Case Report
Malignant Peripheral Nerve Sheath Tumor in a Patient With BAP1 Tumor Predisposition Syndrome Megan C. Kaszuba1, Jose S. Pulido2, Andrew L. Folpe3, Pavel N. Pichurin4, McKinsey L. Goodenberger4, Robert J. Spinner1
Key words BAP1 - Malignant peripheral nerve sheath tumor - Peripheral nerve - Tumor syndrome -
Abbreviations and Acronyms BAP1: BRCA1-associated protein-1 BRCA-1: Breast cancer gene 1 DNA: Deoxyribonucleic acid MPNST: Malignant peripheral nerve sheath tumor mRNA: Messenger ribonucleic acid TPDS: Tumor predisposition syndrome From the 1Department of Neurosurgery, 2Department of Ophthalmology, 3Department of Laboratory Medicine and Pathology, and 4Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA To whom correspondence should be addressed: Megan C. Kaszuba, M.D. [E-mail:
[email protected]] Citation: World Neurosurg. (2018) 109:362-364. https://doi.org/10.1016/j.wneu.2017.10.064 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
- BACKGROUND:
Germline pathogenic variants in BRCA1-associated protein-1 (BAP1), a nuclear ubiquitin carboxy-terminal hydrolase with evidence suggestive of independent tumor suppressor function, predispose affected families to uveal melanoma, cutaneous melanoma, renal cell carcinoma, malignant mesothelioma, and possibly a range of other tumors and malignancies as part of the BAP1 tumor predisposition syndrome, a recently recognized hereditary cancer syndrome.
- CASE
DESCRIPTION: A 50-year-old woman presented with a malignant peripheral nerve sheath tumor of the left fifth metatarsal head. Further examination revealed a right renal mass and left breast mass. Her family history was significant for astrocytoma, melanoma, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, prostate cancer, non-Hodgkin lymphoma, and pancreatic adenocarcinoma. Genetic testing revealed a BAP1 mutation in the proband.
- CONCLUSIONS:
Although there have been reports of sarcomas and meningiomas in patients affected with BAP1 mutations, to our knowledge malignant peripheral nerve sheath tumors in this patient population have not been previously reported. We report a case of malignant peripheral nerve sheath tumor in a patient affected by a BAP1 mutation.
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CASE REPORT
INTRODUCTION BRCA1-associated protein-1 (BAP1) is a nuclear ubiquitin carboxy-terminal hydrolase with evidence suggestive of independent tumor suppressor function. Germline pathogenic variants predispose affected families to uveal melanoma, cutaneous melanoma, renal cell carcinoma, malignant mesothelioma, and possibly a range of other tumors and malignancies as part of the BAP1 tumor predisposition syndrome (BAP1-TPDS), a recently recognized hereditary cancer syndrome. Although there have been reports of sarcomas and meningiomas in patients affected with BAP1 mutations, to our knowledge, malignant peripheral nerve sheath tumors in this patient population have not been previously reported.
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A 50-year-old-woman presented with a 6-month history of a painful soft tissue mass on the lateral plantar aspect of the left fifth metatarsal head. The patient had undergone excisional biopsy of a 2-mm lesion within the capsular tissue of the fifth metatarsophalangeal joint by a podiatrist at an outside facility. She was referred to our institution. Pathologic examination revealed a minute, highgrade malignant peripheral nerve sheath tumor; the strong expression of S100 protein and SOX 10 favored an epithelioid variant arising in association with a nerve. Histologic evaluation (Figure 1) of the left foot mass showed an epithelioid malignant peripheral nerve sheath tumor, clearly arising from a preexisting nerve. Although the tumor was very small, it consisted of clearly malignant-appearing epithelioid cells with high nuclear grade,
prominent nucleoli, easily identified mitoses, and numerous apoptotic cells. By immunohistochemistry the tumor showed a typical immunophenotype for an epithelioid malignant peripheral nerve sheath tumor, with diffuse expression of S100 protein and SOX10, and pericellular collagen IV deposition. Markers of melanocytic differentiation (e.g., hmb45, melan-a, tyrosinase, and microphthalmia transcription factor) were negative. Magnetic resonance imaging performed postoperatively revealed some mild enhancement in the surgical bed of indeterminate significance (there was no comparison imaging). During further examination for staging purposes, a 1.3-m right renal mass was discovered on abdominal computed tomography and positron emission tomography. Additionally, enlarged left axillary lymph nodes were visualized on chest computed
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.064
CASE REPORT MEGAN C. KASZUBA ET AL.
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
Figure 1. Epithelioid malignant peripheral nerve sheath tumor (top), arising from preexisting nerve (bottom); hematoxylin and eosin (H&E) stain, 100 (A). Higher power magnification, showing nests of malignant-appearing, mitotically active, epithelioid cells; H&E stain, 400 (B). By immunohistochemistry the neoplastic cells showed diffuse expression of S100 protein in a nuclear and cytoplasmic pattern; S100 protein stain, 200 (C) and were negative for markers of melanocytic differentiation, including HMB45 (shown here); HMB45 stain, 200 (D).
tomography, and lymph node biopsy demonstrated metastatic breast adenocarcinoma. Subsequent breast magnetic resonance imaging showed a 1-cm left breast mass. The patient underwent fifth ray amputation for further local disease control. The right renal mass was treated by imageguided percutaneous cryoablation. Bilateral mastectomy and axillary lymph node dissection were performed for breast cancer treatment, and histopathologic examination indicated grade 3 invasive
ductal carcinoma with estrogen receptor positive, progesterone receptor positive, and HER-2/neu positive tumor markers. The patient underwent breast cancer chemotherapy with cyclophosphamide and doxorubicin followed by paclitaxel and trastuzumab. Her family history (Table 1, Figure 2) was significant for astrocytoma, melanoma, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, prostate cancer, non-Hodgkin lymphoma, and pancreatic adenocarcinoma. Given her
Table 1. Familial Oncologic History Relation to Patient
Diagnosis
Age at Diagnosis (years)
Sister A
Astrocytoma
39
Sister B
Basal cell carcinoma
38
Melanoma
44
Sister C
Cholangiocarcinoma, hepatocellular carcinoma
39
Brother
Renal cell carcinoma
37
Father
Prostate carcinoma
71
Maternal grandmother Paternal aunt Paternal cousin (female)
Pancreatic carcinoma
68
Non-Hodgkin lymphoma
60
Astrocytoma
Third decade of life
WORLD NEUROSURGERY 109: 362-364, JANUARY 2018
significant personal and family cancer history, the patient underwent genetic evaluation. A cancer gene panel revealed a heterozygous likely pathogenic variant in BAP1 (c.659þ1delG (IVS8þ1delG)). This alteration is a deletion of a single nucleotide at þ1 position of intron 8, involving a canonical splice donor site and predicted to cause abnormal splicing leading to either nonesense-mediated mRNA decay or abnormal protein. The patient was extensively counseled and encouraged to share this information with family members at risk. At time of the preparation of this study, to our knowledge 1 of the proband’s healthy children showed positive test results for this variant. After the genetic findings were available, surveillance was recommended based on our current knowledge of BAP1-associated malignancies and the patient’s family history. An ophthalmologic examination revealed a small nevus of the disc. Skin examination showed multiple nevi, although none met the clinical criteria for biopsy. DISCUSSION The proband in this study carries a single nucleotide deletion in intron 8 of BAP1, which destroys a canonical splice donor site and is predicted to affect splicing. Although to our knowledge this variant has not been described in the literature, it is predicted to cause abnormal splicing leading to either nonesense-mediated mRNA decay or abnormal protein. BAP1 is a deubiquitinating tumor suppressor enzyme involved in a multiprotein complex that regulates cell transcription. BAP1 is located on chromosome 3p21.1. It is localized to the nucleus, where it exerts effects on cell cycle processes, including signaling of DNA damage and repair.1 The protein product also plays a regulatory function in cellular differentiation, cell death, DNA damage response, and gluconeogenesis.2 Similar to other hereditary cancer syndromes, dermal findings may suggest carrier status in affected family members. Benign skin tumors in this population resembling dermal nevi are frequently termed atypical Spitz tumors.3 At present, uveal melanoma, cutaneous melanoma, epithelioid malignant mesothelioma, and clear cell renal carcinoma are associated with the BAP1-TPDS.1,4 BAP1 tumor
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CASE REPORT MEGAN C. KASZUBA ET AL.
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet. 2015;88:273-277. 2. Goldstein AM. Germline BAP1 mutations and tumor susceptibility. Nat Genet. 2011;43:925-926. 3. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013; 13:153-159.
Figure 2. Family tree depicting cancer history. The proband is indicated by the black arrowhead.
spectrum may include basal cell carcinoma, cholangiocarcinoma, leiomyosarcoma, pleomorphic sarcoma, neuroendocrine tumors, meningioma, and paraganglioma.1 Various lung, breast, and ovarian cancers are also described.1 Whereas not all of the cancers reported in the proband’s family have been previously described in association with BAP1, basal cell carcinoma,5 melanoma, cholangiocarcinoma, renal cell carcinoma, and pancreatic carcinoma in this family are possibly associated with BAP1-TPDS. To date, no BAP1-associated malignant peripheral nerve sheath tumors have been reported, to our knowledge. Identification of the BAP1 pathogenic variant in affected patients and families is of clinical importance for surveillance recommendations and a tendency toward more aggressive tumors, earlier age at onset, and propensity to metastasize.3,6
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Determination of organ systems involved in BAP1-TPDS is clinically important for the development of screening guidelines. CONCLUSION Although the currently proposed screening guidelines for patients with BAP1-TPDS include annual physical examination in addition to abdominal imaging studies and ophthalmologic examinations, evidence is emerging of other tumors and cancers, including MPNSTs, in patients with this syndrome, which may affect future screening guidelines.7 Future targeted therapies may offer additional treatment options to patients with MPNSTs related to genetic syndromes.
4. Pilarski R, Cebulla CM, Massengill JB, Rai K, Rich T, Strong L, et al. Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes Cancer. 2014;53:177-182. 5. Rai K, Pilarski R, Cebulla CM, Abdel-Rahman MH. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 2016;89:285-294. 6. Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10:179. 7. Wang A, Papneja A, Hyrcza M, Al-Habeeb A, Ghazarian D. Gene of the month: BAP1. J Clin Pathol. 2016;69:750-753.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 29 August 2017; accepted 11 October 2017 Citation: World Neurosurg. (2018) 109:362-364. https://doi.org/10.1016/j.wneu.2017.10.064 Journal homepage: www.WORLDNEUROSURGERY.org
REFERENCES
Available online: www.sciencedirect.com
1. de la Fouchardiere A, Cabaret O, Savin L, Combemale P, Schvartz H, Penet C, et al. Germline
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