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Ubiquitin-specific peptidase 6 (USP6) is a hominoid-specific gene residing on chromosome 17p13 and serves as a deubiquitinating enzyme with a diverse set of functions including intracellular trafficking, inflammatory signaling, cell transformation and protein turnover. USP6 rearrangements were first identified in aneurysmal bone cysts, resulting in promoter swapping and over-expression of wild type USP6. Several morphologically overlapping fibroblastic/myofibroblastic tumors are known to harbor USP6 rearrangements, including nodular fasciitis, cellular fibroma of tendon sheath, myositis ossificans and fibro-osseous pseudotumor of digits. Over the past few years, fusions involving the USP6 gene and various partner genes have been described in these neoplasms. The current World Health Organization Classification of Tumors of Soft Tissue suggests that USP6-rearranged lesions are typically benign and usually self-limited in their growth. This review provides an updated overview of the clinical, histological and molecular genetic features of USP6-associated fibroblastic/myofibroblastic tumors and discusses how these lesions should be best classified.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age

Mesothelioma in situ (MIS) has recently been investigated as a distinct phase of mesothelioma carcinogenesis. The diagnostic criteria proposed for MIS include a loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC). However, the length of time that MIS typically remains an in situ lesion before progression to invasive disease is still unclear. Herein, we report a case of a Japanese woman in her early seventies who had suffered from recurrent pleural effusions for 15 years, during which MIS developed and progressed to invasive mesothelioma. Retrospective diagnosis of partial MIS, fully developed MIS, and invasive disease was made using BAP1 IHC on three biopsy specimens and via clinical observations with radiological images. MIS and invasive lesions revealed BAP1 loss. The interval from partial or full MIS to invasive disease was 14 and 7 years, respectively. These results support a diagnostic strategy combining histomorphology with genomic-based assays including BAP1 IHC in biopsy tissues from a patient with recurrent pleural effusions.

There are several reports of pleural adenomatoid (microcystic) mesothelioma, but peritoneal adenomatoid mesothelioma is extremely rare. A 64-year-old Japanese woman presented with no symptoms and no asbestos exposure history. An abdominal computed tomography scan revealed multiple hypervascular masses on the liver surface, pelvic cavity and anterior peritoneum. Over 10 pieces of the multiple resected tumors showed numerous microcysts composed of a bland mesothelial cell background with rich capillary vessels. Focally, atypical cells with bizarre nuclei with prominent nucleoli were observed. Adenomatoid mesothelioma was suspected based on histochemical, immunohistochemical and fluorescence in situ hybridization findings. The tumors relapsed 4 years later and metastasized to the lung, but the patient remains alive 7 years after the first tumor resection surgery. Although the prognosis of adenomatoid mesothelioma of pleural origin is poor, the progression of this peritoneal case is slow.

Background The specificity and sensitivity of HEG1 for malignant mesothelioma (MM) is high. The use of BAP1/MTAP immunohistochemistry (IHC) is recommended to separate benign and malignant mesothelial proliferations. We determined how ancillary techniques can be used for the cytological diagnosis of MM with effusion. Methods Cell blocks from effusions from cases with MM, reactive mesothelial cells (RMCs), and carcinomas were analyzed by IHC with HEG1, BAP1, and MTAP and with homozygous deletion (HD) of CDKN2A by fluorescence in situ hybridization. Staining scores were calculated for IHC by adding the number of categories for the staining intensity and the staining extension. Results HEG1 was positive in all (41/41) MMs, but negative in carcinomas, except for ovarian carcinomas. Overall 76.9% (20/26) of RMCs and 28.6% (6/21) of ovarian carcinomas expressed HEG1. BAP1 loss was found in 71.1% of MMs, but none was found in RMCs. MTAP loss was found in 76.2% of MMs, but none was found in RMCs. 73.9% of MMs harbored HD of CDKN2A. There was concordance between loss of MTAP and HD of CDKN2A in 95% of MMs. Conclusion HEG1 is a good marker for mesothelial differentiation in effusion cytology. HD of CDKN2A is frequently observed in cell blocks from effusions of MMs, and MTAP IHC may act as a surrogate for HD of CDKN2A. Cell block analysis is recommended for effusions of unknown origins with the following methods: IHC with HEG1 and claudin 4 to validate the mesothelial origin, followed by BAP1 and MTAP IHC to confirm malignancy.

We herein report a case of coagulation necrosis with granulation and eosinophilic infiltration of the liver. A 37-year-old woman was diagnosed with a new mass lesion in the liver 1 month after breast cancer surgery and admitted for a further examination. Because the tumor occurred immediately after surgery, it was considered essential to determine whether or not it was a metastatic liver tumor from breast cancer. A percutaneous liver tumor biopsy revealed eosinophilic granuloma of the liver, which is considered to have a high possibility of visceral larva migrans with suspected gnathostomiasis infection. A detailed medical history and histological diagnosis are important for making a differential diagnosis.

Neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene located on chromosome 22q12.2, is frequently abnormal in mesothelioma. Recent studies have revealed the effectiveness of diagnostic assays for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. These include detection of homozygous deletion of the 9p21 locus by fluorescence in situ hybridization (FISH) (9p21 FISH), loss of expression of BAP1 as detected by immunohistochemistry, and loss of expression of methylthioadenosine phosphorylase (MTAP) as detected by immunohistochemistry. However, the application of FISH detection of NF2 gene deletion (NF2 FISH) in differentiation of malignant pleural mesothelioma from reactive mesothelial hyperplasia has not been fully evaluated. In this study, we investigated whether NF2 FISH, either alone or in a combination with other diagnostic assays (9p21 FISH, MTAP immunohistochemistry, and BAP1 immunohistochemistry), is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia. This study cohort included malignant pleural mesothelioma (n = 47) and reactive mesothelial hyperplasia cases (n = 27) from a period between 2001 and 2017. We used FISH to examine deletion status of NF2 and 9p21 and immunohistochemistry to examine expression of MTAP and BAP1 in malignant pleural mesothelioma and in reactive mesothelial hyperplasia. Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) was detected in 25 of 47 (53.2%) mesothelioma cases. None of the mesothelioma cases showed homozygous NF2 deletion. Hemizygous NF2 loss showed 53.2% sensitivity and 100% specificity in differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. A combination of NF2 FISH, 9p21 FISH, and BAP1 immunohistochemistry yielded greater sensitivity (100%) than that detected for either diagnostic assay alone (53.2% for NF2 FISH, 78.7% for 9p21 FISH, 70.2% for MTAP immunohistochemistry, or 57.4% for BAP1 immunohistochemistry). Thus, NF2 FISH in combination with other diagnostic assays is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia.

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77–0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.

Adenoid cystic carcinoma (AdCC) with high-grade transformation (AdCC-HGT) is rare, and AdCC-HGT with spindle cell component is particularly rare. The patient was a 65-year-old man with a 5 cm sized swelling of the right submandibular gland. Submandibular sialoadenectomy was performed. Histopathological findings mainly showed conventional AdCC, and minorly showed two other components: (1) the pleomorphic component, a proliferation of atypical pleomorphic epithelial cells forming solid or small clusters and accompanied by necrosis; (2) the spindle cell component, containing atypical spindle cells invading the stroma. Postoperative chemoradiotherapy was performed. Multiple right lung nodular lesions were found on the contrast-enhanced chest CT one month after the surgery. Thoracoscopic pulmonary resection was performed. The lung tumors exhibited a proliferation of atypical spindle cells, accompanied by necrosis. We considered that the spindle cell component of the AdCC-HGT of the submandibular gland developed lung metastases. The patient died seven months after submandibular sialoadenectomy due to respiratory failure. Although rare, our case highlights the importance of recognising spindle cell components in conventional AdCC; even if the area is small, these high-grade transformation areas can metastasise and become prognostic factors.

Aims Laminin (Ln)-γ 2, one of the chains of Ln-332, is a marker of invasive tumours and is frequently expressed as a monomer in malignant tumours. Desmoplastic trichoepithelioma (DTE), some types of basal cell carcinoma (BCC) (infiltrating and morphoeic BCC) and microcystic adnexal carcinoma (MAC) belong to a group of tumours known as sclerosing adnexal neoplasms (SAN) that are frequently difficult to differentiate and often require immunohistochemistry for diagnosis. The aim of this study was to assess the usefulness of Ln-γ 2 expression in the differential diagnosis of DTE, infiltrating/morphoeic BCC, MAC and syringoma. Methods and results In this study, we compared the expression of Ln-γ 2 in infiltrating/morphoeic BCC (n = 28), DTE (n = 26), MAC (n = 10) and syringoma (n = 20). Immunohistochemically, Ln-γ 2 positivity was noted in 96% (27 cases) of infiltrating/morphoeic BCC and 90% (nine cases) of MAC, while all DTE and syringoma cases were negative. Furthermore, Ln-γ 2 expression pattern in infiltrating/morphoeic BCC was different from that in MAC. Ln-γ 2 expression was found in the cytoplasm of tumour cells in infiltrating/morphoeic BCC tumour cells, while in MAC linear expression was noted both along tumour nests and in the cytoplasm. Conclusion Ln-γ 2 is a helpful adjunct in the differential diagnosis of SAN.

We previously characterized the morphological characteristics of malignant pleural mesothelioma (MPM) cells with 9p21 homozygous deletion (HD) using a combination of the virtual microscopy and fluorescence in situ hybridization (FISH). In this study, we investigated whether MPM cells with BRCA1-associated protein 1 (BAP1) loss show the same morphological characteristics identified in MPM cells with 9p21 HD. MPM cells with either BAP1 loss detected by immunocytochemistry (ICC) or 9p21 HD detected by FISH were identified via virtual microscopy prior to ICC or FISH, followed by analysis and quantification of their morphological characteristics. MPM cells with BAP1 loss or 9p21 HD exhibited significantly more frequent cell-in-cell engulfment, multinucleation, and larger multicellular clusters composed of more than 10 cells than reactive mesothelial cells. In conclusion, MPM cells with BAP1 loss or 9p21 HD share similar cytological features, indicating that the same morphological criteria can be used to detect MPM cells harboring such genetic aberrations.

Upper-lobe predominance of elastofibrosis is agreed upon for the diagnosis of clinical pleuroparenchymal fibroelastosis (PPFE). We herein describe a patient with dermatomyositis-related interstitial pneumonia with a histology of lower-lobe predominant PPFE. A 71-year-old woman who had been diagnosed with dermatomyositis-related interstitial pneumonia died of respiratory failure. The computed tomography patterns of the lower lobes showed reticular and ground-glass opacities with traction bronchiectasis. An autopsy revealed that the bilateral lower lobes were sclerotic with decreased air volume. A microscopic examination of the lower lobes showed pleural fibrosis and subpleural elastofibrosis without the structural destruction, indicative of histological PPFE. PPFE histology was also evident in the upper lobes but relatively modest compared to that of the lower lobes. In addition, because the computed tomography images of the patient were suggestive of non-PPFE-type fibrosis, lower-lobe dominant PPFE might be overlooked in daily practice.

Objectives Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. Methods Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. Results Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. Conclusions Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.

Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low- to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95-NCOA1 or -NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95-RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.

Background: This study was performed to investigate the clinical significance of miR-4535 and miR-1915-5p in severe chorioamnionitis. Materials & methods: Amniotic fluid samples from 37 patients with severe chorioamnionitis were subjected to miRNA array analysis and ddPCR™. Diagnostic values were assessed using the receiver operating characteristic curve. The patients were separated into three groups according to Blanc’s criteria. Results: The expression of miR-4535 and miR-1915-5p was significantly correlated with the copy number of 16S rDNA, had extremely high diagnostic accuracy for severe chorioamnionitis, and was linked to maternal and fetal inflammation. Conclusion: miR-4535 and miR-1915-5p serve as promising biomarkers for the diagnosis of severe chorioamnionitis., Lay abstract Chorioamnionitis and fetal inflammatory response syndrome, which is linked to chorioamnionitis, are considered serious diseases in perinatal care. In this study, miR-4535 and miR-1915-5p are recognized as promising biomarkers for the diagnosis of chorioamnionitis before delivery. In particular, the increased expression of miR-4535 in amniotic fluid is expected to be regarded as a positive indicator for fetal inflammatory response syndrome, and the elevated expression of miR-4535 in serum is also considered to predictively diagnose intrauterine infection in pregnancy. Our results highlight that further studies should explore the underlying clinical significance of miR-4535 and miR-1915-5p.

Early diagnosis and initiation of treatment lead to longer survival in malignant pleural mesothelioma (MPM). Since more than 80% of MPM cases start with pleural effusions, cytologic diagnosis with effusion smears is critical for improved clinical outcomes. A three-step approach is usually undertaken for the diagnosis of MPM. The first step is to detect atypical mesothelial cells; the second step is to verify its mesothelial origin using immunohistochemistry (IHC); the third step is differentiating MPM cells from reactive mesothelial hyperplasia (RMH) or reactive mesothelial cells (RMC). Genomic-based ancillary assays that can effectively distinguish MPM from RMH/RMC, including BRCA-1 associated protein-1 (BAP1) and methylthioadenosine phosphorylase (MTAP) IHC and 9p21 and neurofibromin 2 (NF2) fluorescence in situ hybridization (FISH), have recently been developed. These ancillary assays enable the confirmation of the neoplastic and malignant nature of atypical mesothelial cells detected in the cytologic preparations or that of a single layer of surface mesothelial cells found in the in situ phase of mesothelioma. However, cautious interpretation and familiarity with potential challenges of data interpretation while assessing BAP1 and MTAP IHC results in cell blocks are warranted.

Desmoplastic fibroblastoma (also known as collagenous fibroma) is an uncommon benign fibroblastic/ myofibroblastic neoplasm that primarily arises in the subcutaneous tissue of upper extremity. Magnetic resonance imaging reveals a well-defined mass in intimate association with dense connective tissue and prominent low signal intensity on all pulse sequences. Peripheral and septal enhancement is usually seen after intravenous contrast. Histologically, the lesion is paucicellular and consists of spindle to stellate-shaped cells embedded in a collagenous or myxocollagenous stroma with low vascularity. Diffuse and strong nuclear immunoreactivity for FOS-like antigen 1 seems to be characteristic of desmoplastic fibroblastoma. Cytogenetic studies have demonstrated the presence of 11q12 rearrangements and an identical t(2;11)(q31;q12) translocation. This review provides an updated overview of the clinical, radiological, histological, cytogenetic and molecular genetic features of desmoplastic fibroblastoma and discusses the relationship to fibroma of tendon sheath.

Background Giant cell tumor of tendon sheath (GCTTS) is a benign soft-tissue tumor that occurs predominantly in the fingers, with the capacity for local recurrence. The cytogenetic hallmark of GCTTS is the presence of 1p13 rearrangement. Several chromosomal segments have been recognized as translocation partners to 1p13. Herein, we describe a novel cytogenetic finding of GCTTS arising in the right thumb of a 71-year-old man. Case report Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Magnetic resonance imaging demonstrated a nodular mass with reduced signal intensity on both T1- and T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images showed intense heterogeneous enhancement of the mass. After a needle biopsy, complete excision was performed. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy cells, and inflammatory cells. Cytogenetic analysis revealed a reciprocal t(1;1)(p13;p34) translocation as the sole structural aberration. Conclusion To the best of our knowledge, this is the first report of this tumor with t(1;1)(p13;p34).

INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:15 issue:6 pages:1037-1053 ispartof: location:United States status: published

Here, we present a 67-year-old Japanese man who developed insidious-onset nephrotic syndrome. He had a history of occupational asbestos exposure for about 8 years during his 30s, and was found to have pleural effusion 3 years before his present illness. At that time, repeated cytology testing of his pleural effusion found no malignant cells, and pleural biopsy found fibrous pleuritis without evidence of malignant mesothelioma. Percutaneous kidney biopsy found massive deposits of AA-type amyloid in the glomeruli, small arteries, and medulla. Computed tomography showed a calcified mass in the right lower lung that was positive for (67)Ga uptake, but transbronchial lung biopsy and bronchoalveolar lavage found no evidence of malignancy. He was diagnosed with rounded atelectasis and diffuse pleural thickening. As these benign asbestos-related diseases have no standard treatment, we administered low-dose angiotensin II receptor blocker to preserve kidney function. Unfortunately, his nephrotic syndrome persists, with progressive chronic kidney failure. Kidney involvement in patients with asbestos-related disease is rare. To our knowledge, this is the first case to present with secondary amyloidosis. Kidney biopsy should be considered for patients with existing asbestos-related pleuropulmonary diseases who have urinary abnormalities or renal dysfunction, to clarify the incidence and pathophysiology of renal manifestations.

BRCA1-associated protein 1 (BAP1) or methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) or 9p21 fluorescence in situ hybridization (FISH) are useful for the diagnosis of malignant pleural mesothelioma (MPM). However, the effect of these assays on the diagnostic yield of effusion cytology in MPM cases with suspicious cytomorphology or the diagnostic challenges in BAP1 or MTAP IHC have not been fully elucidated. Two cohorts of cytologic preparations obtained from pleural effusions were examined: MPM cases in cohort 1 were used to evaluate whether BAP1 or MTAP IHC or 9p21 FISH increase the diagnostic yield of effusion cytology; cohort 2 included cases suspicious for MPM, to which BAP1 or MTAP IHC was applied to clarify the challenges in the clinical assessment of these assays. In cohort 1 (n = 28), either assay elevated 62.5% of class II or III cases to class V. In cohort 2 (n = 139), 21.7% of BAP1 immunocytochemistry in smears and 10.6% of BAP1 IHC and 9.4% of MTAP IHC in cell blocks, were identified to be challenging. The application of genomic-based assays increased the diagnostic yield of effusion cytology in the diagnosis of MPM. However, diagnostic challenges limit the application of these assays in some cases.

Objectives Histologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis. Materials and Methods We examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH. Results MTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (κ = 0.63). Conclusions With an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis.

Objectives The separation of benign from malignant mesothelial proliferations and exact subclassification of mesothelioma subtypes is crucial to determining patient care and prognosis but morphologically can be very difficult. Methods This session of the 2018 IMIG meeting addressed these problems. Results A new immunohistochemical marker, methylthioadenosine phosphorylase, was shown to correlate well with CDKN2A FISH and is cheaper and faster to run. A 117 gene expression panel also provided good separation on both tissue biopsy and cytology samples. Review of a series of mesotheliomas thought to be biphasic produced only a moderate level of agreement among expert pathologists with some cases being classified as purely epithelioid or sarcomatoid; these classifications had prognostic significance. The entity called transitional mesothelioma was found to behave exactly like sarcomatoid mesothelioma. RNA-seq analysis of a large series of mesotheliomas from a public database showed that, genetically, the morphologic breakdown into epithelioid, sarcomatoid, or biphasic mesotheliomas is artificial because there is a continuous spectrum of genomic changes. There are now criteria for the diagnosis of mesothelioma in situ and this is potentially important, since such cases might be curable. Conclusions This session documented new morphological and molecular approaches to separating benign from malignant mesothelial proliferations and to subclassifying malignant mesoteheliomas in clinical relevant ways.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (

IgG4-related hypophysitis, which is the pituitary gland inflammation caused by IgG4 positive lymphocytes, can affect cavernous sinus and orbital apex leading to developing cranial nerve related symptoms such as orbital apex syndrome (OAS). Here we report a case of hypopituitarism associated with OAS caused by pituitary metastasis of the breast cancer with elevated serum IgG4 level, who initially resembled to IgG4-related hypophysitis. Although this case had some features in common with igG4-related hypophysitis. The symptoms and pituitary enlargement were typical. However, steroid treatment did not improve her symptoms. Thus, we performed a tissue biopsy. Histopathologic examination of the hypophyseal tumor confirmed metastatic breast cancer in her pituitary. Pituitary metastatic tumor should be suspected if a case with OAS was once diagnosed as a cancer., Highlights • We experienced the case with pituitary metastatic tumor mimicking IgG4-related hypophysitis. • Our case demonstrated orbital apex syndrome associated with high level of serum IgG4 and pituitary gland enlargement. • The pathological finding confirmed pituitary metastatic tumor.

BACKGROUND Homozygous deletion of 9p21 detected by fluorescence in situ hybridization (FISH) and loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC) are useful for the differentiation between malignant pleural mesothelioma (MPM) and reactive mesothelial hyperplasia. The authors previously described that IHC expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, was correlated with the deletion status of 9p21 FISH in MPM tissues. In the current study, the authors investigated whether a combination of MTAP and BAP1 IHC could distinguish MPM from reactive mesothelial cells (RMC) in cell blocks obtained from pleural effusions. METHODS The authors examined IHC expression of MTAP and BAP1 in cell blocks obtained from pleural effusions of 45 cases of MPM and 21 cases of reactive mesothelial hyperplasia. Furthermore, IHC expression of MTAP was compared with the deletion status of 9p21 FISH. RESULTS MTAP and BAP1 IHC differentiated MPM from RMC with 100% specificity for both and sensitivities of 42.2% and 60.0%, respectively. The combination of MTAP and BAP1 IHC yielded a sensitivity of 77.8%, which was higher than that of BAP1 IHC alone or 9p21 FISH alone (62.2%). Moreover, a high degree of concordance was observed between the results of MTAP IHC and 9p21 FISH in cell blocks. CONCLUSIONS A combination of MTAP and BAP1 IHC in cell blocks from pleural effusions appears to be a reliable and useful method for differentiating MPM cells from RMC and can be used in the routine diagnosis of MPM. Cancer Cytopathol 2017. © 2017 American Cancer Society.

Aims We occasionally encounter patients with idiopathic pulmonary fibrosis (IPF) who have similar imaging patterns to those of pleuroparenchymal fibroelastosis (PPFE) in the upper lung fields but are not diagnosed as having PPFE clinically. The aim of this study is to identify the clinicopathological features and intrapulmonary distribution of elastic fibres and collagen fibres in these patients. Methods and results We retrospectively reviewed the medical records of patients with a clinical diagnosis of IPF, and selected consecutive patients who underwent autopsy or pneumonectomy for lung transplantation. Patients with histologically confirmed PPFE were also reviewed for comparison. We quantified the collagen fibres and elastic fibres in each lobe as a percentage of the non-aerated lung area (collagen fibre score and elastic fibre score, respectively) in histological specimens by using whole-slide image analysis, and compared these scores between IPF and PPFE patients. In a total of 55 patients (IPF, 48; PPFE, 7), there were no significant differences in the collagen fibre scores between IPF and PPFE patients. The elastic fibre scores in the upper lobe in PPFE patients were significantly higher than those in IPF patients (23.5 versus 10.3, P = 0.005). However, it is of note that, in 12 of 48 IPF patients, the elastic fibre scores of the upper lobes were above the first quartile of those in PPFE patients. Conclusions IPF occasionally shows intense elastosis in the upper lobes, and such cases are histologically indistinguishable from PPFE. There seem to be histologically borderline cases between PPFE and IPF.

// Toyonobu Maeda 1, * , Atsuko Suzuki 1, * , Kaori Koga 2 , Chihiro Miyamoto 3 , Yojiro Maehata 3 , Shigeyuki Ozawa 4 , Ryu-Ichiro Hata 4, 5 , Yoji Nagashima 6 , Kazuki Nabeshima 2 , Kaoru Miyazaki 7 and Yasumasa Kato 1 1 Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, Koriyama 963-8611, Japan 2 Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka 814-0180, Japan 3 Department of Oral Science, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan 4 Department of Dentomaxillofacial Diagnosis and Treatment, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan 5 Oral Health Science Research Center, Kanagawa Dental University Graduate School of Dentistry, Yokosuka 238-8580, Japan 6 Department of Surgical Pathology, Tokyo Women’s Medical University Hospital, Tokyo 162-8666, Japan 7 Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan * These authors contributed equally to this work Correspondence to: Yasumasa Kato, email: yasumasa-kato@umin.ac.jp Keywords: MMP-9, acidic extracellular pH, TRPM5, melanoma, metastasis Received: April 28, 2017 Accepted: August 27, 2017 Published: September 11, 2017 ABSTRACT Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH e ) has been found to increase intracellular Ca 2+ and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca 2+ -dependent monovalent cation channel, is associated with acidic pH e signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH e -induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pH e -induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pH e critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pH e . Treatment of tumor bearing mice with triphenylphosphine oxide (TPPO), an inhibitor of TRPM5, significantly reduced spontaneous lung metastasis. In silico analysis of clinical samples showed that high TRPM5 mRNA expression correlated with poor overall survival rate in patients with melanoma and gastric cancer but not in patients with cancers of the ovary, lung, breast, and rectum. These results showed that TRPM5 amplifies acidic pH e signaling and may be a promising target for preventing metastasis of some types of tumor.

Sarcoma is an uncommon histopathological presentation of sinonasal tumors, comprising ~15% of all cases; liposarcoma is particularly uncommon. An analysis of the available medical literature revealed no prior reports of dedifferentiated liposarcoma (DDLPS) of the sinonasal cavity. This case report presents a rare case of DDLPS of the sinonasal cavity. A 40-year old six-week pregnant female was admitted with a left nasal obstruction. Endoscopic evaluation of the left nasal cavity revealed a polypoid lesion. A computed tomography scan indicated a mass invading the left nasal cavity, maxillary sinus and anterior ethmoid sinus with focal destruction of the surrounding bone. A biopsy of the tumor was performed and hematoxylin and eosin staining of the tissue sections revealed proliferation of atypical and pleomorphic spindle cells with enlarged or elongated hyperchromatic nuclei and occasional vacuolated cytoplasm arranged in short interlacing fascicles or storiform structures, accompanied by tumor necrosis. These findings were consistent with undifferentiated pleomorphic sarcoma. Immunohistochemically, the tumor cells were positive for cyclin dependent kinase 4, mouse double minute 2 homolog (MDM2) and adipophilin. Fluorescence in situ hybridization (FISH) analysis revealed amplification of the MDM2 gene. Recently, undifferentiated pleomorphic sarcoma without areas of well-differentiated liposarcoma but with MDM2 amplification is regarded as conventional DDLPS. In the present case, the tumor was diagnosed as a DDLPS due to the results of histopathological, immunohistochemical and FISH analysis.

Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease characterized by the formation of suprabasal cleavage and acantholysis. As this disease almost always affects the oral mucosa, conventional cytological smears of oral lesions can be used for the initial diagnosis of PV. We report two cases of PV that were initially diagnosed based on cytological smears of an oral sample. As atypical squamous cells were present even in the liquid-based cytological (LBC) smears of the oral lesion in these two cases, this ultimately led to the misinterpretation of squamous cell carcinoma. These findings demonstrate that cytological mimicry of oral PV can occur in malignant cases when there is an absence of appropriate clinical information.

Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare subtype of idiopathic interstitial pneumonia that consists of alveolar septal elastosis and intra-alveolar collagenosis, which is predominantly located in the upper lobes. The aim of this study was to examine the remodeling of the pulmonary arteries in patients with IPPFE. This study included 18 patients with IPPFE, 24 patients with idiopathic pulmonary fibrosis (IPF), and 5 patients without pulmonary disease as controls. We selected muscular pulmonary arteries and calculated the percentage of the thickness of each layer of the wall (intima, media, and adventitia) in relation to the external diameter. We also quantified the percentage of areas of elastic fiber in the media divided by the whole area of the media (medial elastic fiber score). The percentage of adventitial thickness in IPPFE was significantly higher than that in IPF and in control lungs. The percentage of medial thickness did not differ statistically between IPPFE and IPF. However, the medial elastic fiber score in IPPFE was also significantly larger than that in IPF and control lungs. These results suggest that collagenous thickening of the adventitia and medial elastosis are distinct histological features in the muscular pulmonary arteries of patients with IPPFE.

Squamous cell carcinoma of the external auditory canal (SCC‐EAC) is rare and has a poor prognosis. The SCC‐EAC cases with high‐grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low‐grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP‐2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP‐2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC‐EAC patients. High tumoral emmprin expression was associated with high­grade TB, whereas high stromal CD73 expression was associated with high‐grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP‐2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP‐2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP‐2 in tumor invasiveness., High expression of tumoral emmprin and stromal CD73 is an independent poor prognostic factor in pretreatment biopsy samples of squamous cell carcinoma of the external auditory canal. High tumoral emmprin expression is associated with high‐grade tumor budding; high stromal CD73 expression is associated with high‐grade poorly differentiated clusters. Emmprin and CD73 form a complex, and MMP‐2 production from fibroblasts is reduced by knockdown of CD73 in fibroblasts cocultured with squamous cell carcinoma cells.

Objectives Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16 INK4A ( p16 ) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH. Materials and methods We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis. Results Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%). Conclusions A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.

A 55-year-old man was admitted to our hospital for investigation of high fever, decreased consciousness and bilateral visual impairment. His cerebrospinal fluid analysis revealed pleocytosis of mononuclear cells and an increased protein concentration. FLAIR images revealed multiple high-intensity lesions in the frontal lobe, part of which was enhanced with gadolinium. Despite initiating treatment with acyclovir and corticosteroids, his consciousness and visual acuity deteriorated. Immunopathological examination of brain biopsies showed numerous herpes simplex virus type 2-positive neurons and macrophages, leading to a diagnosis of herpes simplex encephalitis (HSE). Fundoscopic examination revealed multiple foci of retinitis with vasculopathies, and inflammation in the anterior chamber and vitreous, indicating acute retinal necrosis (ARN). Foscarnet treatment was initiated in place of acyclovir and his consciousness improved, with a slight improvement in visual acuity. ARN is typically caused by a herpes virus infection limited to the eyeball, and rarely in combination with HSE. In such cases, there is a latency of approximately 2-4 weeks between ARN and the onset of encephalitis. Our case is unique in that HSE and ARN developed simultaneously, and it highlights that there may not always be a latency between the onsets of the two disorders. Finally, foscarnet should be considered in cases of HSE and ARN with acyclovir resistance.

Differentiation of malignant pleural mesothelioma (MPM) from benign mesothelial proliferation remains problematic. Loss of nuclear staining of BRCA1-associated protein 1 (BAP1; detected using immunohistochemistry (IHC)) and homozygous deletion (HD) of p16 (detected using fluorescence in situ hybridization (FISH)) are useful for differentiation of MPM from reactive mesothelial hyperplasia (RMH), but the correlation between BAP1 expression loss and p16 HD has not been fully described. We performed BAP1 IHC and p16-specific FISH for 40 MPM and 20 RMH cases, and measured proportions of cells showing BAP1 expression and p16 HD for each case. The diagnostic accuracy for MPM and the cut-off values of the two methods were assessed using receiver operating characteristic (ROC) analysis. BAP1 expression loss, p16 HD and coexistence of both were present in 27 (67.5 %), 27 (67.5 %) and 17 (42.5 %) MPM cases, respectively. Three MPM cases (7.5 %) and all 20 RMH cases had neither BAP1 loss nor p16 HD. There was no correlation between the results of the two methods. Their combination showed higher sensitivity (92.5 %, 37/40) and estimated probability than BAP1 IHC and p16-specific FISH used alone. BAP1 IHC and p16-specific FISH have independent diagnostic value, and have increased reliability when used in combination, for MPM diagnosis.

Because most of malignant pleural mesothelioma (MPM) patients first present with pleural effusion, detection of mesothelioma cells on effusion smears is critical for early diagnosis. Recently, accumulating evidence indicating that the cytological diagnosis of MPM supported by ancillary techniques is as reliable as that based on histopathology has led to new guidelines for the cytopathologic diagnosis of MPM. Based on the guidelines, a combination of cytomorphological criteria and verification by ancillary techniques is required for the cytologic diagnosis of MPM. Detection of p16 homozygous deletion by fluorescence in situ hybridization (FISH) is the most reliable ancillary technique for differentiating MPM from reactive mesothelial cells (RMC) because of its relatively high sensitivity and extremely high specificity. We showed that the p16 deletion status of MPM cells in pleural effusions reflected that of the underlying invasive MPM tissues, indicating the usefulness of p16 FISH in effusion smear cytology for MPM diagnosis. Thus, for differentiating MPM from RMC, we propose to perform p16 FISH as often as possible. A positive p16 homozygous deletion supports the diagnosis of MPM. However, a negative result does not rule out the possibility of MPM. In such cases, a morphological assessment is critical. Therefore, we analyzed the morphological characteristics of p16 deletion-positive mesothelioma cells using a combination of virtual microscopy and p16 FISH, and identified three morphological characteristics useful for the differentiation, including cell-in-cell engulfment with or without hump formation, multinucleate cells, and larger berry-like cell aggregates. Diagn. Cytopathol. 2016;44:774-780. © 2016 Wiley Periodicals, Inc.

Background Mesothelioma patients often present with serosal effusions, which are ideal for cytopathological diagnoses. However, the morphological overlap between malignant and benign mesothelial proliferation can make a conclusive cytological diagnosis of mesothelioma elusive because immunohistochemical staining does not discriminate definitively between the two in this setting. p16 is deleted in up to 80% of pleural mesotheliomas. The aim of this study was to establish the correlation between the p16 deletion status of the cell block with that of its corresponding tumor using fluorescence in situ hybridization (FISH) analysis for individual patient tumors. Methods Twenty-two biopsies and 24 corresponding cell blocks, containing serosal effusions with atypical mesothelial cells from 22 patients with histologically confirmed pleural mesotheliomas, were analyzed with p16 FISH. Seventeen cell blocks consisting of serosal effusions with reactive mesothelial cells from nonmesothelioma cases were also analyzed. Combined immunofluorescence and FISH were also performed. Results Seventeen of the 22 mesothelioma patients (77.3%) showed homozygous deletions of p16 in the tumor tissue and in the atypical mesothelial cells from the cell blocks. p16 FISH followed by immunofluorescence with EMA was helpful towards identifying the mesothelioma cells in the cell blocks. Conclusion We confirmed that the p16 FISH results obtained from the cell blocks are as reliable as those from the tissue sections. Cell block analysis is recommended for patients with serosal effusions of unknown origins with the following methods: immunohistochemistry should be performed to validate the mesothelial origin, and p16 FISH should be performed to confirm malignancy. Diagn. Cytopathol. 2016;44:591-598. © 2016 Wiley Periodicals, Inc.

Erythropoietin-producing hepatocellular receptor-2 (EphA2) overexpression is prevalent in many types of human cancers, and it has been reported that high EphA2 expression is correlated with malignancy. Recent studies revealed that processing of EphA2 by cleaving off the N-terminal portion by membrane-type 1 matrix metalloproteinase (MT1-MMP) promotes invasion via stimulation of Ras in cancer cells in vitro. The objectives of this study were to investigate the presence and role of EphA2 processing in cutaneous squamous cell carcinoma (SCC) tissues. EphA2 (C-terminal and N-terminal) and MT1-MMP expression patterns and levels were analyzed immunohistochemically in SCC (n = 70) and Bowen disease (BD; n = 20). Levels of MT1-MMP and EphA2 expression were evaluated using digital image analysis. Proximity between MT1-MMP and EphA2 in cancer cells and its effect on EphA2 processing were investigated using a combination of in situ proximity ligation assay (PLA) and Western blotting. Immunohistochemical analyses showed that levels of EphA2 N-terminal expression were significantly lower than those of EphA2 C-terminal expression in SCC, whereas levels of EphA2 C- and N-terminal expression were similar in BD. Western blotting showed processed EphA2 fragments in human SCC tissues. Expression levels of MT1-MMP, EphA2, and processed EphA2 fragments were higher in SCC than BD. Proximity between MT1-MMP and EphA2 in SCC was demonstrated by in situ PLA. Our results suggest possible involvement of MT1-MMP processing of EphA2 in invasiveness of cutaneous SCC.

Ordinary lipoma is cytogenetically characterized by structural rearrangements, particularly translocations, of 12q13-15. By contrast, atypical lipomatous tumors exhibit supernumerary ring or giant marker chromosomes that are composed mainly of amplified material from the 12q13-15 chromosome segment. The present study describes the cytogenetic and molecular cytogenetic findings from a lipomatous tumor with minimal nuclear atypia that was identified in a 49-year-old female patient. Magnetic resonance imaging of the right shoulder revealed a 13-cm fatty mass in the subcutaneous layer that possessed only pencil-line septa. Contrast-enhanced fat-suppressed T1-weighted images demonstrated faint enhancement. A marginal excision was performed. Histologically, the tumor was composed of lobules that consisted of mature adipocytes separated by thin fibrous septa. There was minimal nuclear atypia in certain cells, and a small number of binucleated cells were also observed within the tumor. Immunohistochemically, the tumor cells did not reveal the expression of murine double-minute 2 (MDM2). Cytogenetic analysis revealed a complex karyotype with several numerical and structural alterations, including 12q rearrangements. Spectral karyotyping demonstrated a duplication of chromosome segment 12q13-15. Interphase fluorescence in situ hybridization analysis revealed no MDM2 gene amplification. The present case indicates that duplication of 12q may be associated with minimal nuclear atypia in a subset of lipomatous tumors.

The pathogenesis of pleuroparenchymal fibroelastosis (PPFE), a rare interstitial lung disease, remains unclear. Based on previous reports and our experience, we hypothesized that alveolar epithelial denudation (AED) was involved in the pathogenesis of PPFE. This multicenter retrospective study investigated the percentage of AED and the features of the denudated areas in 26 PPFE cases, 30 idiopathic pulmonary fibrosis (IPF) cases, and 29 controls. PPFE patients had lower forced vital capacities and higher residual volume/total lung capacities in pulmonary function tests compared to IPF and control patients. Histopathologically, subpleural fibroelastosis was observed in PPFE, and AED was observed in 12.01% of cases in the subpleural or interlobular septa regardless of fibroelastosis. The percentage of AED in the PPFE group was significantly higher than that in the IPF group (6.84%, p = 0.03) and the normal group (1.19%, p &lt, 0.001). In the IPF group, the percentage of AED and the presence of PPFE-like lesions in the upper lobes were examined radiologically, but no correlation was found. We showed that AED frequently occurred in PPFE. AED was less frequent in IPF, which, in combination with imaging data, suggests that PPFE may have a different pathogenesis from IPF.

An 80-year-old male with previous workplace exposure to asbestos presented with a history of an increase in the pulmonary-to-hilar mass, measuring more than 50 mm in diameter, likely in the right lower lobe. We first interpreted it as suspicious of primary lung adenocarcinoma with direct invasion to the right hilar lymph node. A right middle and lower lobectomy with partial resection of upper lobe was performed, and gross examination showed a hilar tumor lesion, involving the middle/lower lobe to hilar lymph node and looking whitish to yellow-grayish, partly adjacent to the right pulmonary artery. On microscopic examination, the tumor was located on the extrapulmonary, interlobar pleural fissure, predominantly composed of a proliferation of atypical epithelioid cells, often arranged in an irregular and fused tubular growth pattern with an involvement of pulmonary artery. Immunohistochemically, these atypical cells are positive for several mesothelial markers, including calretinin, cytokeratin 5/6, and WT-1, whereas negative for thyroid transcription factor 1. Furthermore, p16 deletions were specifically detected by fluorescence in situ hybridization, and electron microscopy showed numerous, significantly elongated microvilli. Taken together, we finally made a diagnosis of localized malignant pleural mesothelioma, epithelioid-type, arising in the right interlobar fissure between lower and middle lobes. We should be aware that, owing to its characteristic features, clinicians and pathologists might be able to raise interlobar fissure localized malignant pleural mesothelioma as one of the differential diagnoses, based on careful clinicopathological examinations.

Patients with autoimmune disease–related interstitial lung disease (AID-ILD) occasionally develop radiologic pleuroparenchymal fibroelastosis (PPFE)–like lesions. However, the significance of AID as an etiology of PPFE has not been fully elucidated. The aim of this study is to verify the increase of elastic fibers in AID-ILD patients and evaluate the prevalence of histological PPFE in patients with AID-ILD. We selected cases of clinically diagnosed AID-ILD and idiopathic pulmonary fibrosis (IPF), in which an autopsy had been performed or in which the patient had undergone pneumonectomy for lung transplantation. We quantified the collagen fibers and elastic fibers in each lobe as the percentage of the non-aerated lung area (collagen fiber score and elastic fiber score, respectively) in histological specimens from a total of 73 patients (AID-ILD, n = 24; IPF, n = 49). There were no significant differences in the collagen fiber scores of the AID-ILD and IPF groups. Meanwhile, the elastic fiber scores of the AID-ILD group were significantly greater than those of the IPF group in the whole lung (17.3 ± 7.70 vs 11.6 ± 4.55), and the upper (16.6 ± 8.11 vs 11.2 ± 5.18), and lower (18.0 ± 9.68 vs 12.0 ± 5.55) lobes (all p

An 80-year-old woman was referred to our hospital due to the presence of a mass that was identified on a chest X-ray. A further investigation demonstrated advanced adenoid cystic carcinoma of the lungs. Anti-cancer chemotherapy with docetaxel was carried out and the lesion remained as stable disease. Subsequently, pleural effusion was detected, and an investigation of the pleural effusion revealed the existence of malignant cells with an epidermal growth factor (EGFR) mutation. Gefitinib was administered and the pleural effusion resolved. This is the first case of a positive EGFR mutation of adenoid cystic carcinoma of the lung with a favorable response to an EGFR-tyrosine kinase inhibitor.