This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 65-year-old man presented with two years of left foot numbness and pain that was worse when lying down or sitting. He also complained of back and left buttock pain. He denied leg weakness or bowel/bladder issues. An MRI of the lumbar spine revealed the findings shown in Image A. A chest/abdomen/pelvis CT scan and PET scan showed lymphadenopathy concerning for malignancy. MRI of the brain and the cervical and thoracic spine were negative for lesions. The patient underwent an ultrasound guided right inguinal node/mass biopsy.
Right inguinal node/mass
Whole Slide Image
The whole slide image provided is an H&E-stained image of the mass biopsied in the right inguinal region.
Which of the following is the best diagnosis in this case?
Malignant peripheral nerve sheath tumor
Which tumor predisposition syndrome is most likely associated with this tumor?
Neurofibromatosis Type 1
Neurofibromatosis Type 2
Rhabdoid tumor predisposition syndrome
Which of the following is the most likely molecular alteration in this syndrome-associated tumor?
Pathogenic germline NF2 gene variant
Pathogenic germline TP53 gene variant
Pathogenic germline NF1 gene variant
Pathogenic germline SMARCB1 gene variant
Pathogenic germline VHL gene variant
Discussion and Diagnosis
MRI study in this case revealed multiple solid masses (Image A, arrows) demonstrating heterogeneous contrast enhancement involving the left S1 and right S2 nerves consistent with peripheral nerve sheath tumors. Additional imaging revealed systemic nodules clinically interpreted as lymphadenopathy. Based on these findings, the differential diagnosis included lymphoma and metastatic neoplasm. Tissue obtained from an ultrasound guided biopsy of a right inguinal nodule revealed a spindle cell neoplasm with mild nuclear atypia. The cells were arranged in vague fascicles within a myxoid stroma (Image B and Image C). Tumor cells were diffusely positive for S100 (Image D) and SOX10 (Image E). These findings supported a diagnosis of schwannoma. Based on the patient’s clinical presentation, he was diagnosed with schwannomatosis.
Schwannomatosis is a rare disorder characterized by multiple schwannomas (spinal, intracranial, and cutaneous) and infrequent meningiomas (spinal and intracranial). While bilateral vestibular schwannomas are not a component of the disorder, a unilateral tumor has been reported in rare cases. Schwannomatosis-associated schwannomas are distinctly painful. Some patients may manifest a segmental form of the disorder. The main differential diagnosis is neurofibromatosis type 2 (NF2). Characteristic features of NF2 such as bilateral vestibular schwannomas, a pathogenic germline NF2 variant, or a first degree relative with NF2 are absent. The following are proposed diagnostic criteria for schwannomatosis:
Molecular criteria for definite schwannomatosis:
- Two or more schwannomas or meningiomas (pathology proven) and genetic studies of at least two tumors with LOH for chromosome 22 and two different NF2 mutations OR
- One schwannoma or meningioma (pathology proven) and a SMARCB1 germline pathogenic variant
Clinical criteria for definite schwannomatosis:
- Two or more schwannomas (non-dermal, one pathology proven) and no bilateral vestibular schwannomas (by thin-slice MRI) or
- One schwannoma or meningioma (pathology proven) and a first-degree relative affected by schwannomatosis
Clinical criteria for possible schwannomatosis:
- Two or more schwannomas (no pathology) or
- Severe chronic pain associated with a schwannoma
Schwannomas associated with schwannomatosis display a myxoid stroma. Cutaneous schwannomas may be plexiform. Otherwise, the tumors show no distinctive histopathologic features when compared to sporadic schwannomas.
The majority of schwannomatosis cases are sporadic, and only a small number of familial cases have been reported. Familial cases demonstrate an autosomal dominant pattern of inheritance with incomplete penetrance. Germline mutations in the SMARCB1 gene located on chromosome 22q11.23 were first described in familial cases of schwannomatosis in 2007. The SMARCB1 gene encodes for INI1, a subunit of the SWI/SNF chromatin remodeling complex. In schwannomatosis, SMARCB1 gene variants are typically non-truncating missense mutations, splice-site mutations, or in-frame deletions, which allow for the synthesis of an abnormal protein product. This is reflected in a mosaic pattern of immunoreactivity (mixture of positive and negative nuclei) for INI1 (Image F) in schwannomatosis-associated neoplasms. In contrast, the rhabdoid tumor predisposition syndrome is associated with truncating nonsense and frameshift germline mutations in the SMARCB1 gene that lead to complete absence of nuclear INI1 immunoreactivity in the tumors. It is important to note that the mosaic pattern of INI1 immunoreactivity may also be seen in NF2-associated schwannomas. Therefore, INI1 immunostain is helpful in distinguishing schwannomas associated with syndromes from sporadic ones but does not differentiate between NF2- and schwannomatosis-associated schwannomas. Pathogenic germline variants in the LZTR1 gene located on chromosome 22q11.21 were described in 2014 in familial cases of schwannomatosis without germline variants in the SMARCB1 gene.
Germline variants in the NF2 gene on chromosome 22q12 are not present in schwannomatosis patients. However, inactivating somatic NF2 gene mutations are common in schwannomatosis-associated schwannomas. Based on these findings, a “four-hit mechanism” has been proposed for the formation of tumors in schwannomatosis. This four-hit model involves: a germline mutation in the SMARCB1 gene (hit 1), deletion of the second chromosome 22 harboring the wildtype copy of the SMARCB1 gene (hit 2) and one copy of the NF2 gene (hit 3), and a somatic mutation of the second copy of the NF2 gene (hit 4).
Schwannomatosis patients have an excellent prognosis with no significant increase in mortality, although pain associated with schwannomas may be debilitating. Surgical resection of the tumors is the treatment of choice. Genetic counseling should be provided to newly diagnosed patients and their family members.
Take Home Points
- Schwannomatosis is a tumor predisposition syndrome characterized by multiple non-vestibular schwannomas and less commonly meningiomas.
- Schwannomatosis-associated schwannomas show a myxoid background and a mosaic pattern of immunoreactivity for INI1.
- Schwannomatosis is caused by germline pathogenic variants in SMARCB1 or LZTR1 genes on chromosome 22q.
- Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 2007;80(4):805-810.
- Mansouri S, Suppiah S, Mamatjan Y, et al. Epigenomic, genomic, and transcriptomic landscape of schwannomatosis. Acta Neuropathol. 2020 Oct 6. doi: 10.1007/s00401-020-02230-x. Epub ahead of print
- Piotrowski A, Xie J, Liu YF, Poplawski AB, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014;46(2):182-187.
- Plotkin SR, Blakeley JO, Evans DG, et al. Update from the 2011 International Schwannomatosis Workshop: from genetics to diagnostic criteria. Am J Med Genet A. 2013;0(3):405-416.
- Solomon DA, Perry A. Familial tumor syndromes. In: In: Perry A, Brat DJ. eds. Practical Surgical Neuropathology. Rev 2nd ed. Philadelphia, PA: Elsevier; 2018:515-516.
- Stemmer-Rachamimov AO, Hulsebos TJM, Wesseling P. Schwannomatosis. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK eds. World Health Organization Histological Classification of Tumours of the Central Nervous System. Rev 4th ed. Lyon, France: International Agency for Research on Cancer; 2016:301-304.
- Which of the following is the best diagnosis in this case?
- A. Malignant peripheral nerve sheath tumor
- B. Melanoma
- C. Myxoid fibrosarcoma
- D. Neurofibroma
- E. Schwannoma
- Which tumor predisposition syndrome is most likely associated with this tumor?
- A. Li-Fraumeni syndrome
- B. Neurofibromatosis Type 1
- C. Neurofibromatosis Type 2
- D. Rhabdoid tumor predisposition syndrome
- E. Schwannomatosis
- Which of the following is the most likely molecular alteration in this syndrome-associated tumor?
- A. Pathogenic germline NF2 gene variant
- B. Pathogenic germline TP53 gene variant
- C. Pathogenic germline NF1 gene variant
- D. Pathogenic germline SMARCB1 gene variant
- E. Pathogenic germline VHL gene variant