Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma.

Glioblastoma (GBM) is the most aggressive brain tumor, with a median survival of ∼15 months. Targeted approaches have not been successful in this tumor type due to the large extent of intratumor heterogeneity. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. To uncover the relationships between genetically diverse subpopulations of GBM cells and their native tumor microenvironment, we employ highly multiplexed spatial protein profiling coupled with single-cell spatial mapping of fluorescence in situ hybridization (FISH) for EGFR, CDK4, and PDGFRA. Single-cell FISH analysis of a total of 35,843 single nuclei reveals that tumors in which amplifications of EGFR and CDK4 more frequently co-occur in the same cell exhibit higher infiltration of CD163+ immunosuppressive macrophages. Our results suggest that high-throughput assessment of genomic alterations at the single-cell level could provide a measure for predicting the immune state of GBM.

RETRACTED: Bahmad et al. Histopathologic Findings Associated with Miller-Dieker Syndrome: An Autopsy Report. Diseases 2022, 10, 95.

The Journal retracts the article, Histopathologic Findings Associated with Miller-Dieker Syndrome: An Autopsy Report [...].

Histopathologic Findings Associated with Miller-Dieker Syndrome: An Autopsy Report.

Miller-Dieker syndrome (MDS) is a rare genetic disorder characterized by congenital lissencephaly (absent or diminished cerebral gyri), facial dysmorphisms, neurodevelopmental retardation, intrauterine fetal demise, and death in early infancy or childhood. We present a case of a 4-year-old girl with MDS (17p13.3p13.2 deletion) who was admitted to the hospital due to fever and increased secretions from her nose, mouth, and tracheostomy tube (as she had been on a ventilator and G-tube dependent since birth). During the course of hospitalization, she developed multiorgan failure, third spacing, and significant lactic acidosis. The patient had a cardiorespiratory arrest and expired after 4 months and 8 days of hospitalization. We provide a synopsis of the main autopsy findings, with a focus on the neuropathologic anomalies.

Pulmonary Granulomas and Mycobacterial Infection: Concordance between the Results of Special Stains Performed on Lung Tissue Sections and Tissue Cultures.

Background: The most common cause of infectious pulmonary granulomas worldwide is Mycobacterium tuberculosis. The diagnosis is based on clinical presentation, histopathologic findings, detection of acid-fast bacilli (AFB) in tissue or sputum using special stains, and/or isolation of mycobacteria in cultures or via PCR-based methods. Different studies have shown that high levels of discrepancy exist between these diagnostic approaches in lung tissue specimens. Objective: To assess the degree of concordance between the results of special stains and cultures on lung tissue specimens in the diagnosis of mycobacterial infections. Methodology: Eighty-seven patients with a diagnosis of granulomas (necrotizing and non-necrotizing) on lung tissue specimens were identified. Cohen's kappa was used to measure the general concordance between the results of the histopathological examination (special stains) and bacteriological tissue cultures. Results: With Kinyoun acid-fast stains, 8/48 (16.7%) cases were positive for AFB. With FITE stains, 10/57 (17.5%) cases were positive for AFB. There was strong agreement between Kinyoun acid-fast and FITE stains (Kappa = 0.806; p-value < 0.001). Tissue cultures were performed on 38/87 cases (43.7%), and 10/38 (26.3%) of the cultures were positive for mycobacteria. There was no concordance between Kinyoun acid-fast stains or FITE stains and tissue cultures results. Conclusion: Our observations represent an initial step in the process of reviewing the two methods used at our institution to diagnose mycobacterial infections on lung tissue specimens and highlight the need of incorporating more advanced diagnostic methods such as PCR to confirm mycobacterial infections and improve patient management. Importantly, species-level identification of mycobacteria is necessary to guide treatment.

Intraosseous meningioma mimicking osteosarcoma.

BACKGROUND: Predominantly intraosseous meningiomas are rare entities that include true primary intraosseous meningiomas (PIM), as well as meningiomas that may show extensive bone involvement, such as en plaque meningiomas. Different hypotheses have been proposed to decipher the origin of PIMs, such as ectopic arachnoid cap cell entrapment during birth or after trauma. Surgical resection is the treatment of choice of such lesions. CASE PRESENTATION: We present a case of a 65-year-old man with an enlarging mass in the parieto-occipital region that grew slowly and progressively over 13 years, following head trauma during a motor vehicle accident. One year prior to presentation, he started experiencing daily holocranial headaches and blurry vision. CT and MRI studies revealed a permeative midline calvarial lesion measuring 14 cm in greatest dimension with extensive periosteal reaction, extension into the subcutaneous soft tissues, subjacent dural thickening and intracranial extension with invasion of the superior sagittal sinus. The favored pre-operative clinical diagnosis was osteosarcoma. The abnormal calvarium was excised and histopathological examination confirmed the diagnosis of a predominantly intraosseous calvarial meningioma, WHO grade I. CONCLUSIONS: The present case highlights the importance of histopathologic diagnosis in guiding therapeutic decisions and reiterates the necessity of considering PIM or meningiomas with extensive intraosseous component in the differential diagnosis of calvarial masses, even when imaging suggests a neoplasm with aggressive behavior, such as osteosarcoma.

Intraosseous meningioma mimicking osteosarcoma

Background Predominantly intraosseous meningiomas are rare entities that include true primary intraosseous meningiomas (PIM), as well as meningiomas that may show extensive bone involvement, such as en plaque meningiomas. Different hypotheses have been proposed to decipher the origin of PIMs, such as ectopic arachnoid cap cell entrapment during birth or after trauma. Surgical resection is the treatment of choice of such lesions. Case presentation We present a case of a 65-year-old man with an enlarging mass in the parieto-occipital region that grew slowly and progressively over 13 years, following head trauma during a motor vehicle accident. One year prior to presentation, he started experiencing daily holocranial headaches and blurry vision. CT and MRI studies revealed a permeative midline calvarial lesion measuring 14 cm in greatest dimension with extensive periosteal reaction, extension into the subcutaneous soft tissues, subjacent dural thickening and intracranial extension with invasion of the superior sagittal sinus. The favored pre-operative clinical diagnosis was osteosarcoma. The abnormal calvarium was excised and histopathological examination confirmed the diagnosis of a predominantly intraosseous calvarial meningioma, WHO grade I. Conclusions The present case highlights the importance of histopathologic diagnosis in guiding therapeutic decisions and reiterates the necessity of considering PIM or meningiomas with extensive intraosseous component in the differential diagnosis of calvarial masses, even when imaging suggests a neoplasm with aggressive behavior, such as osteosarcoma.

Paraduodenal Pancreatitis: A Deceptive Abdominal Mass with Unique Histologic Findings.

Paraduodenal pancreatitis (PP) is an uncommon abdominal pathology characterized by scarring of the pancreaticoduodenal space. Diagnosis of this inflammatory process is challenging as its clinical presentation is similar to that of pancreatic cancer. Currently, no definitive radiologic or pathologic features have been established to permit diagnosis of PP without surgical resection. However, the presence of eosinophilic concretions has been reported with increasing frequency in the histologic evaluation of PP. To the best of our knowledge, these concretions are distinctive for PP and not reported in neoplasms commonly involving the pancreaticoduodenal space. Herein, we discuss the case of a 60-year-old man who was found to have PP after pancreaticoduodenectomy for a paraduodenal mass with an initially nondiagnostic biopsy. Retrospective review of the preoperative FNA samples revealed eosinophilic concretions like those found in the final surgical specimen. If the identification of eosinophilic concretions in a background of inflammatory changes was to be accepted as a diagnostic criterion for PP, patients such as ours could be spared the morbidity associated with surgical resection.

Recurrent metastatic breast cancer manifesting as pulmonary tumor thrombotic microangiopathy with interstitial pulmonary fibrosis and infarcts: A clinicopathological correlation.

Pulmonary Tumor Thrombotic Microangiopathy (PTTM) is a fatal complication of malignancy characterized by embolization of tumor cells to the pulmonary vasculature leading to a vascular reaction resulting in stenosis and pulmonary hypertension. Because the clinical manifestations of PTTM overlap with those of other entities, premortem diagnosis is challenging. We describe an unusual case of PTTM as the only clinical manifestation of recurrent metastatic breast cancer. A 50 year-old woman presented with hypoxemia and echocardiographic findings consistent with pulmonary hypertension and cor pulmonale. Correlation of premortem pulmonary imaging with autopsy histopathologic findings revealed that ill-defined ground-glass opacities identified on CT angiogram corresponded to areas of cellular interstitial fibrosis and widespread intrapulmonary tumor emboli involving predominantly small-sized arteries with associated florid intimal fibrosis. The radiologic nodularities and scattered peripheral wedge-shaped consolidations corresponded to evolving pulmonary infarcts on histopathology. Although retrospectively, the imaging findings were concordant with a spectrum of increasing severity of tumor embolization and vascular remodeling, the diagnosis of PTTM was not made premortem. PTTM is a rare entity that must be considered in cancer patients with unexplained hypoxemia, pulmonary hypertension and lung opacities on imaging.

The anatomic substrate of irreversible airway obstruction and barotrauma in a case of hurricane-triggered fatal status asthmaticus during puerperium: Lessons from an autopsy.

Non-fully reversible airway obstruction in fatal asthma is often seen in association with profound structural changes of the bronchial wall, termed airway remodeling. Evidence suggests that heavy precipitation events can trigger epidemics of severe asthma. We present a case of fatal asthma in a young woman with no prior near-fatal exacerbations and postulate that the patient's extensive airway remodeling and puerperal state (susceptibility factors), in combination with a massive allergen challenge during a hurricane landfall (triggering factor), played a central role in her death. The autopsy revealed diffuse obstruction of proximal and distal bronchi by mucous plugs together with transmural chronic inflammation, tissue eosinophilia, extensive goblet cell hyperplasia with MUC-5 expression and airway smooth muscle (ASM) thickening. The observed distribution of airway remodeling was heterogeneous with sparing of the lingula, which exhibited hyperinflation and expansion of perivascular spaces indicative of dissecting air. The massive stagnation of mucus and significant inter-airway structural heterogeneity created an anatomical substrate for unequal airflow distribution facilitating the development of barotrauma. Although not considered conventional risk factors for fatal asthma, we believe that in this case, the patient's puerperal state in conjunction with an extreme environmental event dispersing aeroallergens were major contributors to the development of a fatal asthma attack. Our autopsy findings suggest that effective strategies to evacuate stagnated mucus and induce relaxation of thickened ASM are crucial in the management of life-threatening asthma exacerbations.

Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system.

Pituicytoma is a rare low-grade glial neoplasm that originates in the distribution of the neurohypophysis, including the posterior pituitary lobe and infundibular stalk. The tumor cells resemble pituicytes, which are specialized glial cells of the neurohypophysis. Pituicytoma can be misdiagnosed pre-operatively as a pituitary adenoma due to overlapping clinical and neuroimaging features between these two entities. Pituicytoma can also mimic other neoplasms of the sellar and parasellar regions microscopically - meningioma, schwannoma and pilocytic astrocytoma - and shares immunohistochemical expression of TTF-1 with spindle cell oncocytoma and granular cell tumor of the sellar region, suggesting a common histogenesis. In this short review, we present the key features of pituicytoma, discuss commonalities and distinguishing features from other neoplasms of the sellar and parasellar regions and highlight the importance of recognizing this tumor entity for clinical and surgical management.

Acute gastric volvulus: a deadly but commonly forgotten complication of hiatal hernia.

Gastric volvulus is a rare condition resulting from rotation of the stomach beyond 180 degrees. It is a difficult condition to diagnose, mostly because it is rarely considered. Furthermore, the imaging findings are often subtle resulting in many cases being diagnosed at the time of surgery or, as in our case, at autopsy. We present the case of a 76-year-old man with an extensive medical history, including coronary artery disease with multiple bypass grafts, who became diaphoretic and nauseated while eating. His presumptive diagnosis at arrival to the hospital was an acute coronary event; however, his initial cardiac work-up was negative. A computed tomography scan revealed a type III hiatal hernia. The following day, after consistent complaints of nausea and episodes of nonbloody emesis, he suddenly became hypotensive, tachycardic and had an episode of coffee-ground emesis. Subsequently, the patient's condition suddenly deteriorated and resuscitation attempts were unsuccessful. The autopsy revealed a partially sliding hiatal hernia, which was consistent with the radiologic impression. Additionally, a gastric volvulus was present with extensive, focally transmural necrosis involving the body/fundus. Gastric volvulus is a rare entity with variable, nonspecific clinical presentations, which requires a high level of suspicion for radiologic diagnosis. Acute cases have a high mortality rate and require emergency surgery. This case highlights the value of autopsy in the diagnosis of unsuspected cases of gastric volvulus when death occurs prior to surgical intervention.

Pituitary carcinoma in situ.

OBJECTIVE: Pituitary carcinomas are extremely rare tumors associated with poor prognosis despite surgery, radiation, and chemotherapy. The hallmark of diagnosis implies subarachnoid, brain, or systemic tumor spread. METHODS: We report a case of rapid transformation of atypical nonfunctioning pituitary adenoma to a carcinoma. RESULTS: A 64-year-old woman presented with sudden onset of ophthalmoplegia. Magnetic resonance imaging (MRI) scan showed a pituitary macroadenoma (2.2 x 2.1 cm) with invasion of the right cavernous sinus. Biochemical data was consistent with a nonfunctioning pituitary adenoma. Pathology showed a pituitary adenoma with negative immunohistochemistry for pituitary hormones. The patient returned a month later with weakness, lethargy, and a dilated nonreactive right pupil. MRI showed an invasive large mass (5 x 4.7 cm). After an emergent second transsphenoidal surgery, histopathologic examination revealed a widely infiltrative neoplasm invading the overlying mucosa and showing a high mitotic activity and necrosis and a very high Ki-67 (MIB-1) proliferation index (80%). MIB-1 retrospectively performed on the first specimen was also elevated (30%). Soon after the second surgery, MRI showed a 7.9 x 8.0 cm mass that metastasized to dura mater and extended into the right orbit, right middle cranial fossa, nasopharynx, clivus, posterior fossa, and along the right tentorium cerebelli, resulting in significant compression of the brainstem. CONCLUSION: Development of a pituitary carcinoma from an adenoma is an exceptional occurrence and predictors of such course are currently lacking. A very high Ki-67 proliferation index should raise concern of a pituitary carcinoma in situ or premetastatic carcinoma.

Glioblastoma with oligodendroglioma component (GBM-O): molecular genetic and clinical characteristics.

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics.

Transformation of a Silent Adrencorticotrophic Pituitary Tumor Into Central Nervous System Melanoma.

Silent adrenocorticotrophic pituitary adenomas are nonfunctioning pituitary adenomas that express adrenocorticotrophic hormone (ACTH) but do not cause the clinical or laboratory features of hypercortisolemia. Primary central nervous system (CNS) melanoma is well documented, but rarely originates in the sellar region or pituitary gland. Here we report transformation of an aggressive silent adrenocorticotrophic pituitary adenoma that transformed into CNS melanoma and review other presentations of pituitary melanoma. A 37-year-old woman initially presented with apoplexy and an invasive nonfunctioning pituitary macroadenoma for which she underwent transphenoidal surgery. The patient underwent 3 subsequent surgeries as the tumor continued to progress. Pathology from the first 3 operations showed pituitary adenoma or carcinoma. Pathology from the final surgery showed melanoma and the magnetic resonance imaging characteristics of the tumor had changed to become consistent with CNS melanoma. Dermatologic and ophthalmologic examinations did not identify cutaneous or ocular melanoma. The patient's disease progressed despite aggressive surgical, medical and radiologic treatment. To our knowledge, this is the first report demonstrating transformation of a primary pituitary tumor into melanoma. The mechanism of tumor transformation is unclear, but it is possible that a mutation in the original ACTH-producing tumor lead to increased cleavage of pro-opiomelanocortin or ACTH into α-melanocyte-stimulating hormone, which in turn stimulated the expression of microopthalmia transcription factor, leading to melanocytic phenotype transformation.

The use of neuroimaging to guide the histologic diagnosis of central nervous system lesions.

Recent advances in neuroimaging techniques, particularly in magnetic resonance imaging, have led to substantially improved spatial anatomic resolution such that subtle or small central nervous system lesions, which could go undetected on gross examination of brain sections, are now readily identified on imaging. Although neuroimaging is generally considered the surrogate of gross neuropathology, it is still not a substitute for tissue diagnosis. Rather, it can be a valuable tool for the surgical pathologist in the process of formulating a differential diagnosis based on location and imaging features, as well as in identifying radiologic/pathologic discordance, such as the possible undersampling of a heterogenous glioma, which could lead to underestimation of the tumor grade. The following review focuses on the application of neuroimaging techniques, mainly magnetic resonance imaging, to the histologic diagnosis of central nervous system lesions, and the correlation of imaging features of infiltrative gliomas with histologic findings pertinent to tumor grading. The use of advanced functional magnetic resonance methods, specifically diffusion-weighted imaging, perfusion-weighted imaging, and magnetic resonance spectroscopy is also discussed, as well as the common pitfalls in imaging interpretation.

35-year-old HIV-positive woman with Basal forebrain mass.

A 35-year-old African American woman with HIV/AIDS presented with altered mental status. A CT of the head revealed an infiltrating hypodense intra-axial mass within the basal forebrain. Lumbar puncture showed a lymphocytic pleocytosis, elevated protein and low glucose. PCR analysis of the CSF was negative for Mycobacterium tuberculosis, HSV, VZV, CMV and JC virus. There was low positivity for EBV DNA. Serologic studies were consistent with past infections with EBV and CMV and were negative for toxoplasmosis, histoplasmosis, Cryptococcus and West Nile virus. VDRL was non-reactive. CSF and blood cultures were negative. She soon expired. Post-mortem examination of the patient's brain showed a poorly delineated area of softening and hemorrhage within the basal forebrain. Histologic examination revealed necrotizing encephalitis with perivascular lymphocytes and glial cells with numerous cytoplasmic and intranuclear inclusions. Immunohistochemistry was strongly positive for adenovirus and negative for HSV, CMV, SV40 and EBV. Electron microscopy confirmed the presence virions consistent with adenovirus. We conclude that adenovirus is a rare and sometimes unsuspected cause of encephalitis that may present as a forebrain mass lesion.