Sarah E. Martin

Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study

TP63, a member of the TP53 gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used to aid in the diagnosis of prostate carcinoma, as well as in the identification of myoepithelial cells in other tissues including the breast. p63 is also a marker for squamous cell carcinoma. Recently, it was found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma (RB) protein. Ablation of these p53 family functions blocks the differentiation program and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. We therefore studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin sections from 38 rhabdomyosarcomas, five leiomyomas, five leiomyosarcomas, five rhabdomyomas, five rhabdomyomatous Wilms tumors, three normal cardiac muscles, one medullomyoblastoma, one pleuropulmonary blastoma with rhabdomyomatous differentiation, and one teratoma with prominent rhabdomyoblasts. Each case was also stained with desmin. Unlike the nuclear staining scored in myoepithelial cells, only cytoplasmic staining for p63 was considered positive. Of 38 cases of rhabdomyosarcoma, 36 showed cytoplasmic p63 staining; 24 of these showed highlighting of cross-striations superior to that of desmin. In addition, 5/5 rhabdomyomas, 5/5 rhabdomyomatous Wilms tumors, 1/1 pleuropulmonary blastoma with rhabdomyomatous differentiation, 1/1 teratoma with atypical rhabdoblasts, and 1/1 medullomyoblastoma exhibited cytoplasmic p63 staining. Normal cardiac muscle samples (3/3) also demonstrated positive cytoplasmic staining and distinct cross-striations. Smooth muscle tumors exhibited only very focal and faint cytoplasmic staining in 5/5 leiomyomas and 4/5 leiomyosarcomas. Immunoelectron microscopic study of skeletal muscle showed p63 localization to the Z bands of sarcomeres. We conclude that p63 immunostain is a sensitive marker for skeletal muscle differentiation and highlights the cross-striations of strap cells with exceptional definition.

Glioblastoma with signet-ring morphology: a case report and review of the literature

Primary central nervous system tumors with signet-ring morphology are exceedingly rare. We report an unusual case of glioblastoma with signet-ring cell features in an 81-year-old woman. Microscopic examination revealed a highly anaplastic tumor, with a prominent proportion of tumor cells exhibiting signet-ring appearance characterized by classic round cytoplasmic inclusions and eccentrically positioned nuclei. The tumor cells were immunoreactive for glial fibrillary acidic protein and S100, and negative for cytokeratins, confirming their glial origin. Ultrastructurally, the tumor cells were noted to contain intermediate filaments, and by fluorescence in-situ hybridization analysis, they demonstrated intact 1p/19q. The presence of signet-ring cells in the central nervous system should immediately raise the suspicion of metastatic carcinoma, particularly from the upper gastrointestinal tract. In the present case, however, the morphological and immunohistochemical features were diagnostic of a malignant primary glial neoplasm (glioblastoma). This case highlights the diagnostic difficulties that can arise in such instances, given the rarity of signet-ring morphology in primary central nervous system tumors.

The pathologic spectrum of oculoleptomeningeal amyloidosis with Val30Gly transthyretin gene mutation in a postmortem case

We report the clinical and postmortem pathologic features of a 60-year-old woman with oculoleptomeningeal amyloidosis with a Val30Gly transthyretin gene mutation. Unlike other forms of hereditary amyloidosis, this rare type displays amyloid deposition predominantly in the eyes and central nervous system. Our patient belongs to 1 of only 2 kindreds known to carry this transthyretin mutation. Previous reports focused on examination of the brain and spinal cord, largely ignoring postmortem examination of the eyes. In this case, autopsy examination revealed amyloid deposition in the leptomeninges surrounding the brain, spinal cord, and optic nerves. Subependymal amyloid deposits projecting into the lateral ventricles as well as amyloid deposition in the choroid plexus, retinal vessels, nerve fiber layer of the retina, and vitreous were observed. Amyloid was not identified elsewhere in the body. Awareness of this rare form of hereditary amyloidosis is crucial, given the substantial genetic and therapeutic implications of the diagnosis. Oculoleptomeningeal amyloidosis can be easily diagnosed during life with vitreous biopsy, as was the case in our patient.

Atypical teratoid/rhabdoid tumour in an adult with disseminated mediastinal germ cell tumour

In 1985, Rorke et al. first described a central nervous system (CNS) tumour that was histologically similar to primitive neuroectodermal tumour (PNET) but possessed very different biological features [1]. In children, this unique tumour was diagnosed at an earlier age (median, 16.5 months), compared with CNS PNET (median, 3–5 years), was fatal within 1 year of diagnosis and rarely responded to treatment [1]. The term ‘atypical teratoid/ rhabdoid tumour’ (AT/RT) was eventually coined to bring attention to the combination of rhabdoid, primitive neuroepithelial, epithelial and mesenchymal components characteristic of this tumour [1,2]. There is a male predominance ranging from 1.6:1 to 2:1. Most are supratentorial, usually involving the cerebral hemispheres, although infratentorial examples, including those arising within the spinal cord, are not infrequent [2]. They can spread through the subarachnoid space, a feature that is often noted at diagnosis, and the clinical outcome is very poor, with a mean survival of 11 months following surgery [3,4]. Although AT/RT is a tumour of the very young, rare occurrences in adults have been described [2,3]. The histogenesis of rhabdoid tumours, including AT/RT, is unknown [2]. Given the association with young children and multilineage differentiation, it has been proposed that AT/RTs derive from pluripotent foetal, meningeal, neural crest or germ cells [1]. AT/RTs are associated with a mutation or loss of the INI1 (hSNF5/SMARCB1) locus at 22q11.2 [2]. Loss of SMARCB1/INI1 expression at the protein level is seen in most AT/RTs. A mutation or deletion of SMARCB1/INI1 is seen in as many as 98% of tumours [5]. SMARCB1/INI1 deletion is rarely seen in other tumours with the exceptions of epithelioid sarcoma, renal medullary carcinoma, cribriform neuroepithelial tumour (CRINET), poorly differentiated chordomas, malignant rhabdoid tumour and rhabdoid glioblastoma [6–9]. Here we describe a case of AT/RT presenting in an adult. This case is particularly unique due to its association with disseminated germ cell tumour (GCT) with brain metastases, a previously unrecorded occurrence. This association raises the question of whether AT/RT could be added to the list of secondary malignant tumours to which GCTs may give rise. A 19-year-old man initially presented with galactorrhoea, weight loss and headaches. He was found to have a mediastinal mass, multiple pulmonary metastases, and elevated beta human chorionic gonadotrophin (β-hCG) and alpha fetoprotein (AFP). A testicular examination was normal. A very limited chest wall biopsy demonstrated choriocarcinoma and no other germ cell components. The patient underwent bleomycin, etoposide and cisplatin chemotherapy. However, 5 months after diagnosis he developed brain metastasis, prompting whole brain radiotherapy and salvage chemotherapy consisting of ifosfamide, vinblastine and cisplatin. While the specific location of the brain metastasis was not noted in the medical records and the corresponding imaging studies were no longer available, a head computed tomography (CT) with contrast, performed 17 years later, demonstrated focal encephalomalacia in the right temporal lobe supporting this as the site of the GCT metastasis (Figure 1A). After salvage therapy, the patient went into complete serological remission and partial radiographic remission with residual small but stable pulmonary nodules. Eleven years after his original diagnosis, a chest radiograph demonstrated enlarging paratracheal and mediastinal lymph nodes. Surgical resection yielded lymph nodes with noncaseating granulomas, and a mediastinal mass consisting of mature teratoma (Figure 1C,D). The teratoma contained islands of mature cartilage, smooth muscle, and squamous, respiratory and intestinal type epithelia. It was non-immunoreactive for SALL4 and OCT4, as would be expected in a teratoma. SMARCB1/INI1 immunostaining was preserved (for details regarding immunohistochemical staining, see Supplemental Table S1 – online only). Seven years later, he presented to the emergency department with a headache. Magnetic resonance imaging (MRI) of the brain showed a 4.3 × 2.2 × 2.6 cm mildly enhancing intra-axial mass in the Presented, in part, at the 89 annual meeting of the American Association of Neuropathologists, Charleston, SC, USA, 20–23 June 2013.

Marginal zone B-cell lymphoma involving a longstanding fibrous meningioma: an initial manifestation of systemic disease

The combined presence of meningioma and lymphoma involving the dura is exceptionally rare. A 62-year-old woman, radiologically diagnosed with meningioma 14 years prior but never treated, presented with headaches and visual symptoms. Magnetic resonance imaging demonstrated significant growth of the mass. Surgical resection yielded a composite meningioma and marginal zone B-cell lymphoma. Subsequent systemic workup revealed bone marrow involvement. Low-grade lymphomas rarely metastasize to the central nervous system. When they do, it is usually a result of large cell transformation and typically marks a late event in the course of the disease. This case highlights the necessity of adequate sampling of meningiomas and of including low-grade lymphoma in the differential diagnosis of meningiomas with prominent lymphocytic infiltrates. In addition, this case emphasizes that all patients with lymphoma involving the central nervous system, even when low grade, should receive a full systemic workup.

Temporal and optic pathway pilomyxoid astrocytoma mimicking dural-based lesion: Case report and review of the literature

Pilomyxoid astrocytomas (PMAs) are low-grade tumors that share many common traits with pilocytic astrocytomas. However, PMAs have a more worrisome clinical course, with a higher recurrence rate, lower survival rate, and higher risk of leptomeningeal spread compared to pilocytic tumors. These tumors tend to occur in younger children and are typically located in the area of the optic chiasm or hypothalamus. There are few studies examining the radiographic appearance of these lesions. In this case report, the authors present an unusual radiographic appearance of a PMA in an 11-year-old child. Preoperative images suggested a dural-based, homogenously enhancing lesion coupled with an enlarged optic nerve. Surgery revealed an intraparenchymal lesion of the right temporal lobe. There was hyperintensity on T2 MRI sequences, suggesting infiltration of the tumor along the optic tracts.

A 2-YEAR-OLD BOY WITH HEMOLYTIC UREMIC SYNDROME AND PNEUMOCEPHALUS

Clostridium septicum infection following hemolytic uremic syndrome is rare and carries a poor prognosis, especially when the brain is involved. We report a case of a previously healthy 2-year-old boy who presented with two days of anuria and bloody diarrhea. He was admitted to the local childrens hospital with a diagnosis of hemolytic uremic syndrome, presumably secondary to E. coli O157. He soon required intubation and was noted to have fixed and dilated pupils. Head CT revealed left frontal subcortical white matter vasogenic edema and scattered pockets of pneumocephalus. The patient expired 14 hours after admission. Antemortem blood cultures grew C. septicum. Gross pathologic examination of the brain revealed a large intraparenchymal cerebral hemorrhage in the left frontal and parietal lobes. There was extensive cystic changes as well. Microscopic examination revealed vacuolization and diffuse colonization with rod-shaped bacteria, but without the expected tissue response. There have been only six previously reported cases of C. septicum infection following hemolytic uremic syndrome, four of which had brain involvement. Mortality rate is high, with the only known survivor among those with brain involvement having a brain abscess rather than diffuse pneumocephalus.