Review Question - QID 220828

The patient’s clinical history and histology are consistent with a diagnosis of Malignant Peripheral Nerve Sheath Tumor (MPNST), which is frequently associated with an underlying diagnosis of neurofibromatosis 1 (NF1), as in the case of this patient (Answer 4).

MPNST is a tumor of the cells that form the peripheral nerve sheaths and is frequently associated with NF1 (50% of these tumors occur in patients with NF1), a genetic condition caused by a mutation in the gene encoding for the neurofibromin protein. This condition is characterized by cutaneous mutations (cafe-au-lait spots, neurofibromas, skin fold freckling), Lisch nodules, and associations with specific malignancies. Work-up of a mass in these patients should consist of advanced imaging and potential biopsy. Treatment of MPNSTs predominantly consists of surgical resection with minimal role for chemotherapy or radiation, though their use is occasionally considered in the setting of inoperable lesions. The prognosis of NF-1-associated MPNST is particularly poor, with 5-year survival approximating 30%.

Weisman et al. performed a literature review describing the approaches to neurofibromatosis and schwannomatosis diagnoses through genetic testing. In this article, they review the genetic basis of neurofibromatosis and schwannomatosis and their associations with the development of gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas, MPNSTs, and gliomas. They conclude that NF1 and schwannomatosis are genetic conditions that uniquely predispose patients to a higher risk of developing a diverse set of tumor subtypes and thus necessitate careful genetic counseling and careful surveillance by providers with a comprehensive understanding of these conditions. 

Yao et al. published a comprehensive review of MPNST and described its pathogenesis and management strategies. They discuss that this tumor commonly occurs in the setting of a diagnosis of NF1, prior radiation, or precancerous lesions (plexiform neurofibroma/atypical neurofibromatous neoplasm of unknown biological potential), but can also occur sporadically, which speaks to the complex genetics underlying this condition.  Treatment strategies outside of surgical management have largely questionable efficacy, and this dearth of potential interventions ultimately leads to poor prognoses. They emphasize that the gold standard treatment for this tumor is surgical resection. They conclude that additional research is needed to standardize the diagnostic criteria for this tumor, improve the treatment of these tumors outside the scope of surgery, and better understand the distinctions between sporadic and NF1-associated MPNST. 

Salem et al. described two cases of multifocal MPNST involving the spinal cord in patients with NF1 and reviewed the literature for all cases of such tumors. They illustrated the diagnostic and treatment course of reported cases, which included whole body MRI with contrast, tissue biopsy with findings significant for a “herringbone” pattern of spindle cells, and radical excision followed by adjuvant radiotherapy. They concluded that a solid understanding of this tumor’s behavior and optimal treatment is limited by the rarity of MPNST cases involving the spinal cord and necessitates additional study. 

Figure A demonstrates the characteristic spindle cells with wavy nuclei seen in MPNST. Notably, these findings can also be seen in the histology of fibrosarcoma.

Incorrect Answers:
Answer 1. Achondroplasia is caused by a mutation in the FGFR3 gene that leads to dwarfism, frontal bossing, and spinal pathology. It is not associated with an increased risk of MPNST or the presence of neurofibromas. 

Answer 2. Legius syndrome is caused by a mutation in the SPRED1 gene and can present with cafe-au-lait lesions and skin fold freckling, but is not associated with neurofibromas or an increased risk of MPNST. 

Answer 3. McCune-Albright syndrome is a condition caused by a mutation in the GNAS gene and is associated with cafe-au-lait spots, fibrous dysplasia, and precocious puberty. It is not associated with the formation of neurofibromas or an increased risk of MPNST.

Answer 5. Neurofibromatosis 2 is more commonly associated with the formation of schwannomas, meningiomas, or ependymomas. None of these tumors presents with the same histology as that shown in Figure A.