Clinical Reasoning: A Teenager With Chronic Meningitis-Does Occam's Razor Apply?

A 14-year-old girl presented with subacute onset headache, fever, and vomiting and was managed initially with antibiotics for suspected bacterial meningitis. Her symptoms further evolved over the next few weeks with systemic signs and symptoms favoring chronic meningitis with raised intracranial pressure. After the etiologic workup was unrevealing, she was started on empirical antituberculous therapy. After a period of partial improvement, symptoms recurred with a new-onset focal seizure. Her imaging findings evolved from features suggestive of focal leptomeningitis to multifocal heterogeneous enhancing cortical and subcortical lesions with hemorrhagic foci, leading to brain biopsy that confirmed diagnosis. Our case highlights the utility of diagnostic biopsy in patients with "chronic meningitis" in uncertain cases rather than confining the approach to the law of parsimony. The decision to initiate empirical therapy in chronic meningitis should be considered on a case-by-case basis and take into account factors, such as clinical examination findings, immune status, recent exposures, and potential risks of treatment. Atypical MRI features should lower the threshold for meningocortical biopsy when indicated.

Rapid malignant transformation of an intracranial epidermoid cyst: Report of a case.

Intracranial epidermoid cysts (ECs) occur at various locations along the neuraxis and account for nearly 2% of all intracranial tumors. Considering the frequency of ECs, transformation of ECs into squamous cell carcinomas is a rare occurrence. Here, we report the case of a 39-year-old man who presented with a lesion in the left cerebellopontine angle and underwent gross total resection for the same. Histopathological examination revealed a benign EC with mild chronic inflammation. Five months later, the patient presented with another lesion at the same location with evidence of brainstem bleed. Histopathological examination revealed a moderately differentiated squamous cell carcinoma and remnants of the previous cyst in the form of lamellated keratin, indicating malignant transformation of the EC.

Nonneoplastic and noninfective cysts of the central nervous system: A histopathological study.

Nonneoplastic epithelial cysts involving the central nervous system are diverse and are predominantly developmental in origin. This study represents a surgical series describing the histopathological features of 507 such epithelial cysts with clinical and imaging correlation. Age at surgery ranged from 7 months to 72 years (mean: 33 years) affecting 246 male and 261 female patients. Colloid cyst was the most frequently resected cyst, followed by epidermoid cyst, arachnoid cyst, Rathke cleft cyst, dermoid cyst, neurenteric cyst, Tarlov cyst, and choroid plexus cyst. Diagnosis was based on the location of the cysts and the nature of the lining epithelium. Rathke cleft cyst showed the highest propensity for squamous metaplasia, significant inflammation, and xanthogranulomatous reaction. Ulceration of lining epithelium and calcification were most frequent in dermoid cyst. Radiopathological concordance was maximal for colloid cyst, followed by epidermoid and arachnoid cysts. Epidermoid and dermoid cysts exhibited the highest propensity for local tumor progression, followed by Rathke cleft cyst.

Genetics and muscle pathology in the diagnosis of muscular dystrophies: An update.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders involving the skeletal muscles. They have a progressive clinical course and are characterized by muscle fiber degeneration. Congenital muscular dystrophies (CMD) include dystroglycanopathies, merosin-deficient CMD, collagen VI-deficient CMD, SELENON-related rigid spine muscular dystrophy, and LMNA-related CMD. Childhood and adult-onset muscular dystrophies include dystrophinopathies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Traditionally, muscle biopsy and histopathology along with special pathology techniques such as immunohistochemistry or immunoblotting were used for the diagnosis of muscular dystrophies. However, recent advances in molecular genetic testing, especially the next-generation sequencing technology, have revolutionized the diagnosis of muscular dystrophies. Identification of the underlying genetic basis helps in appropriate management and prognostication of the affected individual and genetic counseling of the family. In addition, identification of the exact disease-causing mutations is necessary for accurate prenatal genetic testing and carrier testing, to prevent recurrence in the family. Mutation identification is also essential for initiating mutation-specific therapies (which have been developed recently, especially for Duchenne muscular dystrophy) and for enrolment of patients into ongoing therapeutic clinical trials. The 'genetic testing first' approach has now become the norm in most centers. Nonetheless, muscle biopsy-based testing still has an important role to play, especially for cases where genetic testing is negative or inconclusive for the etiology.

Role of skin punch biopsy in diagnosis of small fiber neuropathy-A review for the neuropathologist.

Over the last three decades, skin punch biopsy has become the gold standard for diagnosis of small fiber neuropathies, including autonomic neuropathies commonly seen in diabetics, patients with HIV, and children with hereditary sensory autonomic neuropathies and toxin-induced neuropathy. Clinical, biochemical, electrophysiological tests are inconclusive, making it difficult to diagnose and initiate treatment. A skin punch biopsy is easy to perform in the outpatient clinic, is highly sensitive, and provides an objective diagnosis. Importantly, it helps avoid performing invasive nerve biopsy in patients with small fiber neuropathy, thereby preventing complications such as non-healing of the biopsy site, which is common in these patients. Secondly, the greatest advantage of skin punch biopsies is that they can be repeated any number of times, unlike a nerve biopsy, and are useful to evaluate disease progression and therapeutic response. More recently, its use has been expanded to the diagnosis of large fiber neuropathies, inherited demyelinating neuropathies, etc., obviating the need for a nerve biopsy. The European Federation of Neurological Societies has published guidelines for evaluation to ensure uniformity with regard to the site of biopsy, processing, and quantification. The evaluation of the skin biopsy involves morphometric assessment of the intraepidermal nerve fiber density using PGP 9.5 immunostained sections by bright-field microscopy. This review focuses on the practical aspects of skin punch biopsy and its utility for the practicing pathologist.

Glioblastoma with primitive neuronal component: An immunohistochemical study and review of literature.

Glioblastoma with primitive neuronal component, a rare neoplasm, is recognized as a distinct histological pattern of glioblastoma. In this study we report the morphological and immunohistochemical features of three cases of glioblastoma with primitive neuronal component diagnosed at the Institute along with a comprehensive literature review. The cases include: (1) 11-year-old girl with right fronto-parietal lesion, (2) 48-year-old male with right parietal lesion, and (3) 36-year-old male with left fronto-parietal lesion. Case 1 had prior history of glioblastoma. All the cases had classic morphology of glioblastoma along with GFAP-negative and synaptophysin-positive primitive neuronal component. The latter was poorly demarcated from the glial component in case 1, while well-defined in the remaining two. All the three cases exhibited diffuse p53 positivity and a higher MIB-1 labelling index in the neuronal component compared to the glial component. One of them (case 3) was IDH1 R132H-mutant with loss of ATRX expression. None were positive for K27M-mutant H3 or G34R-mutant H3.3. Literature review of 50 published cases of glioblastoma with primitive neuronal component was performed. The age of onset ranged from 3 months to 82 years (mean: 50 years) with M:F of 1.5:1. 18.8% of tumors were IDH-mutant, 87.5% were p53 positive and three cases showed H3F3A gene mutations. There was a greater propensity for neuraxial dissemination, noted in 20% of cases. Overall survival of glioblastoma with primitive neuronal component was similar to that of IDH-wildtype glioblastoma (13 months) which was significantly shorter compared to the overall survival of IDH-mutant glioblastoma (33.6 months).

Mosaic Pattern of H3 K27M-Mutant Protein Expression in a Diffuse Midline Glioma-A Diagnostic Dilemma for the Pathologist.

Diffuse midline glioma, H3 K27M-mutant, is a World Health Organization (WHO) grade IV glioma arising in pons, thalamus, and spinal cord. They show mutations resulting in replacement of lysine at position 27 by methionine (K27M) of histone genes, H3F3A , HIST1H3B, and HIST1H3C. The H3 K27M mutant protein is identified in tumor tissue by immunohistochemistry. As these mutations are clonal and homogeneous, the mutant protein is normally identified in all tumor cells. Here we report a case of diffuse midline glioma with mosaic pattern of expression of H3 K27M mutant protein and discuss the diagnostic and therapeutic implications of this unusual pattern.

Meningioma with rosettes: A rare morphologic pattern.

We describe a case of WHO grade I transitional meningioma with rosettes in a 68-year-old woman. The rosettes were composed of meningothelial cells arranged around dense collagenous cores. Even though the presence of rosettes in tumors of the brain and spinal cord is an indication of neuronal or ependymal differentiation, they are also known to occur in tumors of other lineages. Rosette is an uncommon morphological pattern in meningiomas, with only few cases reported in the literature.

Glioblastoma in adults with neurofibromatosis type I: A report of two cases.

Neurofibromatosis type I (NF1) is a familial tumor syndrome with an autosomal-dominant inheritance. NF1-associated tumors often include neurofibromas, malignant peripheral nerve sheath tumors and pilocytic astrocytomas of the optic nerve. The presentation of NF1 patients with glioblastoma is a rare occurrence, with only a handful of cases reported in the literature. We report two cases of glioblastomas occurring in adults with NF1 and briefly review the relevant literature.

DNA alteration-based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high-risk group.

BACKGROUND: In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra-tumor immune population, compare it to other established biomarkers and to patients' outcome. METHODS: Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT-qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation-dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array-CGH (n = 17), and survival statistics (n = 86). RESULTS: Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1-IRF1 pathway activation. Tumors with IFNγ-signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three-tier stratification) than two (two-tier stratification). CNA-based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease-free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk-groups according to the number of DNA alterations. Immune cell infiltration was increased in the high-risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk-group. CONCLUSIONS: High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon-gamma-related, and associated with poor survival. It allows for two-tier stratification, which is prognostically less efficient than a three-tier one. The best prognostic stratification is by CNA model with three risk-groups where immune cell infiltration impacts only some subgroups.

IDH1 mutation, a genetic alteration associated with adult gliomatosis cerebri.

Recently, mutations in IDH1 and IDH2 have been reported as an early and common genetic alteration in diffuse gliomas, being possibly followed by 1p/19q loss in oligodendrogliomas and TP53 mutations in astrocytomas. Lately, IDH1 mutations have also been identified in adult gliomatosis cerebri (GC). The aim of our study was to test the status of IDH1/2, p53 and of chromosomes 1 and 19 in a series of 12 adult and three pediatric GC. For all tumors, clinico-radiologic characteristics, histopathologic features, status of IDH1/2, p53 and of chromosomes 1 and 19 were evaluated. IDH1 mutations were detected only in GC of adult patients (5/12). They all corresponded to R132H. Additional 1p/19q losses were observed in two of them with histological features of oligodendroglial lineage. Other copy number alterations of chromosomes 1 and 19 were also noticed. The median overall survival in adults was 10.5 months in non-mutated GC and 43.5 months in mutated GC. IDH1 mutations were present in GC of adult patients, but not in those of children. There was a trend toward longer overall survival in mutated GC when compared to non-mutated ones. Concomitant 1p/19q loss was observed in IDH1-mutated GC with oligodendroglial phenotype. These observations contribute toward establishing a stronger link between GC and diffuse glioma. In addition, these results also emphasize the importance of testing for IDH1/2 mutations and 1p/19q deletions in GC to classify them better and to allow the development of targeted therapy.

Renal cell carcinoma associated with granulomatous reaction.

Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by accumulation of epithelioid histiocytes and multinucleate giant cells. The cause of granulomas can be infectious or non-infectious. Granulomas have been described within the stroma of malignancies like carcinomas of the breast and colon, seminoma and Hodgkin's lymphoma, where they represent T-cell-mediated reaction of the tumor stroma to antigens expressed by the tumor. Granulomatous reaction in association with renal cell carcinoma (RCC) is uncommon, with only few published reports in the literature. We describe three cases of conventional (clear cell) RCC associated with epithelioid granulomas within the tumor parenchyma.