Aditya Shivane

Merlin controls the repair capacity of Schwann cells after injury by regulating Hippo/YAP activity

Loss of the Merlin tumor suppressor and activation of the Hippo signaling pathway play major roles in the control of cell proliferation and tumorigenesis. We have identified completely novel roles for Merlin and the Hippo pathway effector Yes-associated protein (YAP) in the control of Schwann cell (SC) plasticity and peripheral nerve repair after injury. Injury to the peripheral nervous system (PNS) causes a dramatic shift in SC molecular phenotype and the generation of repair-competent SCs, which direct functional repair. We find that loss of Merlin in these cells causes a catastrophic failure of axonal regeneration and remyelination in the PNS. This effect is mediated by activation of YAP expression in Merlin-null SCs, and loss of YAP restores axonal regrowth and functional repair. This work identifies new mechanisms that control the regenerative potential of SCs and gives new insight into understanding the correct control of functional nerve repair in the PNS.

Loss of SOX10 function contributes to the phenotype of human Merlin-null schwannoma cells

Loss of the Merlin tumour suppressor causes abnormal de-differentiation and proliferation of Schwann cells and formation of schwannoma tumours in patients with neurofibromatosis type 2. Within the mature peripheral nerve the normal development, differentiation and maintenance of myelinating and non-myelinating Schwann cells is regulated by a network of transcription factors that include SOX10, OCT6 (now known as POU3F1), NFATC4 and KROX20 (also known as Egr2). We have examined for the first time how their regulation of Schwann cell development is disrupted in primary human schwannoma cells. We find that induction of both KROX20 and OCT6 is impaired, whereas enforced expression of KROX20 drives both myelin gene expression and cell cycle arrest in Merlin-null cells. Importantly, we show that human schwannoma cells have reduced expression of SOX10 protein and messenger RNA. Analysis of mouse SOX10-null Schwann cells shows they display many of the characteristics of human schwannoma cells, including increased expression of platelet derived growth factor receptor beta (PDGFRB) messenger RNA and protein, enhanced proliferation, increased focal adhesions and schwannoma-like morphology. Correspondingly, reintroduction of SOX10 into human Merlin-null cells restores the ability of these cells to induce KROX20 and myelin protein zero (MPZ), localizes NFATC4 to the nucleus, reduces cell proliferation and suppresses PDGFRB expression. Thus, we propose that loss of the SOX10 protein, which is vital for normal Schwann cell development, is also key to the pathology of Merlin-null schwannoma tumours.

Activation of multiple growth factor signalling pathways is frequent in meningiomas.

A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR)β was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin‐like growth factor receptor in 47%. Expression was similar in low‐ and high‐grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2‐intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti‐EGFR based therapies may be less effective in meningiomas with 22q loss.

Expression of c-Jun and Sox-2 in human schwannomas and traumatic neuromas

Schwann cells myelinate axons of the peripheral nervous system. This process of myelination is regulated by various transcription factors. c‐Jun and Sox‐2 are negative regulators of myelination and control Schwann cell differentiation and plasticity. Schwannoma cells within tumours no longer express myelin markers, and show increased proliferation and decreased apoptosis. We have shown previously that several signalling pathways are activated in schwannoma cells in situ, in particular the c‐Jun N‐terminal kinase (JNK) pathway. Both in vitro and in vivo we have demonstrated that c‐Jun and Sox‐2 are co‐regulated in Schwann cells and evidence shows that both these proteins regulate myelination negatively. In this study, we aimed to characterize the expression of c‐Jun and Sox‐2 in schwannoma and traumatic neuroma.

A tale of the unexpected: Amyloidoma associated with intracerebral lymphoplasmacytic lymphoma

Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, λ-light chain secreting plasmacytoma adjacent to an amyloid mass comprising aggregated monoclonal immunoglobulin light chains. We described a patient with intracerebral amyloidoma associated with a localised lymphoplasmacytic lymphoma and no systemic paraproteinaemia, tumour or amyloid deposits.

Basic Pathologic Reactions

This chapter deals with the ways in which the cellular constituents of the nervous system (neurons and glial cells) react to various insults. The severity and duration of the insult determine whether the final outcome is reversible or irreversible. Identification of these basic pathologic reactions helps the pathologist in making a diagnosis and also provides clues towards the aetiology of the pathological process.

A clinicopathologic study of 11 rosette-forming meningiomas: a rare and potentially confusing pattern

described in experimental studies of subarachnoid epineph-rine injection in dogs [12], have only since been reported twice. One case report describes a secretory meningioma with rosette formation associated with Moyamoya disease [10]. This feature was also briefly mentioned and illustrated in the 1982 monograph by Dr. John Kepes [5]. However, to date, no studies have examined the spectrum or signifi-cance of rosette formation in meningiomas. Herein, we present our experience with meningiomas showing rosette formation.A total of 11 rosette-forming meningiomas were identi-fied from 11 patients from the authors’ files. Information regarding neuroimaging features and clinical presentation was obtained from the medical records at the institutions from which the cases originated. All cases were classified and graded utilizing the 2007 World Health Organization (WHO) scheme [6] (Fig. 1).Histochemical and immunohistochemical stains per-formed as part of the diagnostic workup or as part of a con-sult workup included EMA, progesterone receptor (PR), vimentin, reticulin, trichrome, GFAP, CD99, CAM 5.2, Ki-67, CD34, collagen IV, and synaptophysin.The clinical details are highlighted in Supplemen-tary Table 1, with patients ranging in age from 18 to 86 (median: 60) years and a F:M ratio of 1.8. Imaging studies were available in all 11 cases and showed features indis-tinguishable from those of conventional meningioma. All tumors were intracranial, single masses, ranging from 3.2 to 6.2 cm in greatest dimension.Histologic, histochemical, and immunohistochemical features are summarized in Table 1 and Supplementary Table 2. All but one case showed rosettes with central vari-ably collagenized eosinophilic structures, while gland-like lumens (i.e., “true rosettes) were also seen in 4 cases (in one it was the only form of rosette and in another it was Meningiomas are amongst the most common intracranial neoplasms and display a remarkable morphologic diversity, which may prove diagnostically challenging in some cases. Rosette formation is an exceptionally rare and mostly an unappreciated feature in meningiomas, other than the ependymoma-like perivascular pseudorosettes encountered in papillary meningioma [7, 11] and rarely, in non-papillary counterparts [9]. Although these perivascular structures should perhaps be termed ‘meningothelial pseudorosettes’ and may coexist with other rosette forms, these were not the focus of the current study.In tumor pathology, rosette formation is usually con-sidered as evidence of either neuronal or ependymal dif-ferentiation, but has also been described in rare examples of osteosarcoma, lymphoma and melanoma [2, 3, 8]. To our knowledge, meningothelial rosettes, which were first

EBV+ HHV-8+ Multicentric Castleman Disease With Plasmablastic Aggregates in an HIV+ Man: An Evolving Clinicopathologic Entity

We report a case of EBV+ and HHV-8+ multicentric Castleman disease with plasmablastic aggregates in an HIV-positive individual. A 41-year-old man presented in early 2015 with fevers, sweats, weight loss, intractable itching, and on subsequent testing was found to be HIV positive. Investigations showed cervical lymphadenopathy and splenomegaly. He was treated for HIV and his symptoms resolved. His symptoms recurred in January 2016, and a provisional diagnosis of multicentric Castleman disease was entertained. The HHV-8 (human herpesvirus-8) and EBV (Epstein-Barr virus) viral load was elevated. A left supraclavicular lymph node core biopsy was performed, which showed features of multicentric Castleman disease with plasmablastic aggregates that are EBV (EBER) and HHV-8 positive. He responded well to rituximab treatment and remains well with no symptoms at recent follow-up.

Metabolic, Toxic and Nutritional Diseases

The functioning of nervous system can be affected by disturbances in metabolic substrates such as glucose and electrolytes, accumulation of toxic substances and deficiency of essential nutrients such as vitamins. This group of diseases are clinically important because correction of the metabolic disturbance may result in restoration of normal function. The majority of these conditions have relatively non-specific neuropathological features, but some conditions have characteristic gross and microscopic pathology. The clinically relevant conditions and those with characteristic neuropathology are discussed in detail.

Peripheral Nerve Diseases

Peripheral nerve diseases are very uncommon, except in the elderly population, and in many cases the aetiology remains unknown despite investigations. In certain situations a nerve biopsy may be helpful in the investigation of patients, particularly where there is a reasonable likelihood of detecting a treatable disorder, and a skin biopsy may also help in confirming the presence of a small fibre neuropathy. The techniques for nerve biopsy and laboratory investigation are described, along with a detailed classification of peripheral neuropathies and their key pathological findings.