Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Cytopathology and diagnostics of Warthin's tumour.

Warthin's tumour (WT) is a benign epithelial salivary tumour, one type of salivary adenoma. Histologically, WT is structured of two components, epithelial tissue that often lines cystic formations and lymphoid tissue in the tumour stroma. FNA is a reliable diagnostic approach in the diagnosis of salivary gland lesions allowing a highly accurate categorization of benign tumour-like lesions, benign tumours and malignant tumours. In the proposed Milan reporting system of salivary gland lesions, WT is categorized in the IVA group of benign neoplasms. Accurate cytological diagnosis is straightforward when three characteristic components are present: oncocytes, either isolated or associated in clusters, lymphocytes and lymphoid cells and often an inflammatory/necrotic-like substance. Also, specific features of scintigraphy and radiological imaging contribute to the diagnosis of WT. WT is categorized according to Seifert G. et al in 4 types, depending on the proportions of the epithelial component and lymphoid stroma. Differential cytopathological and pathohistological diagnosis include other salivary gland lesions with lymphoid, oncocytic epithelial and cystic components. In some cases, such as the metaplastic WT variant, there are additional cytopathological and histological diagnostic difficulties. Moreover, bilateral, multicentric or multiple and infrequently seen extra-salivary localizations of WT are associated with further cytopathological diagnostic difficulties. Also, a rare possibility of malignant transformation of the epithelial or lymphoid component of WT as well as possible association with other primary tumours remains a challenge in accurate cytopathological and histological diagnosis of WT.

Cluster Analysis of Chronic Rhinosinusitis Suggests Gender-Based Differences.

PURPOSE: We aimed to evaluate the interaction between the overall severity of chronic rhinosinusitis (CRS) before treatment and subjective improvement following surgical or medical treatment. PROCEDURES: A group of 97 patients with CRS completed the visual analog scale (VAS) symptom score and the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire in the moment of their sinus computerized tomography (CT) scan. Data were analyzed via a 2-step cluster analysis based on gender, polyp presence, CT scan, and VAS scores for symptoms. RESULTS: There were 3 clusters: the first cluster comprised 37 female patients with CRS without nasal polyps (CRSsNP), the second cluster comprised 30 patients with CRS and NP (CRSwNP; 15 males and 15 females); and third cluster had 30 male patients with CRS without NP (CRSsNP). Different symptom patterns between clusters were identified. After adjustment for polyp presence, gender, eosinophilia (p = 0.021), and the SNOT-22 score (p = 0.005) were found to be better outcome predictors than the CT score (p = 0.26). CONCLUSION: Long-term patient satisfaction is significantly associated with the subjective symptom severity prior to treatment, i.e., postnasal drip and overall disease severity (SNOT-22 score), but not with the objective severity of the disease (CT score and inflammation).

ISCHEMIC PITUITARY APOPLEXY, HYPOPITUITARISM AND DIABETES INSIPIDUS: A TRIAD UNIQUE TO NECROTIZING HYPOPHYSITIS.

- A rare case of necrotizing hypophysitis (NH) in a 52-year-old man presenting with pituitary apoplexy and sterile meningitis is described. This case indicates that the diagnosis of NH could be made without biopsy, based on concomitant presence of diabetes insipidus, hypopituitarism and radiologic features of ischemic pituitary apoplexy. Conservative management of pituitary apoplexy should be advised in NH. Additionally, this is the first report of a case of sterile meningitis caused by ischemic pituitary apoplexy.

Masqueraded sebaceous gland carcinoma of the lower eyelid in a young pregnant patient.

The purpose of this case report is to present misdiagnosed sebaceous gland carcinoma of the lower eyelid with rapid growth in a young woman during pregnancy. Eyelid sebaceous gland carcinoma is a relatively rare tumor and a disease primarily of older patients. It occurs more commonly in oriental populations and with a predilection for the upper eyelid. Early diagnosis and appropriate treatment may help improve disease control and patient survival.

Diagnostic Accuracy of Preoperative CT and Endoscopy Staging in Early Laryngeal Cancer.

OBJECTIVES: This study aims to evaluate the diagnostic accuracy of preoperative computed tomography (CT) and intraoperative endoscopic tumor staging with regard to histopathologic staging in patients with early laryngeal cancer. STUDY DESIGN: A retrospective nonrandomized single-institution comparative cohort study including 109 patients. SETTING: A tertiary surgical center. METHODS: Patients were treated for T1a, T1b, and T2a laryngeal squamous cell carcinoma by endoscopic laser surgery. The outcome measures were the presence of under- or overstaging in endoscopic and CT findings and positive postoperative margins. RESULTS: Endoscopic overstaging as compared with histopathologic T category correlated with rising tumor category (P = .001; odds ratio [OR], 69.1) and CT findings showing anterior commissure involvement (P = .002; OR, 9.54), while endoscopic understaging correlated with rising tumor histologic grade (P = .039; OR, 4.28) and smaller tumor size (P = .011; OR, 6.39). CT overstaging vs histopathologic T category correlated with CT findings showing anterior commissure involvement (P = .001; OR, 21.76), supraglottic involvement (P = .001; OR, 59.98), subglottic involvement (P = .001; OR, 39.94), rising clinical T category (P = .01; OR, 9.11), and rising tumor histologic grade (P = .004; OR, 10.95). CT understaging as compared with histopathologic T category correlated with smaller clinical T categories (P = .002; OR, 12.72) and smaller tumor histologic grade (P = .030; OR, 7.02). Rising age, rising tumor size, anterior commissure involvement on CT, and tumor extension into the supraglottis were risk factors for positive margins. CONCLUSION: Our results indicate that CT adds little valuable information in differentiating small superficial lesions in the glottis, while systematically overstaging cases of early laryngeal cancer. In T1a and T1b glottic tumors, endoscopy should be the preferred diagnostic method.

[Pathology diagnosis of idiopathic inflammatory myopathies]. / Patologijska dijagnoza idiopatskih upalnih miopatija.

The idiopathic inflammatory myopathies represent a group ofimmunologically mediated diseases characterized by inflammation of skeletal muscle potentially leading to irreversible damage. On the basis of clinical, histological and immunological features dermatomyositis, polymyositis and sporadic inclusion-body myositis are recognized as separate entities. A definitive diagnosis of idiopathic inflammatory myopathies requires detailed histological, histochemical, immunohistochemical and electron-microscopic analysis of adequate muscle biopsy sample. However, in spite of thorough morphological analysis distinction of these disorders is not always straightforward and a close clinicopathological correlation is often essential to reach a correct diagnosis. Detailed morphological features ofidiopathic inflammatory myopathies and their relationship to pathogenesis is outlined.

Characteristics of typical and atypical meningiomas on ADC maps with respect to schwannomas.

The differences in apparent diffusion coefficient (ADC) between typical and atypical meningiomas and schwannomas were investigated, with 41 patients included in the study. There were no significant differences in ADC values or ADC ratios between typical and atypical meningiomas. The discrimination between schwannomas and the typical and atypical meningiomas on ADC maps was reliable, with significant differences in ADC values and ratios and with the narrow range of ADC values in meningiomas.

Expression Levels and Localizations of DVL3 and sFRP3 in Glioblastoma.

The expression patterns of critical molecular components of Wnt signaling, sFRP3 and DVL3, were investigated in glioblastoma, the most aggressive form of primary brain tumors, with the aim to offer potential biomarkers. The protein expression levels and localizations in tumor tissue were revealed by immunohistochemistry and evaluated by the semiquantitative method and immunoreactivity score. Majority of glioblastomas had moderate expression levels for both DVL3 (52.4%) and sFRP3 (52.3%). Strong expression levels were observed in 23.1% and 36.0% of samples, respectively. DVL3 was localized in cytoplasm in 97% of glioblastomas, of which 44% coexpressed the protein in the nucleus. sFRP3 subcellular distribution showed that it was localized in the cytoplasm in 94% of cases. Colocalization in the cytoplasm and nucleus was observed in 50% of samples. Wilcox test indicated that the domination of the strong signal is in connection with simultaneous localization of DVL3 protein in the cytoplasm and the nucleus. Patients with strong expression of DVL3 will significantly more often have the protein in the nucleus (P = 6.33 × 10-5). No significant correlation between the two proteins was established, nor were their signal strengths correlated with epidemiological parameters. Our study contributes to better understanding of glioblastoma molecular profile.

Epithelioid hemangioma of the orbit: case report.

Epithelioid hemangioma (EH) and Kimura's disease (KD) were once considered different stages of the same disease, as they share many clinical and histopathologic similarities. Nowadays, they are considered as two different entities, but some authors still confuse these terms. Our objective is to present a case of EH occurring in a very uncommon location and to emphasize the microscopic and clinical differences between EH and KD. We present a case of EH of the orbit in an 83-year-old man diagnosed after histopathologic evaluation of a mass that was surgically removed from the orbit. The tumor showed typical microscopic appearance with pathognomonic epithelioid endothelial cells. The diagnosis was also confirmed by immunohistochemical analysis. Our case clearly illustrates typical appearance of EH and the main differences between EH and KD are thoroughly discussed.

INITIAL SYMPTOMATIC PITUITARY METASTASIS IN A PATIENT WITH PROSTATE FOAMY GLAND CARCINOMA: TAILORING SAFE AND EFFECTIVE THERAPY.

Metastases to pituitary gland are unusual and mostly asymptomatic, presenting with local symptoms in one of ten patients, and only 3%-5% of them are of prostate origin. Here we report and evaluate the effectiveness and safety of multimodal treatment in a patient with pituitary metastasis of a prostate foamy gland carcinoma. A 78-year-old male patient presented with blurred vision and headache without a previous history of malignancy. Magnetic resonance imaging scans revealed a large sellar mass, with infiltration of the surrounding structures. Maximal transsphenoidal reduction of pituitary metastasis was performed, with a histologic finding of metastatic prostate foamy gland adenocarcinoma. Evaluation of the prostate specific antigen revealed a very high level (1461 ng/mL) and foamy gland carcinoma was found on prostate needle biopsy. The patient received 3D conformal external beam radiotherapy with 6 MV photons to the sellar and parasellar region with a tumor dose of 44 Gy, followed by androgen deprivation therapy. Follow up magnetic resonance imaging done after radiotherapy showed shrinkage of the tumor process, with rapid prostate specific antigen decline to 0.3 ng/mL. The visual function was fully established and headache resolved. On the last follow up 14 months after the diagnosis, the patient was alive and free from clinical signs of disease. Tailored treatment, including limited radiotherapy in a higher palliative dose, in a patient with foamy gland symptomatic pituitary metastatic disease resulted in good local and systemic control of the disease. In older male patients with clinical and/or radiologic characteristics suggestive of metastatic pituitary disease, the prostate specific antigen test should be included as part of the work-up.

Long-term follow-up of children with chronic relapsing polyneuropathy.

Long-term follow-up of three children with early-onset chronic inflammatory demyelinating polyneuropathy is presented. A 3-year-old male (Patient 1) manifested initially progressive muscle weakness during 6 months with spontaneous regression, followed by two severe relapses at 5 and 6 years of age. Decreased arylsulfatase A activity was present in Patient 1 (17.6) and his family members (24.1-40 nmol/mg/hour). Arterial hypertension up to 20/12 kPa was present in two patients in the initial phase associated with muscle stiffness, occasional meningism, and left ventricular hypertrophy in one of them (Patient 3). Subsequently, they both developed two mild relapses at 3.5 and 6 years of age. Clinical outcome was excellent in all three cases, although clinical course, therapy response, and electrophysiologic outcome was quite different in the only patient with low arylsulfatase A activity. The significance of this difference is discussed.

[Myopathy with rhabdomyolysis as an adverse effect of simultaneous treatment with cerivastatin and gemfibrozil]. / Miopatija s rabdomiolizom kao nuspojava istodobnog lijecenja cerivastatinom i gemfibrozilom.

Drug-induced myopathy and/or rhabdomyolysis have been reported with use of some statins and fibric acid derivatives. The risk of adverse effects is increased with their concomitant use. We report the case of myopathy with rhabdomyolysis during the concomitant use of cerivastatin and gemfibrozil.

[Diagnostic value of myocardial biopsy in the diagnostic algorithm in cardiomyopathies in children]. / Dijagnosticka vrijednost biopsije miokarda u dijagramu dijagnostickog toka kardiomiopatija u djece.

The purpose of this work was to show the importance of myocardial bioptate analysis using different methods in the diagram of diagnostic flow in primary cardiomyopathies in children. According to the guidelines of the Task Force on Cardiomyopathies of the WHO/ISFC, we identified 121 children (50 f and 71 m) as having cardiomyopathy, giving an average occurrence for all cardiomyopathies of 38.81 for each 10,000 pts examined in our outpatient clinics for paediatric cardiology. The dilated cardiomyopathy (DCM) was identified in 52 pts (42.9%), hypertrophic cardiomyopathy (HCM) in 43 pts (35.5%) and restrictive cardiomyopathy (RCM) in 6 pts (4.8%). We placed 11 pts (9.0%) in the group of specific cardiomyopathies. In nine pts (7.4%), it was impossible to classify the cardiomyopathy. Most of those with DCM had been diagnosed prior to the age of 3 years (RR 1.9, 95% CI 1.4-2.47). There were no statistically significant differences in the incidences of DCM as compared to HCM (Z 0.923, p < 0.1779), but we encountered a significantly lower occurrence of RCM (Z 6.044, p < 0.001). The biopsy of endocardium and myocardium was done to confirm the etiology of primary cardiomyopathy in 22 pts, 12 m and 10 f, age 1 to 17 (average age 9.5y). The bioptates were analysed by light microscope (Dallas criteria) in all pts, 13 bioptates by direct immunofluorescence, 8 by immunohystochemical method (two hystochemically by the method of coloring with Kongo red, one by the microscopy in polarised light), 7 by electron microscope, and 5 by PCR method where DNA and RNA of cardiotrophic viruses was used. Out of 10 pts with DCM, in 4 myonecrosis as a consequence of acute myocarditis and in 6 signs of late inflammatory processes, as a consequence of chronic immunologic myocarditis, were found. In 4 of them rebiopsy proved complete healing. In 5 pts with HCM the diagnosis was confirmed hystologically. One bioptate was analysed by electron microscope to rule out mitochondriopathy. Out of 4 pts with RCM due to inflammation, in 3 pathohistological findings proved diagnosis and in one showed primary amyloidosis. In one patient pathohystological finding showed fibroelastosis. In one patient heart tumor (fibroma) has been found.

Mitochondrial myopathy associated with a novel 5522G>A mutation in the mitochondrial tRNA(Trp) gene.

We report a novel pathogenic mutation of the mitochondrial transfer RNA (tRNA) gene for tryptophan in a patient with isolated myopathy and persistently elevated creatine kinase. Muscle studies revealed ragged red fibres and decreased activity of respiratory chain complex I and cytochrome c oxidase (COX). Sequencing of the 22 mitochondrial tRNA genes revealed a mutation m.5522G>A, which alters a conserved base pairing in the D-stem of the tRNA for tryptophan. The mutation was heteroplasmic with a mutational load between 88 and 99% in COX-negative fibres. This case contributes to the genetic heterogeneity of mitochondrial diseases caused by mutations in mitochondrial tRNA genes.

Postintubation tracheal injuries--case series and literature review.

SUMMARY - Post-intubation tracheal injury is a rare and potentially fatal complication. The most common causes are overinflation ofendotracheal tube cuffs and multiple intubation attempts in emergency cases. The diagnosis is based on clinical and radiological suspicion of tracheal injury confirmed by fiberoptic bronchoscopy. Decision between conservative and surgical management of the injury depends on clinical presentation (respiratory instability, concomitant diseases), lesion characteristics (lesion site, size, and number), and time elapsed from injury to diagnosis. We present three cases ofpost-intubation tracheal injury. In two cases, the patients were treated conservatively; in the third case, the patient died from asphyxia caused by thrombus occlusion of the trachea after a longitudinal tracheal lesion. Pre-anesthetic examination did not indicate any possibility of difficult intubation in any of the patients; however, in one of the patients admitted through the emergency department, emergency intubation was performed.

Pituitary metastasis presenting as ischemic pituitary apoplexy following heparin-induced thrombocytopenia.

Pituitary apoplexy (PA) typically results from infarction or hemorrhage in a pituitary adenoma, while PA in nonadenomatous pituitary gland is uncommon. Prothrombotic states have never been recognized as precipitating factors for PA. The authors report a case of an elderly female who received prophylactic fractionated heparin therapy due to sepsis, consequent rhabdomyolysis, and overt disseminated intravascular coagulation. On the seventh day of heparin therapy, she reported sudden vision loss, ptosis, diplopia, and severe headache. Severe thrombocytopenia and positive antibodies to the complex of platelet factor 4 and heparin confirmed heparin-induced thrombocytopenia type 2 (HIT). Magnetic resonance imaging disclosed a homogenous pituitary tumor mass with pronounced sphenoid sinus mucosa thickening and two hypointense zones within the tumor mass on contrast-enhanced images consistent with focal ischemic necrosis. The tumor was confirmed to be squamous cell carcinoma with no signs of necrosis. Ischemic necrosis was found within marginal pituitary tissue. This is the first reported case of ischemic PA associated with pituitary metastasis and the first case in which HIT triggered PA. Our case demonstrates that prothrombotic states such as HIT can precipitate ischemic PA. Pituitary metastasis can present with ischemic PA, but radiological features differ from those described in pituitary adenomas. Segregated low-signal intensity zones within the tumor mass on postcontrast images indicate partial infarction of the tumor, which could be a special feature of ischemic PA in pituitary metastasis and has never been described in pituitary adenomas. These are all novel findings and might enlighten the pathogenesis of PA.

Tumor-like multiple sclerosis.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system. Tumor-like manifestation of multiple sclerosis is one of the rare clinical variants and it is frequently misdiagnosed. This is a report on a 45-year-old man who presented with right-sided hemiparesis. Initial computed tomography and magnetic resonance imaging studies of the brain revealed a large hyperintense signal lesion in the left hemisphere surrounding the cerebral edema. Low grade glioma was among the likely differential diagnoses. The patient underwent surgery. Brain biopsy showed demyelination. Lumbar puncture was performed and cerebrospinal fluid was positive for intrathecal synthesis of immunoglobulins. Other findings were compatible with the unusual form of multiple sclerosis. This case report illustrates a demyelinating process mimicking tumor lesions of the brain and it is of high importance to consider the diagnosis of multiple sclerosis on differential diagnosis of a tumor-like lesion of the central nervous system.