Prognostic Significance of p53 and p63 in Diffuse Large B-Cell Lymphoma: A Single-Institution Experience.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. We evaluated the immunohistochemical (IHC) expression of p63 and p53 in DLBCL and their significance on overall survival (OS) and progression-free survival (PFS). We conducted a retrospective cohort study of 177 patients with DLBCL who presented to Mount Sinai Medical Center of Florida (Miami Beach, Florida) between 2010 and 2020. IHC staining for p63 and p53 protein expression was performed. A significant correlation was found between p63 positivity and p53 expression, p53/p63 co-positivity, Ki-67 proliferation index, MYC expression, and MYC/BCL2 double expression. Regardless of the germinal center B-cell like (GCB) subgrouping, there was a trend among p53+ patients to have MYC/BCL2 double expression, positive MYC expression, and lower OS and PFS. A tendency of poor OS was seen in p53+ patients in the non-GCB, GCB, and double expressors subgroups and poor PFS in p53+ patients regardless of the subgrouping. In conclusion, our results suggest that p63 and p53 may represent potential additional prognostic biomarkers in DLBCL and may be included in the initial diagnostic work up of patients with DLBCL.

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.

Hemophagocytic Lymphohistiocytosis in the Setting of Therapy-Induced Acute Myeloid Leukemia: An Autopsy Report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory disorder that occurs due to immunologic dysregulation. HLH can be primary (hereditary) or secondary to infections, autoimmune diseases, immune deficiencies, metabolic diseases, drugs, or malignancies. Lymphoid neoplasms mostly accompany malignancy-associated HLH. We present a case of a 12-year-old boy with a history of precursor B lymphoblastic leukemia (B-ALL), who subsequently developed chemotherapy-induced acute myeloid leukemia (t-AML). The patient was admitted for febrile neutropenia and initial laboratory tests revealed hemophagocytic lymphohistiocytosis (HLH). The hospital course was complicated by multiple infections and septic shock. The patient received several broad-spectrum antimicrobials, dexamethasone, as well as a pericardial drain to drain the hemorrhagic pericardial effusion. Despite intervention, the patient expired, and an autopsy was performed. We provide a synopsis of the main autopsy findings.

Clinical, histopathologic, and immunoarchitectural features of dermatopathic lymphadenopathy: an update.

Dermatopathic lymphadenopathy is a distinctive form of paracortical lymph node hyperplasia that usually occurs in the setting of chronic dermatologic disorders. The aim of this study is to update our understanding of the clinicopathologic and immunophenotypic features of dermatopathic lymphadenopathy. The study cohort was 50 lymph node samples from 42 patients diagnosed with dermatopathic lymphadenopathy. The patients included 29 women and 13 men with a median age of 49 years (range, 12-79). Twenty-two (52%) patients had a dermatologic disorder, including mycosis fungoides (n = 6), chronic inflammatory dermatoses (n = 13), melanoma (n = 1), squamous cell carcinoma (n = 1), and Kaposi sarcoma in the context of human immunodeficiency virus infection (n = 1). Twenty (48%) patients did not have dermatologic manifestations. Lymph node biopsy specimens were axillary (n = 22), inguinal (n = 21), cervical (n = 4), and intramammary (n = 3). All lymph nodes showed paracortical areas expanded by lymphocytes; dendritic cells, including interdigitating dendritic cells and Langerhans cells; and macrophages. Melanophages were detected in 48 (98%) lymph nodes. Immunohistochemical analysis provided results that are somewhat different from those previously reported in the literature. In the paracortical areas of lymph node, S100 protein was expressed in virtually all dendritic cells, and CD1a was expressed in a significantly greater percentage of cells than langerin (80 vs. 35%, p < 0.0001). These results suggest that the paracortical regions of dermatopathic lymphadenopathy harbor at least three immunophenotypic subsets of dendritic cells: Langerhans cells (S100+, CD1a+(high), langerin+), interdigitating dendritic cells (S100+, CD1a+(low), langerin-), and a third (S100+, CD1a-, langerin-) minor population of dendritic cells. Furthermore, in more than 60% of dermatopathic lymph nodes, langerin highlighted trabecular and medullary sinuses and cords, showing a linear and reticular staining pattern, which could be a pitfall in the differential diagnosis with Langerhans cell histiocytosis involving lymph nodes.

Pontocerebellar Hypoplasia Maps to Chromosome 7q11.23: An Autopsy Case Report of a Novel Genetic Variant.

Pontocerebellar hypoplasias are a group of autosomal recessive neurodevelopmetal disorders with varied phenotypic presentations and extensive genetic mutational landscape that are currently classified into ten subtypes. This classification is based predominantly on the genetic iterations as the phenotypic presentations are often broad and overlapping. Pontocerebellar hypoplasia type-3 (PCH3) is an autosomal recessive disorder characterized by a small cerebellar vermis, hyperreflexia, and seizures, described in Middle Eastern families in association with a homozygous truncating mutation of the PCLO gene in locus 7q11-21. This is a case of PCH, with previously unreported novel genetic alterations. The patient is a 1-week-old girl, born at term to a 26-year-old G4P0A3 woman in a nonconsanguinous relation. At birth, the baby was depressed and hypertonic with abnormal tonic-clonic movements of extremities. MRI revealed cerebellar and brainstem hypoplasia. Postmortem examination revealed a palmar simian crease. The cerebellum measured 2.5 cm from side to side and 1 cm from rostral to caudal. The vermis was rudimentary. Sectioning revealed a flattened linear fourth ventricle, scant abortive cerebellar foliae, and a markedly small cerebellum when compared with the cerebrum and with age-matched size. H&E-stained sections of cerebellum revealed scant rudimentary foliae. A rudimentary unilateral embolliform nucleus was identified. The remaining cerebellar nuclei were absent. Chromosomal microarray showed an interstitial duplication of 841 kB on chromosome 7q11.23. Locus 7q11.23 contains FGL2 and GSAP genes and is 5 MB upstream of the 7q11-21 region, suggesting a possible linkage. This novel genomic finding possibly represents a new familial variant of PCH closely associated with PCH-3 and further strengthens its association with the 7q11 locus.

Spontaneous perforation of small intestine followed by rupture of the cystic artery: the natural history of Vascular Ehlers-Danlos Syndrome.

Vascular Ehlers-Danlos Syndrome (VEDS) is a rare autosomal dominant disorder caused by mutations in the COL3A1 or COL1A1 genes. Its mortality is secondary to sudden and spontaneous rupture of arteries or hollow organs. The genotype influences the distribution of arterial pathology with aneurysms of intra-abdominal visceral arteries being relatively uncommon. We describe the case of a young man with probable VEDS who died of a spontaneous rupture and dissection of the cystic artery. The patient initially presented with abdominal pain due to an unrecognized spontaneous perforation of the small intestine complicated by sepsis. We postulate that inflammatory mediators may have triggered the arterial rupture due to remodeling and weakening of vessel walls. The phenotype of the patient's vascular damage included bilateral spontaneous carotid-cavernous sinus fistulae and dissection with pseudoaneurysm formation of large- and medium-sized arteries, predominantly the abdominal aorta and its branches. The autopsy uncovered a long history of vascular events that may have been asymptomatic. These findings along with a positive family history supported the VEDS diagnosis. Loeys-Dietz, Marfan, and familial thoracic aortic aneurysm and dissection syndromes were ruled out based on the absence of arterial tortuosity, eye abnormalities, bone overgrowth, and the distribution of vascular damage among other features. Interestingly, microscopic examination of the hippocampus revealed a focus of neuronal heterotopia, commonly associated with epilepsy; however, the patient had no history of seizures. The natural course of VEDS involves the rupture and dissection of arteries that, if unrecognized, can lead to a rapid death after bleeding into free spaces.

Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry.

Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.

Strong desmin expression in a congenital desmoplastic infantile ganglioglioma mimicking pleomorphic rhadomyosarcoma: a case report including ultrastructural and cytogenetic evaluation and review of the literature.

PURPOSE: Desmoplastic infantile gangliogliomas (DIGs) are rare tumors of infancy. Herein, we describe an unusual case of DIG diagnosed by prenatal ultrasound. METHODS: This 5-day-old newborn was delivered after a prenatal ultrasound revealed a large cystic mass in the left cerebral hemisphere along with an echogenic solid component. RESULTS: The tumor revealed a glial and neuronal proliferation in a background of desmoplasia more typical of DIG and a minor component with a more primitive, immature appearance to the glioneuronal elements. A significant component of the tumor was composed of pleomorphic eosinophilic spindle cells in whorls and interlacing fascicles that showed a strong, sharp, and diffuse positivity for desmin, thus mimicking rhabdomyosarcoma. However, the tumor cells were GFAP (+), INI-1 (+), and myogenin (-). Mitoses were seen both in the more spindle cell astroglial areas as well as the more primitive neuroepithelial cells. The MIB-1 proliferation index was brisk, exceeding 15 %, and in areas it was estimated to be as high as 30 %. Such high proliferation index has been described and accepted in the more primitive neuroepithelial areas, but not in the terminally differentiated, spindle cell astroglial areas as in our case. Our patient was incidentally diagnosed prenatally. To our knowledge, this case is the first documented congenital DIG diagnosed prenatally. CONCLUSIONS: This case highlights the pitfalls in diagnosing DIG, which can mimic a rhabdomyosarcoma. Furthermore, it underscores the importance of re-evaluating the grading of these tumors or at least segregating the variants where the prognosis may be more guarded.

Balamuthia mandrillaris and Acanthamoeba amebic encephalitis with neurotoxoplasmosis coinfection in a patient with advanced HIV infection.

We describe a patient with advanced HIV infection and Balamuthia mandrillaris and Acanthamoeba amebic encephalitis with Toxoplasma gondii coinfection. A multidisciplinary effort and state-of-the-art diagnostic techniques were required for diagnosis. Our patient is the first reported case of an HIV-infected person with dual Balamuthia mandrillaris and Acanthamoeba amebic encephalitis with neurotoxoplasmosis coinfection.

Medically intractable epilepsy in Sturge-Weber syndrome is associated with cortical malformation: implications for surgical therapy.

PURPOSE: Anecdotal reports have described cortical malformations in epileptic patients with Sturge-Weber syndrome (SWS). No data are available regarding the prevalence and significance of this association. METHODS: We reviewed retrospectively the clinical profile, preoperative magnetic resonance imaging (MRI) studies, and pathology reports of all patients with SWS and medically intractable epilepsy evaluated in our epilepsy surgery program between 1979 and 2006. RESULTS: Twelve patients (male/female = 7/5) were identified. Mean age at seizure onset was 11.1 +/- 16.7 months. Seizures occurred daily in seven patients and weekly in five patients. A facial port-wine stain was noted in 10 cases. Eleven patients evidenced developmental delay and eight were hemiparetic. Eight patients underwent excisional surgery for epilepsy (mean age 10.3 +/- 6.5 year), including hemispherectomy (n = 4) and focal cortical resection (n = 4). Tissue was available for neuropathology in six operated cases and revealed polymicrogyria (n = 3) and cortical dysplasia (n = 4). Polymicrogyria was associated with cortical dysplasia in one child. Brain MRIs were reviewed in 10 of 12 patients and were consistent with cortical malformations in all cases. CONCLUSIONS: We conclude that cortical malformations are frequent in patients with medically intractable epilepsy and Sturge-Weber-syndrome and may be the primary cause of epilepsy.

Von Hippel-Lindau (VHL) disease: an update on the clinico-pathologic and genetic aspects.

von Hippel-Lindau (VHL) disease is an inherited multisystem familial cancer syndrome caused by mutations of the VHL gene on chromosome 3p25. A wide variety of neoplastic processes are known to be associated with VHL disease. The consequences of the VHL mutations and the pathway for tumor development continue to be elucidated. This paper will detail the variety of tumors associated with VHL disease and discuss the genetic mechanisms that lead to the predisposition for neoplasia.

Congenital glioblastoma: a clinicopathologic and genetic analysis.

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP-positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long-term survivors received chemotherapy, whereas the three short-term survivors did not. Paraffin-embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.

Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population.

Necrosis and vascular proliferation are the pathologic features that distinguish the most malignant infiltrative astrocytoma, glioblastoma (GBM), from those of lower grades. In GBM, hypercellular zones called pseudopalisades typically surround necrotic foci. Although these cells are known to secrete high levels of proangiogenic factors that promote tumor growth, their origins are ill defined. We propose that pseudopalisades represent differing stages and histologic samplings of astrocytoma cells migrating away from a hypoxic/anoxic focus, often triggered by a central vaso-occlusive event. This proposition is based on our findings that pseudopalisading cells are 5-50% less proliferative and 6-20 times more apoptotic than adjacent astrocytoma, indicating that cell accumulation does not result from increased proliferation or resistance to apoptosis. Coexisting inflammatory cells account for <2% of pseudopalisading cells and cannot account for hypercellularity. Pseudopalisading cells show nuclear expression of hypoxia-inducible factor 1 alpha, consistent with their hypoxic nature, and hypoxia induces a 20-60% increase in glioma cell migration in vitro. Hypoxic cells in vitro and pseudopalisades in GBM specimens show enhanced gelatinase activity, typical of an invasive phenotype. These results suggest that pseudopalisading cells are migrating at the periphery of a hypoxic center. To uncover a potential source of hypoxia and sequence of structural events leading to pseudopalisade formation, we performed a morphometric analysis of 234 pseudopalisades from 85 pretreatment GBMs. We found distorted, degenerating, or thrombosed blood vessels within the center of more than half the pseudopalisades, suggesting that at least a subset of pseudopalisades are two-dimensional histologic representations of tumor cells migrating away from a vaso-occlusive event.

Primary central nervous system posttransplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorders (PTLDs) represent a spectrum ranging from Epstein-Barr virus (EBV)-driven polyclonal lymphoid proliferations to EBV+ or EBV- malignant lymphomas. Central nervous system (CNS) PTLDs have not been characterized fully. We reviewed the clinical, radiologic, and pathologic features of 12 primary CNS PTLDs to define them more precisely. Patients included 10 males and 2 females (median age, 43.4 years) who were recipients of kidney (n = 5), liver (n = 2), heart (n = 2), peripheral blood stem cells (n = 2), or bone marrow (n = 1). All received immunosuppressive therapy. CNS symptoms developed 3 to 131 months (mean, 31 months) after transplantation. By neuroimaging, most showed multiple (3 to 9) intra-axial, contrast-enhancing lesions. Histologic sections showed marked expansion of perivascular spaces by large, cytologically malignant lymphoid cells that were CD45+, CD20+, EBV+ and showed light chain restriction or immunoglobulin gene rearrangement. In distinction to PTLDs in other organ systems, CNS PTLDs were uniformly high-grade lymphomas that fulfilled the World Health Organization criteria for monomorphic PTLDs. Extremely short survival periods were noted for each CNS PTLD that followed peripheral blood stem cell transplantation. Survival of others with CNS PTLD varied; some lived more than 2 years.

Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.

The SOD1 mutant mouse is the most widely used model of human amyotrophic lateral sclerosis (ALS). To determine where and when the pathological changes of motor neuron disease begins, we performed a comprehensive spatiotemporal analysis of disease progression in SOD1(G93A) mice. Quantitative pathological analysis was performed in the same mice at multiple ages at neuromuscular junctions (NMJ), ventral roots, and spinal cord. In addition, a patient with sporadic ALS who died unexpectedly was examined at autopsy. Mice became clinically weak at 80 days and died at 131 +/- 5 days. At 47 days, 40% of end-plates were denervated whereas there was no evidence of ventral root or cell body loss. At 80 days, 60% of ventral root axons were lost but there was no loss of motor neurons. Motor neuron loss was well underway by 100 days. Microglial and astrocytic activation around motor neurons was not identified until after the onset of distal axon degeneration. Autopsy of the ALS patient demonstrated denervation and reinnervation changes in muscle but normal appearing motor neurons. We conclude that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.

May 2003: 57-year-old-woman with acute loss of strength in her right upper extremity and slurred speech.

The May 2003 COM. A 57-year-old woman presented with slurring of her speech and right arm weakness. Her past medical history included idiopathic hypertrophic subendocardial stenosis (IHSS), arthritis, asthma, congestive heart failure, hypertension and NIDDM. Neurological examination showed persistent word finding difficulty but her motor and sensory function had essentially returned to normal. Extensive laboratory studies were unrevealing. Imaging studies showed a meningeal lesion over the left posterior parietal lobe and the findings suggested an infectious or inflammatory process. A biopsy of the involved dura and meninges was performed and revealed leptomeningeal Rosai-Dorfman disease. Emperipolesis was noted. The finding of emperipolesis is characteristic of Rosai-Dorfman disease of the leptomeninges, but in 30% of cases, this feature will not be identified. Large pale histiocytes of Rosai-Dorfman disease are immunoreactive for S-100 protein and KP1, but negative for CD1a. The differential diagnosis of a chronic inflammatory infiltrate containing numerous, large histiocytes includes granulomatous diseases such as Wegener graulomatosis and sarcoid, Hodgkin disease, and Langerhans histiocytosis. CNS Rosai-Dorfman most commonly involves patients between 20- and 40-years-old, with a slight male predominance. Approximately 75% of cases are intracranial, whereas 20% involve the spine. Over 90% of CNS Rosai-Dorfman cases involve the leptomeninges and are seen by neuroimaging as a dural-based, contrast-enhancing masses that often elicit vasogenic edema in the underlying brain. Thus, clinically and radiologically, the disease is thought to represent meningioma. Leptomeningeal Rosai-Dorfman disease is considered a benign condition and in most cases surgical resection is the treatment of choice. Although the number of cases in the literature is small, disease progression following surgical resection is uncommon. Little is known regarding the pathogenesis of Rosai-Dorfman disease. Most have suggested that it represents either an autoimmune disease or a reaction to an infectious agent that has yet to be discovered. Currently it is best considered a benign, idiopathic histiocytosis.