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Patients with post-acute COVID-19 (PA-COVID) syndrome or long COVID-19 syndrome develop persistent symptoms and complications that last beyond 4 weeks of the initial infection. There is limited information regarding the pulmonary pathology in PA-COVID patients who require bilateral orthotopic lung transplantation (BOLT). Our experience with 40 lung explants from 20 PA-COVID patients who underwent BOLT is described. Clinicopathologic findings are correlated with best evidence from literature. The lung parenchyma showed bronchiectasis (n = 20) and severe interstitial fibrosis with areas resembling the nonspecific interstitial pneumonia (NSIP) pattern of fibrosis (n = 20), interstitial fibrosis not otherwise specified (n = 20), and fibrotic cysts (n = 9). None of the explants exhibited a usual interstitial pneumonia pattern of fibrosis. Other parenchymal changes included multinucleated giant cells (n = 17), hemosiderosis (n = 16), peribronchiolar metaplasia (n = 19), obliterative bronchiolitis (n = 6), and microscopic honeycombing (n = 5). Vascular abnormalities included thrombosis of a lobar artery (n = 1) and microscopic thrombi in small vessels (n = 7). Systematic literature review identified 7 articles reporting the presence in 12 patients of interstitial fibrosis showing the NSIP pattern (n = 3), organizing pneumonia/diffuse alveolar damage (n = 4) and not otherwise specified (n = 3) patterns. All but one of these studies also reported the presence of multinucleated giant cells and none of the studies reported the presence of severe vascular abnormalities. PA-COVID patients undergoing BOLT show a pattern of fibrosis that resembles a mixed cellular-fibrotic NSIP pattern and generally lack severe vascular complications. As the NSIP pattern of fibrosis is often associated with autoimmune diseases, additional studies are needed to understand the mechanism of disease and learn whether this information can be used for therapeutic purposes., (Published by Elsevier Inc.)

Introduction: Acinic cell carcinoma of the salivary gland (ACC-SG) is characterized by recurrent rearrangements in the nuclear receptor subfamily 4 group A member 3 (NR4A3). Immunostaining using an antibody targeting this rearrangement, neuron-derived orphan receptor 1 (NOR-1), has been recently studied on surgical specimens and cell block material of fine-needle aspirates for the diagnosis of ACC-SG. Our goal was to evaluate whether NOR-1 immunostaining could reliably be performed on destained cytologic preparations., Materials and Methods: This was a retrospective multi-institutional study. Immunostaining with the NOR-1 antibody (sc-393902 [H-7], Santa Cruz Biotechnology Inc.) was performed at a titer of 1:30 on destained cytologic preparations. ACC-SG cases (n = 17) were represented by twelve cases with alcohol-fixed preparations (n = 12), including direct smears and SurePath preparations, as well as 5 cases with air-dried preparations (n = 5). These were compared to 27 mimicker lesions (n = 27): normal acini (4), chronic sialadenitis (3), oncocytoma (2), pleomorphic adenoma (6), Warthin tumor (8), mucoepidermoid carcinoma (1), secretory carcinoma (2), and salivary duct carcinoma (1)., Results: The positivity of NOR-1 in ACC-SG cases was 100% on destained alcohol-fixed preparations (12/12) and 60% on air-dried preparations (3/5). All 27 mimicker lesions were negative for NOR-1 (0/27). Evaluation of 2 ACC-SG cases with both types of cytologic preparations showed that NOR-1 was positive on the alcohol-fixed slides but negative on the air-dried slides., Conclusions: NOR-1 immunostaining can reliably be performed on alcohol-fixed direct smears and liquid-based preparations for the diagnosis of ACC-SG. Air-dried preparations show a lower positivity rate and may be less suitable for diagnostic immunostaining., (Copyright © 2022 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Context.—: Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target., Objectives.—: To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin., Design.—: Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (≥2+ intensity in ≥50% of tumor)., Results.—: Claudin-18 staining was not significantly different across dysplasia categories in the gastroesophageal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001)., Conclusions.—: Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.

Insulinoma-associated protein 1 (INSM1) is shown to be an excellent marker for neuroendocrine differentiation. However, the diagnostic utility of INSM1 in medullary thyroid carcinoma (MTC) has not yet been extensively investigated. INSM1 staining was performed on 21 MTCs, 7 MTC mimickers (including 3 papillary carcinomas, 2 poorly differentiated carcinomas, 1 follicular adenoma, and 1 nodular plasma cell hyperplasia), and 3 cases of C-cell hyperplasia. INSM1 staining of these cases was compared with the traditional MTC markers including calcitonin (CT), monoclonal carcinoembryonic antigen (mCEA), chromogranin A (CgA), and synaptophysin (Syn). The H -score was generated using the QuPath program, an open-source image analysis software. All 21 MTC cases and 3 C-cell hyperplasia cases were positive for all markers. The MTC mimickers were entirely negative for INSM1. INSM1 and Syn displayed, more consistently, high expression with minimal variability than CgA that showed a wide range of expression with significant variability. mCEA and CT exhibited mostly a high expression with some variability. Being a nuclear stain, interpretation was easier with INSM1 compared to other cytoplasmic markers. INSM1 is an excellent marker for neuroendocrine differentiation, entirely applicable in the diagnosis of MTC and C-cell hyperplasia with high sensitivity and specificity. In comparison with the traditional MTC markers, INSM1 is unique in the crisp nuclear staining pattern with a consistent, diffuse, and strong expression. INSM1 can be potentially combined with CT or mCEA as a dual stain, especially when the lesional tissue is limited for a panel of immunostains.

Acinic cell carcinoma of the salivary gland (ACC-SG) is characterized by a recurrent chromosomal rearrangement (t(4; 9)(q13; q31)) that upregulates the transcription factor NR4A3. Studies conducted on formalin-fixed paraffin-embedded (FFPE) tissue have found that nuclear expression of a monoclonal antibody NR4A3 (NOR-1) is a sensitive and specific diagnostic marker for ACC-SG. The aims of this study were to evaluate the performance of the NOR-1 antibody and to compare its utility in separating ACC-SG from its mimics on cytology cell block specimens. Cell blocks were obtained from 70 fine-needle aspiration specimens from multiple institutional archives over a 7-year period (2013-2019). These included 10 cases of conventional low-grade ACC-SG, 1 case of dedifferentiated high-grade ACC-SG, and 59 cases of non-ACC-SG. An automated immunohistochemistry system (Bond-III, Leica) was used for the detection of NR4A3, using the commercially available antibody NOR-1 (sc-393902 [H-7], Santa Cruz Biotechnology Inc.). Optimization of the antibody on the cell blocks was successfully completed by increasing the titer from 1:100 (suggested titer for FFPE specimens) to 1:30. Distinct nuclear reactivity was observed in all 11 cases of ACC-SG (10 of 11 with 3+ diffuse nuclear positivity and 1 case with 2+ focal reactivity). Expression of NR4A3 was absent in all non-ACC-SG cases in the cell blocks. Application of the NOR-1 immunohistochemical staining in fine-needle aspirates of salivary gland tumors for which ACC-SG is a diagnostic consideration successfully distinguishes ACC-SG from its cytologic mimics and provides an early opportunity for oncologic intervention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cancer stem cells are initiating cells of cancer and propagate its growth through self-renewal and differentiation of its daughter cells. CD133 is a cell surface antigen that is present on glioma stem cells and has been used to prospectively isolate glioma stem cells. We hypothesized that a major histocompatibility complex (MHC)-independent and long-lasting immune response against CD133 could be generated by transfecting CD133 mRNA into dendritic cells and vaccinating animals with experimental gliomas. To test this hypothesis, we developed a novel humanized mouse model using CD34-positive hematopoietic stem cells. We confirmed the robust simultaneous activation of CD8- and CD4-positive T cells by dendritic cell vaccination with modified CD133 mRNA leading to a potent and long-lived immune response, with subsequent abrogation of CD133-positive glioma stem cell propagation and tumor growth. This study for the first time demonstrates in both a humanized mouse model and in a syngeneic mouse model of glioblastoma that targeting a glioma stem cell-associated antigen is an effective strategy to target and kill glioma stem cells. This novel and simple humanized mouse model for immunotherapy is a significant advance in our ability to test human-specific immunotherapies for glioblastoma., (© 2020 The Authors.)

Background: The Paris System (TPS) acknowledges the need for more standardized terminology for reporting urine cytopathology results and minimizing the use of equivocal terms. We apply TPS diagnostic terminologies to assess interobserver agreement, compare TPS with the traditional method (TM) of reporting urine cytopathology, and evaluate the rate and positive predictive value (PPV) of each TPS diagnostic category. A survey is conducted at the end of the study., Materials and Methods: One hundred urine samples were reviewed independently by six cytopathologists. The diagnosis was rendered according to TPS categories: negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), low-grade urothelial neoplasm (LGUN), suspicious for high-grade urothelial carcinoma (SHGUC), and high-grade urothelial carcinoma (HGUC). The agreement was assessed using kappa. Disagreements were classified as high and low impacts. Statistical analysis was performed., Results: Perfect consensus agreement was 31%, with an overall kappa of 0.362. Kappa by diagnostic category was 0.483, 0.178, 0.258, and 0.520 for NHGUC, AUC, SHGUC, and HGUC, respectively. Both TM and TPS showed 100% specificity and PPV. TPS showed 43% sensitivity (38% by TM) and 70% accuracy (66% by TM). Disagreements with high clinical impact were 27%. Of the 100 cases, 52 were concurrent biopsy-proven HGUC. The detection rate of biopsy-proven HGUC was 43% by TPS (57% by TM). The rate of NHGUC was 54% by TPS versus 26% by TM. AUC rate was 23% by TPS (44% by TM). The PPV of the AUC category by TPS was 61% versus 43% by TM. The survey showed 33% overall satisfaction., Conclusions: TPS shows adequate precision for NHGUC and HGUC, with low interobserver agreement for other categories. TPS significantly increased the clinical significance of AUC category. Refinement and widespread application of TPS diagnostic criteria may further improve interobserver agreement and the detection rate of HGUC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2019 Bakkar, et al.; Licensee Cytopathology Foundation Inc.)

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.

The pericytic (perivascular myoid cell) family of tumors is a distinctive group of mesenchymal neoplasms encountered in superficial sites and only rarely seen in viscera. The pericytic family subtends a spectrum of lesions, namely, glomus tumors and variants; myopericytoma, including myofibroma; and angioleiomyoma. In light of the contemporary classification of pericytic lesions, we identified and reviewed 17 cases of renal pericytic tumors from the files of 6 referral centers. These tumors presented over an age range of 17 to 76 years (mean 46.7, median 53), with essentially equal male-female ratio. History of hypertension (available in 11 patients) was noted in 7 (64%), which persisted even after surgical resection, including in 2 younger patients (17 and 30 years). The tumors (1.7-11.0 cm) included glomus tumors (n=11); glomangiomyoma (n=1); glomus tumor with atypical features (n=1); and angioleiomyoma (n=1), as well as tumors showing features overlapping pericytic tumor subtypes (n=3). The histomorphology observed in these renal examples closely resembled that of their soft tissue counterparts, a subset with symplastic changes and atypical features, and pericytic immunophenotype. Despite large size and deep site, no progression was identified during a median of 7 months follow-up (1-62 months). In context of prior reported experience, our series identifies a wide morphologic spectrum, including lesions presenting composite morphologies. Taken with the experience of others, our series further corroborates that malignant behavior is rare, and that criteria associated with aggression among soft tissue pericytic tumors may not be predictive for those in the kidney., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The limited clinical success of anti-HGF/MET drugs can be attributed to the lack of predictive biomarkers that adequately select patients for treatment. We demonstrate here that quantitative digital imaging of formalin fixed paraffin embedded tissues stained by immunohistochemistry can be used to measure signals from weakly staining antibodies and provides new opportunities to develop assays for detection of MET receptor activity. To establish a biomarker panel of MET activation, we employed seven antibodies measuring protein expression in the HGF/MET pathway in 20 cases and up to 80 cores from 18 human cancer types. The antibodies bind to epitopes in the extra (EC)- and intracellular (IC) domains of MET (MET4 EC , SP44&#95;MET IC , D1C2&#95;MET IC ), to MET-pY1234/pY1235, a marker of MET kinase activation, as well as to HGF, pSFK or pMAPK. Expression of HGF was determined in tumour cells (T&#95;HGF) as well as in stroma surrounding cancer (St&#95;HGF). Remarkably, MET4 EC correlated more strongly with pMET ( r  = 0.47) than SP44&#95;MET IC ( r  = 0.21) or D1C2&#95;MET IC ( r  = 0.08) across 18 cancer types. In addition, correlation coefficients of pMET and T&#95;HGF ( r  = 0.38) and pMET and pSFK ( r  = 0.56) were high. Prediction models of MET activation reveal cancer-type specific differences in performance of MET4 EC , SP44&#95;MET IC and anti-HGF antibodies. Thus, we conclude that assays to predict the response to HGF/MET inhibitors require a cancer-type specific antibody selection and should be developed in those cancer types in which they are employed clinically.

Although metastases and high-mortality are frequent in high-grade endometrial sarcomas (HGSs), these findings are less commonly seen in low-grade endometrial stromal sarcomas (LGESSs), even in cases with lymphovascular invasion (LVI). We hypothesized that the "bulging plugs" of tumor characteristic of LVI in LGESS are fundamentally different from LVI seen in HGS. We reviewed 70 uterine sarcomas: 42 HGSs (high-grade endometrial stromal sarcomas, undifferentiated uterine sarcoma, and leiomyosarcoma) and 28 LGESSs. All cases had LVI documented on the histologic slides. Immunostains for CD31, ERG, and D2-40 were performed. LGESS harbored cohesive intravascular tumor foci with direct communication from the main tumor and attached to the vessel wall. The intravascular foci included tumor cells and small arteriole-type vessels and were surrounded by a thin fibrous band. Vascular markers confirmed the LVI and highlighted positively stained endothelial cells separating intravascular tumor foci from the blood itself. In contrast, intravascular tumor foci in HGS were composed of discohesive cells clusters, lacking the features described in LGESS. Only 8 (30.8%) patients with LGESS had recurrence/metastases (6 with lung metastasis); only 1 patient died of disease. Thirty (77%) patients with HGS had recurrence/metastases, 27 (69%) patients had lung metastases, and 22 (56.4%) patients died of disease. We propose that in most LGESSs, LVI represents vascular intrusion; manipulation or trauma is potentially responsible for tumor cell detachment into the circulation increasing the chances of recurrence/metastases. Classic LVI features were identified in HGS. This important distinction may allow for better management of patients and avoid unnecessary treatment in LGESS, reducing morbidity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rectal neuroendocrine tumors (NETs) can be classified by histologic pattern and secretory products. Recently, rectal NETs have been noted to exhibit immunohistochemical (IHC) positivity for Islet 1 and PAX8, which are generally considered markers for NETs of pancreatic origin. In this study, we sought to characterize the IHC staining profile of rectal NETs and determine whether there was any correlation between the histologic pattern of rectal NETs and their IHC profile. Fifty-six primary rectal NETs were histologically reviewed and stained with antibodies against Islet 1, PAX8, CDX2, chromogranin A, and synaptophysin. In a subset of 31 cases, immunoreactivity for serotonin, pancreatic polypeptide (PP), and prostatic acid phosphatase (PAP) was also studied. By morphology, the tumors studied included 55 % trabecular, 27 % solid nested, 4 % acinar, and 14 % mixed patterns. Islet 1 was positive in 89 % and PAX8 in 79 % of cases. CDX2 was negative in all 56 cases. Cytoplasmic staining was observed for chromogranin A in 30 % of cases and for synaptophysin in all 56 cases. Cytoplasmic staining for serotonin, PP, and PAP was present in 16, 61, and 97 % of cases, respectively. There was no correlation between histologic pattern and IHC staining pattern with any of the antibodies studied. We have demonstrated that Islet 1 and PAX8 are not entirely specific for NETs of pancreatic origin, as they are expressed in a majority of rectal NETs. Since rectal NETs may show an IHC staining profile which mirrors that of pancreatic NETs (Islet 1 and PAX8-positive, CDX2-negative), a metastatic rectal NET should be considered in the differential diagnosis and ruled out clinically in the work-up of a metastatic NET of unknown primary origin which exhibits this staining profile.

We encountered an undescribed histologic feature of papillary urothelial neoplasms: "urothelial eddy", which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis.

We report 13 cases of anaplastic large cell lymphoma (ALCL) associated with breast implants. Patient age ranged from 39 to 68 years, and the interval from implant to ALCL was 4 to 29 years. All tumors were composed of large, pleomorphic cells that were CD30 and ALK1, and all 7 cases assessed had monoclonal T-cell receptor γ-chain rearrangements. Two patient subgroups were identified. Ten patients presented with effusion surrounded by fibrous capsule without a grossly identifiable tumor mass. Nine patients had stage I and 1 had stage II disease. Eight patients underwent implant removal and capsulectomy. Four patients received chemotherapy and 4 radiation therapy. All patients were alive without disease at last follow-up. A second subgroup of 3 patients had effusion and a distinct mass adjacent to the implant. One patient had stage I and 2 stage II disease. One patient had a 3-year history of lymphomatoid papulosis, and 1 patient had a 1-year history of CD30 T-cell lymphoma adjacent to the breast before the diagnosis of ALCL associated with breast implant. Two patients received chemotherapy and 1 radiation therapy. Two patients died 2 and 12 years after diagnosis, respectively. We conclude that the clinical behavior of ALCL associated with breast implants is heterogeneous. Patients who present with effusion without a distinct mass have an indolent disease course, similar to CD30 lymphoproliferative disorder of skin. In contrast, patients who present with a distinct mass may have advanced stage or possibly systemic disease and have a poorer prognosis.

Our previous study utilizing the 2008 NCI six-category system (also known as The Bethesda System) for reporting thyroid fine-needle aspirations (FNA) identified considerable overlap in diagnosis and in assigned malignancy risk estimates for the "follicular lesion of undetermined significance (FLUS)" and "follicular neoplasm (FN)" categories and for the "suspicious for malignancy (Susp)" and "malignant" categories. We proposed a simplified Bethesda System for reporting thyroid FNAs that provided four non-overlapping, statistically significant, and more clinically relevant diagnostic categories: unsatisfactory, benign, FLUS/FN, and Susp/malignant. In the current study, six cytopathologists participated in a blinded retrospective review of 60 thyroid FNAs and kappa statistics were utilized to compare the intra- and inter-observer diagnostic agreements obtained using the six-category and the simplified four-category schemes. Surgical follow-up was used to determine which scheme provided more discrete malignancy risk estimates. Use of the simplified four-category scheme significantly improved intra- and inter-observer diagnostic agreement levels, significantly increased the sensitivity of FNA for a diagnosis of carcinoma in the subsequently resected thyroid glands, and provided non-overlapping malignancy risk estimates for each diagnostic category., (Copyright © 2011 Wiley Periodicals, Inc.)

Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods. The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-). In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-). In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.

Just two and a half decades ago adult renal cell neoplasms, i.e., those arising from the renal tubules or collecting duct epithelium, were subdivided into two major subtypes: "clear cell carcinoma" and "granular cell carcinoma." Subsequent detailed morphologic and/or cytogenetic studies have resulted in the recognition of several distinctive subtypes of adult renal epithelial neoplasms, which has led to the promulgation of a refined contemporary histologic classification of these tumors. This study examines the prognostic significance of histologic subtyping in accordance with the new classification in a consecutive series of 405 cases treated at a single institution. Cases were histologically classified into 28 (7%) benign tumors [27 (6.7%) renal oncocytomas, 1 (0.2%) metanephric adenoma] and 377 (93%) malignant tumors [255 (63%) conventional (clear cell) renal cell carcinoma, 75 (18.5%) papillary renal cell carcinoma, 24 (5.9%) chromophobe renal cell carcinoma, and 23 (5.7%) renal cell carcinoma, unclassified]. A total of 25 (6.6%) malignant tumors showed evidence of sarcomatoid change. Kaplan-Meier survival analysis with log-rank test showed histologic type (p = 0.002), Fuhrman's nuclear grade (p = 0.001), TNM stage (p = 0.001), vascular invasion (p = 0.001), and necrosis (p = 0.001) to be significantly associated with disease-specific survival and progression-free survival, based on follow-up of 368 patients (mean 64.5 months, median 56 months). The 5-year disease-specific survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 100%, 86%, 76%, and 24%, respectively; no patient with a benign tumor diagnosis progressed or died of disease. The 5-year progression-free survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 94%, 88%, 70%, and 18%, respectively. Malignant tumors with sarcomatoid change had a 35% and 27%, 5-year disease-specific and progression-free survival, respectively. Cox proportional hazards regression analysis showed TNM stage (p = 0.001), nuclear grade (p = 0.01), and necrosis (p = 0.05) to be significant predictors of disease-specific survival. In conclusion, our study shows that the histologic categorization of adult renal epithelial neoplasms performed by routine light microscopic hematoxylin and eosin-based examination in accordance with the contemporary classification scheme has prognostic utility.

Paneth cell-like metaplasia has been reported in the epithelium of the epididymis and prostatic adenocarcinomas. We studied the expression of group II phospholipase A2 (PLA2), a marker of Paneth cell differentiation, in six orchiectomy specimens with Paneth cell-like metaplasia. Both immunohistochemistry for group II PLA2 protein and in situ hybridization for the mRNA of group II PLA2 gave negative results in all six cases but positive reaction for lysozyme. The results show that the cells of the Paneth cell-like metaplasia are not true Paneth cells.

Little is known about the association of angiomyolipoma and adult renal-cell neoplasia. We studied the clinicopathologic features of 36 patients with concurrent angiomyolipoma and renal-cell neoplasia from the consultation and surgical pathology files of nine institutions. HMB-45 immunoreactivity was analyzed in both neoplasms. Twenty-five sporadic cases of patients with angiomyolipoma and renal-cell neoplasia and 11 cases of patients with tuberous sclerosis, as defined by Gomez' criteria, had mean ages of 59 and 53 years, respectively, and female-male ratios of 2:1 and 5:1, respectively. The mean size of the angiomyolipomas was 1 cm in the sporadic cases and 3 cm in those patients with tuberous sclerosis (medians: 0.5 and 3 cm, respectively, P =.002). The mean sizes of the renal-cell neoplasms were 5 cm in sporadic cases and 6 cm in patients with tuberous sclerosis (medians: 4 and 5 cm, respectively; P =.88). In both clinical settings, angiomyolipoma was more commonly the incidental tumor. Clear-cell (conventional) renal-cell carcinoma was the most common renal-cell neoplasm in both groups of patients, accounting for approximately two thirds of the tumors. In patients with tuberous sclerosis, 27% of renal-cell neoplasms were oncocytomas, compared with 8% in sporadic cases (P =.15). Papillary neoplasia, chromophobe, and collecting-duct renal-cell carcinoma were found only in sporadic cases. All of the 22 renal-cell neoplasms studied were negative for HMB-45, whereas all 25 angiomyolipomas studied were positive.

Sarcomatoid renal cell carcinoma is not a distinct histologic entity and represents high-grade transformation in different subtypes of renal cell carcinoma. It is not known whether any particular histologic type has a predilection for sarcomatoid change or whether the primary histologic type of renal carcinoma undergoing sarcomatoid change affects prognosis. Of 952 consecutively histologically subtyped renal cell carcinomas, the incidence of sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma, 3% in papillary renal carcinoma, 9% in chromophobe renal carcinoma, 29% in collecting duct carcinoma, and 11% in unclassified renal cell carcinoma. One hundred one renal cell carcinomas with sarcomatoid change were studied, and clinicopathologic parameters were correlated with outcome. The mean age of patients was 60 years (range, 33-80 years), and the male-to-female ratio was 1.6:1. The median tumor size was 9.2 cm (range, 3-25 cm). The primary histologic subtype of the carcinoma component was conventional (clear cell) renal carcinoma in 80 cases, papillary renal carcinoma in eight, chromophobe renal carcinoma in seven, collecting duct carcinoma in two, and unclassified renal cell carcinoma in four. The sarcomatoid component resembled fibrosarcoma in 54 cases, malignant fibrous histiocytoma in 44, undifferentiated sarcoma (not otherwise specified) in three with focal rhabdomyosarcomatous component in two of them. The spindled elements accounted for 1% to 99% of the sampled tumor (median, 40%; mean 45%). The histologic grade of the spindled elements was intermediate to high in 92 cases and low in nine cases. Most cases were TNM stages III and IV (seven stage I, six stage II, 63 stage III, and 25 stage IV). Follow-up was available in 88 patients; 61 (69%) patients died of disease and had a median survival time of 19 months. Distant metastases, most frequently to the lungs, were documented in 51 (66%) of 77 patients who had available clinical information regarding distant metastasis. The disease-specific survival rate was 22% and 13% after 5 and 10 years, respectively, compared with a cohort of renal cell carcinomas without sarcomatoid change with a 5-and 10-year disease-specific survival of 79% and 76%, respectively. Kaplan-Meier survival analysis showed that tumors with high TNM stage (p = 0.0027), at least 50% sarcomatoid component (p = 0.0453), and angiolymphatic invasion (p = 0.0282) were associated with decreased survival rates. The primary histologic subtype of the carcinoma component and the type and grade of the sarcomatoid component did not affect survival. In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable in predicting outcome among renal cell carcinomas with sarcomatoid change (p = 0.018; risk ratio, 6.984 and 8.439). Compared with a cohort of renal cell carcinomas without sarcomatoid change, sarcomatoid tumors tended to present at a more advanced stage (p = 0.0001). Also, when adjusted for stage, necrosis, and tumor size, patients with tumors with sarcomatoid differentiation had a worse prognosis than did patients with tumors without sarcomatoid change (p = 0.0001). In conclusion, sarcomatoid change in renal cell carcinoma portends a worse prognosis. Because tumors with even a small component of sarcomatoid change may have an adverse outcome, this finding, when present, should be noted in the surgical pathology report.

Renal cell carcinomas often show varying degrees of necrosis and cystic change. The prognostic importance of necrosis so extensive that only a few tumor cells can be identified is not clear. We gathered clinicopathologic and follow-up data on a group of eight such cases ("type I"). These patients were compared with two other groups of renal cell carcinomas: those with extensive necrosis (>50%), yet with readily identifiable tumor ("type II"), and cancers with extensive cystic change not resulting from necrosis, usually multiloculated ("type III"). The groups showed similar demographic characteristics, and within each group there was great variation in tumor size. Conventional (clear cell) histology was more common than papillary morphology in all groups. The type II neoplasms tended to be of higher nuclear grade and pathologic stage than the other groups. While one of six type I patients with follow up progressed 131 months after diagnosis, eight of 20 type II patients showed progression. None of the six type III patients with follow up progressed. We conclude that renal cell carcinomas showing extensive necrosis are capable of aggressive behavior, and patients with these lesions cannot be assured of cure following surgery. Pathologists must be aware of this entity and extensively sample any renal lesion showing extensive necrosis. The tumors showing a greater amount of viable neoplastic cells yet at least 50% necrosis had a higher rate of progression than did the type I patients. The lack of progression of any of the type III cases supports the idea that type III multiloculated cystic renal cell carcinomas may carry a distinctly better prognosis than other forms of renal cell carcinoma.

Clear cell sarcoma of the kidney is a distinct, highly malignant pediatric neoplasm. Its occurrence in adults is extremely rare and the subject of isolated case reports. We present a series of four cases (three males and one female) identified in an adolescent and in young adults (16, 18, 20, and 25 years) with flank mass (three cases), hematuria (two cases), flank pain (two cases), and hypertension (one case). Three patients had stage III disease and one had stage I disease (National Wilms' Tumor Study staging system). All tumors had predominantly or exclusively the classic histology of a monotonous proliferation of uniform small round cells with evenly distributed fine chromatin, although focal microcyst formation (two cases) and spindled architecture (one case) (variant patterns) were also noted. Therapy in all cases consisted of surgery and chemotherapy with or without radiation. Follow-up data (29-202 months) showed distant metastases in all four cases, including the lung (four cases), bone (two cases), and the liver (two cases). Three patients died of disease at 29, 59, and 63 months (mean, 50.3 months), and one patient is alive with no evidence of disease at 202 months. Ultrastructural features included scattered primitive junctions, short and irregular cytoplasmic extensions, and scant to a moderate amount of mitochondria. Immunohistochemical study (three cases) showed immunoreactivity with vimentin (two cases) and no reaction with cytokeratin, epithelial membrane antigen, S-100 protein, or desmin. Flow cytometric analysis showed diploid DNA content in three primary tumors and tetraploidy in one metastatic tumor. The proliferative activity (S-phase fraction) was low to intermediate (mean, 9.8%). Our data suggest that clear cell sarcoma of the kidney in the young adult age group resembles its pediatric counterpart in ultrastructural and immunohistochemical characteristics, proclivity for skeletal and visceral metastasis, DNA diploid status with relatively low S-phase, and aggressive clinical course. Clear cell sarcoma of the kidney in adult patients, although rare, must be differentiated from sarcomatoid carcinoma, sarcomas, and round cell tumors because of its unique characteristics in comparison to other renal neoplasms.

A retrospective review of bile (BL) and biliary tract brushings (Br) obtained by endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) was undertaken to determine the sensitivity and specificity of cytology in the diagnosis of pancreaticobiliary malignancies. A total of 104 cytologic specimens (PTC-BL 15, PTC-Br 13, ERCP-BL 8, ERCP-Br 68) received between 1990 and mid-1994 from 77 patients who had undergone ERCP and/or PTC primarily for biliary stricture were reviewed. Specimens were unsatisfactory/ inadequate in 11 (10.6%), benign in 41 (39.4%), suspicious in 25 (24%), and positive for malignant cells in 27 (26%). Follow-up was available in 74/77 patients; 46 (59.7%) had tissue confirmation while 28 (32.5%) had adequate clinical follow-up based on chart review. Of those with histologic confirmation, there were 32 malignant and 14 benign cases. The overall sensitivity and specificity of PTC- and ERCP-obtained cytologic specimens were 88.9 and 95.7% respectively. There was only one false positive case (ERCP-Br). Overall positive predictive value was 96% negative predictive value 88%, and accuracy 96%. PTC had a significantly lower sensitivity rate (42.8%) and higher rate for unsatisfactory specimens (21%) compared with ERCP-obtained material (100 and 1.9%). Bile obtained by PTC or ERCP appeared less sensitive in detecting malignancies compared with endoscopic brushing using either technique (BL 50% vs. Br 100%). All three false negative cases were PTC-BL specimens. Of the 17 suspicious cases, eight were confirmed histologically as malignant, four were clinically consistent with malignancy, and five showed marked inflammatory atypia on biopsy. Positive predictive value and accuracy rate of a "suspicious cytology" diagnosis were 69 and 80.5%, respectively. Inadequate specimen, poor cellular preservation, and cells obscured by bile all interfere with proper cytologic evaluation. Experience is necessary to appreciate subtle malignant changes in well differentiated carcinomas. Communication between the cytopathologist and the clinician is critical in the accurate interpretation and proper management of the patients.

The authors report the histologic and immunohistochemical findings of two cases of diffuse embryoma of the testis, a distinct form of mixed-germ-cell tumor characterized by diffuse, orderly arrangement of embryonal carcinoma (EC) and yolk sac tumor (YST) with scattered trophoblastic components. The patients were 37 and 38 years old when they presented with a right testicular tumor, which was confined to the testis (stage I) in both cases. Histologically, the tumor was composed predominantly of intimately intermingled EC and YST components in almost equal proportion. The tumor cells were arranged in necklacelike fashion; the EC cells formed glandular structures rimmed by a single cell layer of YST cells. The YST component was highlighted by positive staining for alpha-fetoprotein and strong staining for cytokeratin, whereas the EC component was positive for Ki-1 (BerH2, CD30) antigen, was negative for alpha-fetoprotein, and stained more weakly for cytokeratin. The randomly distributed few trophoblastic elements stained for human chorionic gonadotropin. The patients are alive with no evidence of disease, 11 years and 9 months after surgery, respectively. This newly described but distinct variant of mixed-germ-cell tumor should be differentiated from polyembryoma, which is composed of multiple discrete embryoid bodies.

Pulmonary malacoplakia associated with Rhodococcus equi, an opportunistic Gram-positive coccobacillus, is unusual. Although this patient is the ninth reported to have pulmonary malacoplakia, he is only the third patient with the acquired immunodeficiency syndrome who has been reported to have pulmonary malacoplakia associated with R equi infection. The patient was a 49-year-old man infected with the human immunodeficiency virus who on initial examination was found to have cavitary pneumonia in the right upper lobe of the lung. Histologic examination of an open-lung biopsy specimen revealed sheets of foamy intraalveolar macrophages that contained coccobacillary organisms and some "targetlike" cytoplasmic inclusions. Electron-microscopic studies showed Michaelis-Gutmann bodies, some of which contained residual bacterial fragments. Cultures of the lung tissue, urine, and blood yielded growth of Gram-positive coccobacilli subsequently identified as R equi. In immunocompromised patients, the possibility of malacoplakia should be considered in the differential diagnosis of diffuse pulmonary infiltrate composed of foamy intraalveolar macrophages.