Jeffrey Schowinsky

Update on PML and PML-IRIS Occurring in Multiple Sclerosis Patients Treated With Natalizumab

Abstract The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction–based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.

Natalizumab-associated complication? First case of peripheral T cell lymphoma

Natalizumab (TYSABRI, Biogen Idec) is a therapeutic monoclonal antibody approved in 2004 for treatment of patients with the relapsing form of multiple sclerosis (MS). The drug reduces MS relapses, as well as new inflammatory lesions on MRI, and is highly clinically effective. Unfortunately, soon after approval, occurrence of progressive multifocal leukoencephalopathy (PML), due to reactivation of JC virus was reported with use of drug in two MS patients [6, 8] and one with inflammatory bowel disease [15]. Natalizumab was temporarily removed from the market. Availability resumed in 2006 with monitoring programs in place, including serological testing for JC virus exposure [3, 4]. As of 31 December 2011, over 95,300 patients have used natalizumab worldwide and, despite cautious use, 207 PML cases have occurred (https://medinfo.biogenidec.com). Other rare neoplastic [13] and infectious [2] complications seen in immunosuppressed patients are also starting to be reported. A 39-year-old woman with relapsing-remitting MS presented at age 36 (August 2007) with left hemisensory syndrome 5 weeks postpartum after her forth pregnancy. MRI was consistent with demyelination. On her second relapse (January 2008), multiple new MRI lesions were found and she met McDonald Criteria for definite MS. She had three more relapses over the next several months and was started on glatiramer acetate (October 2008). Due to relapses and an active MRI, she was switched to natalizumab (March 2009). She received 17 consecutive infusions. In August 2010, she noted left scalp tenderness, and in October 2010 had onset of vertigo, nausea without vomiting, and confusion. Emergent brain MRI in October 2010 revealed a new extra-axial mass overlying the left parietal convexity. The mass encircled the inner and outer tables of skull, with an enhancing intracranial part and smaller enhancing subgaleal component (Fig. 1a). JC virus serology was negative. Neurosurgical resection material revealed peripheral T cell lymphoma, unspecified, with severe cytological atypia, brisk mitotic rate (Fig. 1b), diffuse immunoreactivity for CD3 (Fig. 1c), and exceedingly high MIB-1 labeling (Fig. 1d). Lymphoma was negative for CD4, CD7, CD8, CD20, CD30, TdT, CD1a, and ALK-1 by immunohistochemistry, negative for Epstein Barr virus (EBV) by in situ hybridization, and clonal by gene rearrangement (Fig. 1e). Flow cytometry of tissue confirmed negativity for CD4, CD7, and CD8. This aggressive subtype represents about half of all peripheral T cell lymphomas in Western countries and is of unknown etiology. Initial bone marrow biopsy was positive for lymphoma cells. She was treated with Hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and received donor stem cell transplant. Core biopsy of L2 vertebral body remained Accepted for abstract presentation at the 101st annual United States and Canadian Pathology meeting, Vancouver, B.C., March 2012.

Tibial adamantinoma: late metastasis to the brain.

Most of the tumors that metastasize to the brain are carcinomas (1); sarcomas represent only a very small percentage. Due to improved therapies for aggressive sarcomas with resultant longer posttreatment life spans and the long-recognized propensity of several types of more indolent sarcomas for late metastasis, neuropathologists should anticipate seeing these tumors more frequently. The following case study illustrates this point and documents the occurrence for future reference. A 52-year-old woman on routine surveillance imaging presented with a left frontal duraYbased enhancing lesion thought to be most consistent with meningioma (Fig. 1A). A 3-month followup image demonstrated significant growth in this lesion with apparent intraparenchymal extension of an enhancing dura-based mass (Fig. 1B). Her medical history was significant for adamantinoma of the right tibia that had been resected 32 years before, at age 20 years. Given the rapid growth of this lesion and its imaging appearance being more consistent with metastasis, she underwent surgical excision. She also had several presumed pulmonary metastases (data not shown). Intraoperative resection of the lesion demonstrated that much of the tumor was subarachnoid and intraparenchymal, with only loose, if any, dural attachment. Intraoperative squash preparations showed a hypercellular, monomorphic, spindle-cell neoplasm composed of small to medium cells with mild to moderate atypia and coarse linear eosinophilic cytoplasm (Fig. 1C). An intraoperative diagnosis of high-grade spindle-cell neoplasm was made; anaplastic meningioma could not be excluded. Permanent sections confirmed cohesive growth of the tumor and verified the intraoperative impression that the tumor was actually embedded within brain parenchyma and was likely a metastasis (Fig. 1D). The tumor did not have many features that are often seen in primary adamantinomas, such as biphasic growth, basaloid appearance, well-defined epithelial structures, and bone formation. The main growth pattern was storiform to fascicular, with bundles of tumor cells approximately 10 to 15 cells wide. Other areas possessed a trabecular to vaguely pseudoglandular growth pattern, with 1-cellthick cords of tumor cells interconnecting to form a network of rings surrounding a mucinous ground substance. Nuclear chromatin pattern was open, with some stranded chromatin; most nuclei contained 1 or 2 small but distinct, mildly eosinophilic nucleoli (Fig. 1E). The tumor cells had moderate amounts of pale eosinophilic cytoplasm,with cytoplasmic vacuoles giving the cytoplasm a frothy appearance. Intercellular borders were not distinct. Immunohistochemical studies showed that most tumor cells were immunoreactive with antibodies to podoplanin (D2-40) (2), p63 (3), pancytokeratin (AE1/AE3) (4) (Fig. 1F, G, H, respectively), and cytokeratin 19 (4). A minority of tumor cells showed nuclear expression of p53. There was no significant immunostaining positivity for cytokeratin 8/18 (CAM5.2) or cytokeratin 7, as has been reported for adamantinoma of long bones (4). E-cadherin was also strongly immunopositiveVanother feature that can be seen in adamantinoma (5). Tumor cells were negative for antiepithelial membrane antigen and antinuclear progesterone receptor antibodies. MIB1 immunohistochemistry showed labeling in up to 20% of tumor cells (Fig. 1I). Adamantinoma is a very rare primary bone tumor that most commonly presents in young adults during the third and fourth decades of life (6Y10). It shows a marked predilection for involving the anterior portion of the tibial metaphysis or diaphysis, with such involvement present in up to 90% of cases. The tumor is characterized by slow growth and gradual development of a variable set of symptoms that often persist for years before diagnosis. The tumor is occasionally multifocal within a single bone and rarely involves more than one bone. Unlike the more sarcomatoid appearance of this metastasis, primary adamantinoma typically shows a biphasic growth pattern with a mixture of epithelial and stromal components. The epithelial component is densely cellular and most often consists of islands of basaloid to squamous cells. The epithelial component may also show a spindle-cell pattern (usually with storiform growth) or a tubular pattern. All 4 patterns may be present in a single tumor. The stromal component is also often arranged in a storiform pattern but is much less cellular than the epithelial component, with bland spindled cells and small blood vessels. Foci of woven bone formation are present within the stromal component and may be organized into lamellar bone in peripheral portions of the tumor (11Y13). Recurrences and metastases of adamantinoma frequently consist solely of the epithelial component, which is more often present in a spindle-cell pattern, as was seen in this patient. Adamantinomas metastasize in around 10% to 30% of patients, most often to the regional lymph nodes, lung (14), and bone (6Y10). We were unable to document metastases of this type of sarcoma to the brain using online search engines, and we only identified one other case after tracing backward to older references in several textbooks. To our knowledge, this case represents the second reported instance of metastasis to the brain (10). More importantly, the case highlights adamantinoma’s previously reported potential for late metastasis (6) and/or late recurrence (15). Factors reported to favor the development of recurrence and/or metastases include age younger than 20 years, pain at presentation, lack of squamous differentiation, and male sex (7, 10). This patient developed metastasis to the brain more than 30 years after her original diagnosis but also in association with lung lesions; thus, this likely represents a ‘‘secondary metastasis’’ from the lung lesions. Antecedent clinical history was well documented in her case but is not available in many patients, particularly for events occurring decades before presentation. Several sarcomas are noted for their propensity for late metastasis, including synovial sarcoma (16), alveolar soft part sarcoma (17, 18), and low-grade fibromyxoid sarcoma (19). The diagnostic task

Prominent Vascular and Perivascular Eosinophilic Infiltrates Heralding CNS Mycosis Fungoides

Brain parenchymal involvement of mycosis fungoides (MF) is very rare. This study reports a patient with known cutaneous MF (under treatment) who presented with a CNS syndrome and multiple brain lesions. Brain biopsy demonstrated massive eosinophilic infiltrates but no MF cells. Despite treatment, new lesions developed and the patient died. At autopsy, there was massive involvement MF cells, suggesting that the eosinophilic infiltrates presaged the severe involvement of the CNS by MF.

Myxoid Liposarcoma of the Thigh with Metastasis to the Left Ventricle of the Heart

Case: This report describes a sixty-one-year old man who was diagnosed with a myxoid liposarcoma of the left thigh that was resected and then treated with radiation therapy. He underwent yearly surveillance imaging but presented seventeen years after initial resection with symptoms of heart failure. He was found to have a cardiac abnormality that was first thought to be a pseudoaneurysm but was later shown to be a myxoid liposarcoma, presumably metastatic. Conclusion: Myxoid liposarcoma can present with late metastasis, including to the heart.

Immunohistochemical analysis of HMGA2 expression fails to provide evidence of a neoplastic basis for ‘primary’ synovial lipomatosis

lial, myogenic or melanocytic differentiation have been reported. Rare cases of Ewing sarcoma with cartilaginous and/or osseous formation have been reported, just as in our two cases. For these morphologically atypical cases, a test of the EWSR1 rearrangement becomes the key to correct diagnosis. Mesenchymal chondrosarcoma exhibits a characteristic bimorphic pattern, which is composed of undifferentiated small cells and nodules of well-differentiated cartilaginous tissue frequently with calcification or ossification observed within the central portion of the cartilaginous nodule. A novel, recurrent HEY1–NCOA2 gene fusion was found in mesenchymal chondrosarcoma based on a genomewide screen of exon-level expression data from Affymetrix Exon Arrays. For our second case, we regarded it first as a mesenchymal chondrosarcoma by only the morphology, but with the positive FISH test for EWSR1 rearrangement, we considered that Ewing sarcoma was a more convincing diagnosis. The first patient received two cycles of multi-agent chemotherapy after surgery, and has been diseasefree for 51 months. The second patient received expanded operation and was disease-free for 27 months. We consider that the relatively long-term outlook may be due to complete surgical resection of these two superficially localized cases.

Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia: a multi-institutional study

Abstract Acute lymphoblastic leukemia (ALL) in infants <1-year-old is biologically different from ALL in older children. Although KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL. In a multi-institutional review involving four medical institutions, 54 cases of infantile B-ALL were identified. Patients were divided into congenital and non-congenital groups with multiple age subgroups. Male predominance was seen in congenital cases compared to female in non-congenital cases. There were decreasing trends of hyperleukocytosis, central nervous system involvement, KMT2A rearrangements, lineage switch, and mortality, versus increasing trends of CD10 expression and non-KMT2A abnormalities. Statistically significant differences emerged at 3 and 9 months, the latter was not previously described. Poor-prognostic risk factors decreased with age, the last trimester of infantile B-ALL essentially merging with pediatric B-ALL.