies have been reported, they remain uncommon and heterogeneous.

In the present case, the exact histopathological subtype of the previously diagnosed thyroid carcinoma could not be confirmed due to the absence of original pathological material. This represents a significant limitation in the oncologic interpretation of the case. Importantly, molecular and clinical data indicate that anaplastic thyroid carcinoma (ATC) is characterized by extremely aggressive behavior and poor prognosis, with most patients experiencing rapid clinical deterioration despite therapy [9,10]. Furthermore, genomic studies show distinct mutational landscapes across differentiated, poorly differentiated, and anaplastic thyroid carcinomas [11].

The prolonged survival observed in this patient, as well as the historical therapeutic course, is not typical of classical ATC as defined in current guidelines [10]. Therefore, the possibility that the original tumor represented a differentiated or poorly differentiated thyroid carcinoma rather than a true anaplastic subtype cannot be excluded. This uncertainty precludes definitive retrospective classification and underscores the limitations of relying solely on historical clinical records for tumor subtype assignment.

Finally, this case emphasizes the role of radiologists in recognizing imaging–clinical discordance and avoiding premature diagnostic closure. Advanced MRI techniques, including diffusion-weighted imaging, perfusion imaging, and MR spectroscopy, provide complementary structural, physiological, and metabolic information that can significantly refine diagnostic reasoning. In this case, these modalities were instrumental in identifying a previously unrecognized neurocutaneous disorder and preventing continued misclassification of indolent lesions as metastatic disease.

Conclusion

This case illustrates that a prior history of malignancy should not preclude the diagnosis of a concurrent genetic syndrome. In this patient, multimodal MRI combining morphological, diffusion, and spectroscopic imaging played a key role in reclassifying lesions initially interpreted as metastases. Radiological findings prompted targeted clinical examination, leading to the diagnosis of neurofibromatosis type 1. This case highlights the importance of integrating advanced imaging with clinical assessment to avoid anchoring bias and diagnostic premature closure in oncologic patients.

Ethics approval

Our institution does not require ethical approval for reporting individual cases.

Patient consent

Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.