A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy

Abstract

Background: Valosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset.

Results: Upon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50-60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear.

Conclusion: This is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.

Trial registration: ClinicalTrials.gov NCT01353430.

Keywords: Anaplastic pleomorphic xanthoastrocytoma; Cancer; Frontotemporal dementia; IBMPFD; Multisystem proteinopathy; Myopathy; Paget disease of bone; Peripheral nerve sheath tumor; Thymoma; VCP.

Fig. 1

Case 1 MRI of the gluteal and pelvic area. Imaging displays a large heterogeneous enhancing mass in the posterior lateral soft tissues of the right gluteal region. Low-grade peripheral nerve sheath tumor deep to the right gluteus maximus.A- Axial B. Coronal C. Sagittal MRI. T1WI = T1 weighted image. T2WI-_FS = T2 weighted, fat-suppressed. T1WI-_FS + contrast = T1 weighted, fat suppressed with contrast

Fig. 2

a. Histologic features of tumor resection from right gluteal region of Case 1. Section showing low-grade malignant peripheral nerve sheath tumor with hypercellular fascicles of mitotically active (arrows) spindle cells with enlarged hyperchromatic nuclei. (H&E, 200x) b. Immunohistochemistry of case 1 tumor and peripheral nerve control. The staining showed strong nuclear and cytoplasmic reactivity with mild differences between the control and the tumor

Fig. 3

Case 2 brain MRI axial plane. Imaging shows lobulated heterogeneous solid left posterior frontal mass with foci of internal hemorrhage and surrounding edema causing significant mass effect and mild to moderate midline shift. A. T2WI = T2 weighted image. B. FLAIR = Fluid attenuated inversion recovery. C. SWI = Susceptibility weighted imaging

Fig. 4

a Histologic features of tumor resection from left posterior frontal lobe of Case 2. Anaplastic pleomorphic xanthoastrocytoma composed of epithelioid glial cells with minimal pleomorphism (A) (H&E, 200x). Anaplastic features include less pleomorphism than is typical for low grade PXA, areas of necrosis (not pictured), and increased proliferation evidenced by Ki67 (B) (Immunohistochemistry for Ki67, 200x). b. Immunohistochemistry of case 2 tumor and frontal cortex control. The staining shows strong nuclear and cytoplasmic reactivity with mild increase in the staining in patient tumor cells

Fig. 5

Chest of Case 4 at age 76 years. Chest photograph 41 years after radical mastectomy shows severe atrophy of pectoralis major muscle dating from irradiation in childhood