Histopathologic Classification Schemes Research Articles

Clinical Identification of Oncogenic Drivers and Copy-Number Alterations in Pituitary Tumors.

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone-secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials.

Prognostic Value of Histologic Classification of ANCA-Associated Glomerulonephritis.

A kidney biopsy is preferred for the diagnosis of ANCA-associated vasculitis with renal involvement. The aim of our study was to evaluate the prognostic value of a histopathologic classification scheme recently proposed by an international consortium of renal pathologists in a large Norwegian cohort. Patients diagnosed with ANCA-associated GN were included from the Norwegian Kidney Biopsy Registry 1991-2012. Renal morphology was classified as focal, mixed, crescentic, or sclerotic. Study end point was ESRD. Patients were followed from kidney biopsy to end of 2012. Two hundred fifty patients with ≥10 glomeruli in the biopsy were included in our study. During a median follow-up of 3.5 years (0.7-7.6), 60 cases of ESRD occurred. Ninety-six (38%) biopsies were classified as focal, 61 (24%) biopsies were classified as mixed, 71 (28%) biopsies were classified as crescentic, and 22 (9%) biopsies were classified as sclerotic; 1- and 5-year cumulative renal survival rates were 96% and 90%, respectively, for the focal class, 86% and 75%, respectively, for the mixed class, 81% and 69%, respectively, for the crescentic class, and 56% and 51%, respectively, for the sclerotic class. By multivariate Cox regression analyses, the sclerotic class had a significantly worse renal prognosis than the focal (hazard ratio, 9.65; 95% confidence interval, 2.38 to 39.16) or combined mixed/crescentic classes (hazard ratio, 3.27; 95% confidence interval, 1.41 to 7.61), but no significant differences in outcome were observed in the crescentic class compared with the mixed class (hazard ratio, 1.13; 95% confidence interval, 0.44 to 2.87) or the combined mixed/crescentic class compared with the focal class (hazard ratio, 1.93; 95% confidence interval, 0.61 to 6.12). Accuracy by receiver operator characteristic curve analysis was estimated to be 0.72 (95% confidence interval, 0.65 to 0.80). In 108 additional patients with three to nine glomeruli in the biopsy, the prognostic value of this classification scheme was unchanged. The histopathologic classification is a predictor of renal outcome of moderate quality. Merging the mixed and crescentic classes in the future could simplify the scheme.

Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.

Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

Clinicopathologic characteristics and outcomes of renal thrombotic microangiopathy in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis.

Thrombotic microangiopathy (TMA) in ANCA-associated vasculitis (AAV) has been mainly reported in isolated case reports. The aim of this study was to analyze clinical and pathologic characteristics and prognosis of patients with renal TMA in ANCA-associated GN in a large cohort of Chinese patients. Clinical and renal histopathologic data of 220 patients with biopsy-proven ANCA-associated GN from 1996 to 2013 were retrospectively analyzed. Patients were followed up for a median period of 32 (interquartile range [IQR], 12-65) months, and outcomes of patients were analyzed. Among the 220 patients with ANCA-associated GN, 30 were identified having concomitant renal TMA by pathologic evaluation. Compared with the non-TMA group, patients with renal TMA presented with more severe renal injury, as evidenced clinically by a higher level of serum creatinine at diagnosis (5.0 [IQR, 3.5-9.0] versus 3.2 [IQR, 1.7-6.8] mg/dl; P=0.02) and pathologically by a higher percentage of cellular crescents (15.0% [IQR, 6.9%-34.9%] versus 6.9% [IQR, 0%-21.1%]; P=0.04) and more severe interstitial infiltration (2 [IQR, 2-2] versus 2 [IQR, 1-2]; P=0.03) in renal biopsies. Furthermore, multivariate analysis showed that renal TMA was independently associated with mortality of patients with AAV after adjusting for age, sex, initial serum creatinine, tubular atrophy, and interstitial fibrosis (hazard ratio, 1.92; 95% confidence interval, 1.08 to 3.41; P=0.03) or for age, sex, the histopathologic classification scheme proposed by Berden et al. (J Am Soc Nephrol 21: 1628-1636, 2010), tubular atrophy, and interstitial fibrosis (hazard ratio, 1.95; 95% confidence interval, 1.07 to 3.55; P=0.03). Renal TMA in ANCA-associated GN is not rare and presents with more severe renal injury. Renal TMA is independently associated with all-cause mortality in patients with AAV.

Validation of a histopathologic classification scheme for antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Antineutrophil cytoplasmic antibody-associated small-vessel vasculitides cause multiple organ system disease including rapidly progressive glomerulonephritis. Recently, Berden et al (J Am Soc Nephrol. 2010;21:1628-1636) proposed a new histopathologic classification scheme separating renal biopsies into 4 classes: focal, crescentic, mixed, and sclerotic. We validated the prognostic implications of this classification scheme in a retrospective cohort study of 67 individuals with antineutrophil cytoplasmic antibody glomerulonephritis who underwent kidney biopsy in Calgary, Alberta, between 2005 and 2010. Their biopsies were rescored according to the classification scheme of Berden et al. Additional tubulointerstitial parameters were also scored. Clinical information including demographics and creatinine values at presentation and 1-year follow-up was retrieved. The mean age was 60 years. Forty-one percent were female. Biopsies were classified as follows: 35% crescentic, 32% mixed, 21% focal, and 11% sclerotic. Ten patients (14%) died within 1 year. Among surviving patients, the overall mean (95% confidence interval) change in estimated glomerular filtration rate (eGFR) at 1 year was 11 (7-15) mL/min per 1.73 m(2), and this change significantly differed (P = .02) between the classes: 19 (11-27) mL/min per 1.73 m(2) with crescentic histology, 11 (1-21) mL/min per 1.73 m(2) with focal, 8 (3-13) mL/min per 1.73 m(2) with mixed, and -4 (-7 to -1) mL/min per 1.73 m(2) with sclerotic. Tubulointerstitial pathology parameters did not predict outcomes. Patients with crescentic class biopsies showed significantly more improvement in eGFR at 1 year compared with the mixed (P = .04) and sclerotic (P = .005) classes. The focal class was associated with the highest eGFR values at presentation and 1 year. These findings validate the prognostic utility of the Berden classification scheme and suggest that it may be generalizable.

Classification, Molecular Characterization, and the Significance ofPtenAlteration in Leiomyosarcoma

Leiomyosarcoma is a malignant smooth muscle neoplasm with a complicated histopathologic classification scheme and marked differences in clinical behavior depending on the anatomic site of origin. Overlapping morphologic features of benign and borderline malignant smooth muscle neoplasms further complicate the diagnostic process. Likewise, deciphering the complex and heterogeneous patterns of genetic changes which occur in this cancer has been challenging. Preliminary studies suggest that reproducible molecular classification may be possible in the near future and new prognostic markers are emerging. Robust recapitulation of leiomyosarcoma in mice with conditional deletion of Pten in smooth muscle and the simultaneous discovery of a novel role for Pten in genomic stability provide a fresh perspective on the mechanism of leiomyosarcomagenesis and promise for therapeutic intervention.

Oligodendroglioma and Its Variants: Radiologic-Pathologic Correlation

Oligodendroglioma is the third most common glial neoplasm and most commonly arises in the frontal lobe. It occurs in males more frequently, and the peak manifestation is during the 5th and 6th decades. Children are affected much less commonly. The clinical presentation is often of several years duration with most patients presenting with seizures, reflecting the strong predilection of this tumor to involve the cortical gray matter. Current histopathologic classification schemes recognize two main types of tumors: well-differentiated oligodendroglioma and its anaplastic variant. Less commonly, neoplastic mixtures of both oligodendroglial and astrocytic components occur and are termed oligoastrocytomas, with both well-differentiated and anaplastic forms. Surgical resection is the mainstay of initial treatment, and many patients experience a long progression-free period. Recent genotyping has revealed chromosomal loss of 1p and 19q as a genetic signature in most oligodendrogliomas, and these tumors respond favorably to chemotherapy. Hence, radiation therapy is now generally reserved for partially resected tumors and cases that failed to benefit from chemotherapy. At cross-sectional imaging, the tumor characteristically involves the cortical gray matter and frequently contains calcification. Robust enhancement is not a common feature and suggests transformation to a higher histologic grade. Advanced magnetic resonance imaging techniques and metabolic imaging play increasingly important roles in both pre- and postoperative assessment of these complex neoplasms.

Correlation of Histopathologic Findings with Clinical Outcome in Necrotizing Fasciitis

Necrotizing fasciitis is an uncommon disease with high morbidity and mortality rates. Little is known about the role of histopathologic examination in disease prognosis. A retrospective study was conducted to determine what correlations, if any, exist between the histopathologic features of resected tissue in patients with necrotizing fasciitis and clinical outcome. Eighty-two cases of necrotizing fasciitis that occurred between January 1990 and December 2002 were identified. Histopathologic findings were available for review in 63 cases. A novel histopathologic classification scheme, based on hematoxylin-eosin and Gram stain results, was developed. The classification scheme included 3 stages: stage I, characterized by an intense neutrophilic response and an absence of bacteria in infected tissue; stage II, characterized by the presence of a moderate-to-severe neutrophilic response and positive Gram stain results or by minimal to absent neutrophilic response with a negative Gram stain result; and stage III, characterized by the presence of few or no polymorphonuclear leukocytes and a Gram stain result positive for bacteria during histopathologic examination. Patients with stage I findings had a significantly lower risk of death than patients with stage III findings (7.1% vs. 47%; odds ratio [OR], 0.1; 95% confidence interval [CI], 0.01-0.8; P=.03). Patients with stage II findings had a significantly lower mortality rate than patients with stage III findings (14.2% vs. 47%; OR, 0.2; 95% CI, 0.04-0.9; P=.04). Due to the small number of deaths (n=11) in patients for whom histopathologic examination of resected tissue was performed, multivariate analysis was not done. Results of this study suggest that histopathologic findings may correlate with clinical outcome in cases of necrotizing fasciitis. Because the histopathologic scheme is based on results of commonly available stains, it could be easily adopted for use in other institutions that could further evaluate its usefulness as a prognostic tool.

Advances in the diagnosis, molecular genetics, and treatment of pediatric embryonal CNS tumors.

Embryonal central nervous system (CNS) tumors are the most common group of malignant brain tumors in children. The diagnosis and classification of tumors belonging to this family have been controversial; however, utilization of molecular genetics is helping to refine traditional histopathologic and clinical classification schemes. Currently, this group of tumors includes medulloblastomas, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, ependymoblastomas, and medulloepitheliomas. While the survival of older children with nonmetastatic medulloblastomas has improved considerably within the past two decades, the outcomes for infants and for those with metastatic medulloblastomas or other high-risk embryonal CNS tumors remain poor. It is anticipated that the emerging field of molecular biology will greatly aid in the future stratification and therapy for pediatric patients with malignant embryonal tumors. In this review, recent advances in the diagnosis, molecular genetics, and treatment of the most common pediatric embryonal CNS tumors are discussed.

Classification, pathogenesis and molecular pathology of primary CNS lymphomas.

Classification, pathogenesis and molecular pathology of primary central nervous system lymphomas (PCNSL) pose major clinico-pathologic problems. Application of histopathologic classification schemes developed for nodal lymphomas, i.e. the Kiel Classification and the Working Formulation, is not reliable and clinically not relevant for PCNSL. The more recent REAL Classification will simplify subtyping of PCNSL, but reliability and clinical significance remain to be determined. There are virtually no experimental data on whether PCNSL develop outside of the brain, or whether they arise from polyclonal lymphoproliferations within the brain. Mutations of oncogenes and tumor suppressor genes have been analyzed in only a few tumors, and their type and frequency is essentially unknown. In conclusion, compared with both neuroectodermal brain tumors and nodal lymphomas, and given the increasing incidence and clinical impact of PCNSL, there is a remarkable lack of histopathologic consensus as well as a surprising shortage of pathogenetic and molecular genetic information.

Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study.

There is a need to develop a single prognostically significant classification of rhabdomyosarcomas (RMS) and other related tumors of children, adolescents, and young adults which would be a current guide for their diagnosis, allow valid comparison of outcomes between protocols carried out anywhere in the world, and should enhance recognition of prognostic subsets. Sixteen pathologists from eight pathology groups, representing six countries and several cooperative groups, classified by four histopathologic classification schemes 800 representative tumors of the 999 eligible cases treated on Intergroup Rhabdomyosarcoma Study II. Each tumor was classified according to each of the four systems by each of the pathologists. In addition, two independent subsamples of 200 of the 800 patients were reviewed according to the new system, so that 343 distinct patients were reviewed once, and 57 of these twice. A study of the survival rates of all subtypes in the sample of 800 patients led to the formation of a new system. This was tested on two independent subsets of 200 of the original cases and found to be reproducible and predictive of outcome by univariate analysis. A multivariate analysis of the 343 patients classified according to the new system indicated that a survival model including pathologic classification and known prognostic factors of primary site, clinical group, and tumor size was significantly better at predicting survival than a model with only the known prognostic factors. This new classification, termed International Classification of Rhabdomyosarcoma (ICR) by the authors, was reproducible and predictive of outcome among patients with differing histologies treated uniformly on the Intergroup Rhabdomyosarcoma II protocols. We believe it should be utilized by all pathologists and cooperative groups to classify rhabdomyosarcomas in order to provide comparability among and within multi-institutional studies.

Environmental associations and histopathologic patterns of carcinoma of the lung: the challenge and dilemma in epidemiologic studies.

An update of histopathologic classification schemes is provided for carcinoma of the lung and factors that influence proportional distributions of cell types, i.e., sources and preparations of tissue specimens, observer variability, and use of secondary sources of information. Consideration is given to the natural history and to current knowledge of the demographic characteristics of cell types of carcinoma of the lung. A review of studies reporting histopathologic associations with environmental exposures suggests that no single type of carcinoma of the lung is specifically associated with exposure to tobacco smoke, arsenic, or beryllium. Furthermore, studies concerned with exposure to asbestos, chloroethers, chromates, nickel, vinyl chloride, and radioactivity lack sufficient information to conclude definitively that only one specific lung cancer cell type is associated with these exposures. In conclusion, an exclusive association of a single cell type of carcinoma of the lung with exposure to the physical or chemical agents reviewed has not been demonstrated.