The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D)

Abstract

Background: To investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D.

Results: The XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and the brain showed vacuolization of the neuropil in the cerebrum, cerebellum and brainstem, and patchy Purkinje cell loss. Axonal neuropathy and chronic denervation atrophy of the skeletal muscles were observed in the XP-A patient, but not in the XP-D patient.

Conclusions: These clinical manifestations and autopsy findings indicate advanced involvement of the central and peripheral nervous system. Despite similar defects in DNA repair, different clinicopathological phenotypes are seen in the four cases, and therefore distinct patterns of neurodegeneration characterize XP-D, XP-A and XP-C patients.

Figure 1

XP patients studied. A and B: Case 1 XP-A patient (A) at age 17y with numerous freckle-like pigmented lesions on sun exposed skin and (B) at 37y with marked cachexia and thinning of subcutaneous tissues of face and chest. She had more that 100 surgical procedures on her face for removal of skin lesions. C: Case 2 XP-D patient at age 40y. She had been well protected from sun exposure since early childhood and had only few pigmented lesions and skin cancers. D: Case 3 XP-C patient, at age 29y with multiple freckle-like pigmented lesion on sun exposed skin and cheilitis. The patient underwent many surgical procedures for removal of skin cancers on her face. E and F: Case 4 XP-C patient, at age 28y (E) with multiple pigmented lesions, telangiectasia, cheilitis and corneal clouding. Multiple surgical procedures were performed on her face for removal of skin cancers and at age 48y (F) following exenteration of both orbits for treatment of ocular squamous cell carcinomas.

Figure 2

Case 1. XP-A A: Two consecutive Computed Tomography (CT) images of the brain obtained at age 20y. There are no focal brain abnormalities and no appreciable brain atrophy. B: Two axial T1-weighted Magnetic Resonance Images (MRI) of the brain in the same patient obtained at age 41y. There is evidence of prominent brain atrophy manifested by enlargement of the ventricles and widening of the intracranial subarachnoid spaces. C: Gross atrophy of the right brain hemisphere (right, comparable image to 2B) in comparison to the normal brain at the same age and gender (left). Loss of brain substance appears to be greater in the white matter. D: Thinning of cortex of the right temporal lobe (H&E, x 40). E: Luxol fast blue stain of the right temporal lobe showing patchy loss of myelination.

Figure 3

Case 3. XP-C A-B: MRI images of brain tumor. A: Axial post contrast T1-weighted MRI image of the brain obtained at age 29y showing a space occupying lesion in the left frontal lobe. The lesion demonstrates decrease signal intensity and does not enhance. The lack of enhancement after contrast indicates low histologic grade of this tumor. B: Axial post contrast T1-weighted MRI image of the brain in the same patient obtained five years later. There is evidence of tumor recurrence after surgery. The tumor demonstrates abnormal increased enhancement on the post contrast scan. This feature is indicative of malignant transformation. C: Histologic features of the primary tumor (as shown in A), a low grade astrocytoma (inset shows slightly atypical cells). D: Histologic features of the recurrent tumor, a glioblastoma. The tumor is characterized by increased cellularity, and pseudo-palisading necrosis (arrow), multinucleated tumor cell is shown in inset. E: Immunohistochemistry shows that the tumor cells are positive for IDH1 (X200). F: Pigmented lesion showing irregular size, shape and color. G: Histology of F showing melanoma in situ (x400).

Figure 4

Case 1. XP-A Axonal neuropathy and denervation atrophy of skeletal muscle. A: Electron microscopy showing mild to moderate reduction in the number of large myelinated axons accompanied by increased collagen and axonal degeneration and axonal atrophy consistent with axonal neuropathy. B: Skeletal muscle showing marked variation in fiber size, with rounded and angulated atrophic fibers, pyknotic nuclear clumps, fibrosis with fat replacement.

Figure 5

Case 2 XP-D Neuropathologic changes. A: Thick calvarium (2.3 cm, frontal). B: Global cerebral atrophy with dilated ventricles and thinned corpus callosum. C-D: Thinning of the cortical ribbon with vacuolization of the neuropil, neuronal loss and gliosis in the right frontal (C, x100) and parietal cortex (D, x200). E-F: Patchy loss of Purkinje cells in the right cerebellum with Bergman gliosis and axonal torpedos (E, x40; F, x200). G: Patchy myelin pallor in the right cerebellum (x100). H: GFAP highlights the reactive astrocytes in parietal lobe (x200).

Figure 6

Case 2 XP-D. Hippocampal sections showed neuronal loss involving CA2/CA3 sectors (A, X200); Neuropil disorganization seen in basal ganglia (B, X200) and midbrain-pontine areas (C, X200).

Figure 7

Case 2 XP-D. Neuropathologic changes. A and B, No specific abnormality was appreciated in peripheral nerve stained with H&E (A, x100) and LFB/PAS (B, x100). C and D, Periganglial lymphocytic infiltration of Auerbach’s plexus in the esophagus (C, x40; D, x 200).

Figure 8

Case 4 XP-C Neuropathologic changes. A: The cerebellum shows focal loss of Purkinje cells (x100). B-E: Sections of optic nerves and geniculate nuclei reveal degenerative changes, including axonal loss, gliosis, and fibrosis (arrows) in keeping with the patient’s 10 year history of bilateral orbital exenterations (B. H&E x200; C. immunostain for Bielschowsky, x200 D. Masson stain, x200, E. LFB/PAS stain, x200). F. Dorsal root ganglia show severe neuronal loss and accompanying fibrosis (H&E, x200).

Figure 9

Case 4 XP-C Carcinomatosis. Well differentiated mucinous adenocarcinoma of endocervical origin (A, x200), caused extensive abdominal carcinomatosis and involved diaphragm (B, x200).