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Introduction Desmoplastic malignant pleural mesothelioma (DMPM) is a sarcoma type mesothelioma, comprising about 5% of malignant pleural mesotheliomas. Although effusion cytology is commonly used as the primary diagnostic approach for mesothelioma, this may not be useful for DMPM due to its desmoplastic nature and bland cellular atypia. We hereby report a case of DMPM diagnosed through autopsy along with its cytological features that have not been described previously. Case presentation A male in his 60s with a history of occupational asbestos exposure was referred to our hospital with right chest pain. Chest computed tomography scan showed right pleural effusion. Thirteen months later, the patient died of respiratory failure. In autopsy, the scrape-imprint smear and the pleural effusions cytology were performed. The scrape-imprint smear samples exhibited spindle cells with mild nuclear atypia and grooves with fibrous stroma. In the pleural effusion cytology, spindle cells having mild nuclear atypia and grooves with loose epithelial connections were observed. Histological examination of the right pleura showed spindle cells proliferating with dense collagen fibers, as seen in cytological samples, thus rendering the diagnosis of DMPM. Diagnosis was confirmed by fluorescence in situ hybridization. Conclusion Cytological procedures, such as pleural effusion cytology and scrape-imprinting method, may be useful as an ancillary tool in the diagnosis of rare tumors such as DMPM.

Composite hemangioendothelioma (CHE) displaying neuroendocrine differentiation is a rare histologic variant that is often mistaken for angiosarcoma, having a predilection for visceral locations and being associated with an aggressive clinical course. Their pathogenesis is still evolving, with only 2 cases to date from separate studies reporting a recurrent PTBP1-MAML2 fusion. Herein, we report two new cases of neuroendocrine CHE harboring PTBP1-MAML2 fusions occurring in two elderly patients (70-year-old male and 71-year-old female), both involving neck lymph nodes. The first case presented with multifocal cervical lymphadenopathy, while the second case occurred unifocally in an enlarged neck lymph node. Histologically, the tumors displayed heterogenous architectural patterns with areas reminiscent of benign cavernous hemangioma, retiform hemangioendothelioma, epithelioid hemangioendothelioma, and angiosarcoma. Cytologically, the cells were monotonous with round to ovoid nuclei, open to fine chromatin, scant to moderate cytoplasm, and frequent vacuolization. In addition, the first case showed focal solid areas of large epithelioid cells with severe nuclear atypia, enlarged nuclei and prominent nucleoli, resembling epithelioid angiosarcoma. Tumor cells were diffusely positive for vascular markers and focally positive for synaptophysin. In both cases, a next-generation sequencing fusion panel confirmed an in-frame fusion between PTBP1 exon 10 and MAML2 exon 2. One case with clinical follow-up showed stable recurrent disease and metastatic lung deposits following treatment. Both patients were alive at 3 months and one year following initial diagnosis. Our findings lend further support to classifying CHE with PTBP1-MAML2 fusions as a distinct variant of CHE with unique clinicopathologic features, including neuroendocrine features. This article is protected by copyright. All rights reserved.

Background Although evaluation of nuclear morphology plays a crucial role in the diagnosis and categorisation of breast lesions, the criteria used to assess nuclear atypia rely on the subjective evaluation of several features that may result in inter- and intra-observer variation. This study aims to refine the definitions of cytonuclear features in various breast lesions. Methods ImageJ was used to assess the nuclear morphological features including nuclear diameter, axis length, perimeter, area, circularity, and roundness in 160 breast lesions comprising ductal carcinoma in situ (DCIS), invasive breast carcinoma of no special type (IBC-NST), tubular carcinoma, usual ductal hyperplasia (UDH), columnar cell change (CCC) and flat epithelial atypia (FEA). Reference cells included normal epithelial cells, red blood cells (RBCs) and lymphocytes. Results Reference cells showed size differences not only between normal epithelial cells and RBCs but also between RBCs in varied-sized blood vessels. Nottingham grade nuclear pleomorphism scores 1 and 3 cut-offs in IBC, compared to normal epithelial cells, were 1.4x that of mean maximum Feret's diameter and 2.4x that of mean nuclear area, respectively. Nuclear morphometrics were significantly different in low-grade IBC-NST vs. tubular carcinoma, low-grade DCIS vs. UDH, and in CCC vs. FEA. No differences in the nuclear features between grade matched DCIS and IBC were identified. Conclusion This study provides a guide for the assessment of nuclear atypia in breast lesions, refines the comparison with reference cells and highlights the potential diagnostic value of image analysis tools in the era of digital pathology.

BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.

Here, we report two cases showing tumor-like white matter lesions; one case was diagnosed as having inflammatory disease, and the other was diagnosed as having astrocytoma. Their outcomes were completely distinct despite similar pathology. Prior to biopsy, perfusion computed tomography (CT) and magnetic resonance imaging (MRI) were conducted. The two mass-forming lesions were distinct in edema level and vascularity patterns on CT and MRI. However, pathological examination of brain biopsy specimens revealed commonalities, including (1) proliferation of glial cells, (2) perivascular lymphocytic infiltration, and (3) appearance of numerous macrophages. Although atypical astrocytes proliferated in both cases, nuclear atypia was more distinct in case 2 than in case 1. The immunohistochemical results were the same for both cases: isocitrate dehydrogenase 1 (IDH1) R132H mutation was negative, and alpha thalassaemia mental retardation X-linked (ATRX) was retained. Faint immunoreactivity for p53 was observed in a few glial cells, and Ki-67 immunoreactive cells were markedly reduced in numbers (< 1%). Inflammatory reactions were evident in both cases: T cells dominantly infiltrated over B cells in the perivascular area in case 1, whereas both T and B cells infiltrated in case 2. Molecular analysis revealed wild-type IDH1 and IDH2 in both cases. However, a telomerase reverse transcriptase (TERT) sequence mutation was detected in case 2 but not in case 1. Eventually, case 1 was diagnosed as having inflammatory lesions, whereas case 2 was diagnosed as having diffuse astrocytoma associated with inflammatory reactions. The prognosis was favorable for case 1, whereas case 2 died 10 months following biopsy. These data indicated the diagnostic value of molecular analysis, for example, a TERT mutation, in association with the radiological findings. Although in case 2, histopathological evidence did not suggest high-grade glioma, the case met the new diagnostic criteria: "diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma, World Health Organization (WHO) grade IV," according to cIMPACT-NOW, update 3. Thus, interdisciplinary approaches are essential for accurate diagnosis of newly categorized white matter diseases.

Malignant transformation of gastric leiomyoma has not been reported, and therefore it is considered to have virtually no malignant potential. We report a case of gastric leiomyosarcoma arising from leiomyoma. The patient is a 72-year-old man with a submucosal mass measuring 20 mm in diameter, which was incidentally identified by an endoscopic surveillance. A biopsy suggested a diagnosis of leiomyosarcoma, and local excision was performed. Pathological examination revealed that the tumor was composed of two distinct components: typical leiomyoma-like area in the periphery and leiomyosarcoma component exhibiting higher cellularity, prominent nuclear atypia, necrosis, and increased mitosis. Immunohistochemically, in the latter, p53 overexpression, increased Ki-67 labeling index, and attenuated expression of smooth muscle markers were noted. This is the first report to demonstrate the presence of leiomyoma-leiomyosarcoma sequence in the stomach that is well recognized in the uterus. Our observation highlights the potential occurrence of malignant transformation of gastrointestinal leiomyoma.

Background The Bethesda System for Reporting Thyroid Cytopathology contains an atypia of undetermined significance (AUS) category with heterogeneous and distinct inclusion criteria. The purpose of this study was to investigate differences in malignancy rates and molecular alterations based on the presence of different criteria. Methods A laboratory information search was conducted to identify thyroid fine-needle aspiration specimens signed out as AUS. The cases were reclassified as architectural atypia (3A), cytologic atypia (3C), both architectural and cytologic atypia (3B), or Hurthle cell aspirate (3H). Surgical follow-up and concurrent molecular test results, if available, were collected. Results Five hundred ten specimens, including 258 reclassified as 3A, 40 reclassified as 3B, 119 reclassified as 3C, and 86 reclassified as 3H, were identified. The risks of malignancy for the subcategories were 13.4%, 26.3%, 44.1%, and 13.8%, respectively. Additionally, BRAF V600E mutations were more prevalent in specimens with cytologic atypia (3B/3C), whereas low-risk alterations, including KRAS, PTEN, and PAX8-PPARy2, were more prevalent in those with architectural atypia (3A). Conclusions Subdividing AUS specimens on the basis of the type of atypia can yield categories associated with distinct molecular alterations and risks of malignancy.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.

Context.— Female adnexal tumor of probable Wolffian origin (FATWO) often is a diagnostic challenge given its rarity, histologic heterogeneity, and lack of specific immunoprofile. Objective.— To further understand the clinicopathologic and immunohistochemical features of this rare entity. Design.— We studied the clinical, morphologic, and immunohistochemical features of a cohort of 11 FATWO cases from our institute. Results.— Patients' age ranged from 25 to 76 years (mean, 55 years). Tumor size ranged from 0.5 to 18 cm (mean, 2.7 cm). Histopathologically, most tumors presented with low-grade cytologic features with low mitotic activity and lack of necrosis. Three main growth patterns were appreciated: solid, tubular, and sievelike patterns. Higher-grade nuclear atypia, increased mitotic activity, and focal necrosis were seen in 2 cases. These 2 cases were clinically considered malignant FATWO mainly because of their extra-adnexal involvement. Immunohistochemical studies found that tumor cells were positive for CD10 (11 of 11, 100%), AE1/3 (8 of 8, 100%), CAM 5.2 (4 of 5, 80%), and cytokeratin 7 (CK7; 7 of 10, 70%), and focally positive for calretinin (4 of 10, 40%), inhibin (4 of 10, 40%), epithelial membrane antigen (EMA; 3 of 9, 33%), and steroidogenic factor-1 (SF-1; 2 of 8, 25%). Lack of immunoreactivity to PAX8 and GATA3 in almost all cases indicates that FATWO is different from the tumors derived from the Müllerian or mesonephric origins. All patients with available follow-up had favorable prognosis. Conclusion.— The broad spectrum of clinical presentation, various morphologic features, and overlapping immunophenotype suggest that FATWO is a diagnosis of exclusion until it is further defined at the molecular and immunohistochemical levels.

Objective Primary osteosarcoma of the jaw bones is very rare, and histological features of gnathic osteosarcoma remain obscure. The purpose of this study was to describe the clinicopathological features of gnathic osteosarcoma. Materials and methods Seven cases of gnathic osteosarcoma from Japan diagnosed during the period between 2000 and 2016 were examined retrospectively. The histology of the surgical pathology materials was reviewed by two pathologists. Clinical information was obtained from the hospital's information system. Results Of the seven cases, two patients had secondary osteosarcomas. As for the five cases of primary osteosarcoma, their ages ranged from 26 to 58 years (mean: 36.2, median: 28). Histologically, three cases were fibrotic tumors composed of spindle‐shaped cells with mild to moderate nuclear atypia and the collagenous stroma accompanied by woven bones or mature lamellar‐like bones. Two cases had cartilage formation. MDM2 and CDK4 expression was observed in two out of three cases on immunostaining. The histopathology of these three cases was regarded as the counterpart of low‐grade osteosarcomas, namely, parosteal osteosarcoma and low‐grade central osteosarcoma, arising in long bones. Conclusions The surprisingly high incidence (60%, 3/5 cases) of low‐grade osteosarcoma explains the reason why gnathic osteosarcomas present a more favorable prognosis than osteosarcomas arising in long bones. Furthermore, it provides insight into the tumorigenesis mechanism of low‐grade osteosarcomas arising in the jaw and other sites.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor’s expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P

The term squamoid cyst of pancreatic ducts (SCOP) has been proposed recently, and it is a very rare benign lesion. We report a case of SCOP in a patient who underwent laparoscopic distal pancreatectomy. A 51-year-old woman presented with a pancreatic cystic lesion (3.3 cm) as an incidental finding on abdominal ultrasonography. A computed tomography scan showed a well-defined cystic lesion in the body of the pancreas with peripheral nodular calcification. Histology showed a unilocular cyst with a thin, fibrotic wall, and it was surrounded by normal-appearing pancreatic tissue. The lining of the cyst was composed of stratified non-keratinized squamous epithelium without significant nuclear atypia. Immunohistochemistry showed positive nuclear p63 expression in the cyst lining. The final diagnosis of SCOP was established. It is important to distinguish SCOPs from mucinous pancreatic cysts that have malignant potential. Preoperative diagnosis of SCOP is still difficult, and further studies are needed to identify specific preoperative characteristics that can accurately distinguish this lesion.

Complete hydatidiform mole (CHM) is a premalignant proliferative disease of the placenta characterized by misexpression of imprinted gene products, most notably p57. The majority of CHM exhibit immunohistochemical absence of p57 protein in villous mesenchyme (VM) and cytotrophoblast (CT) and are thus p57 VM/CT concordant. However, some gestations show loss of p57 in only VM or CT, either in all chorionic villi or a subset thereof (VM/CT discordant). Here, we present a rare case of a p57 VM/CT-discordant CHM with diffuse retention of p57 expression in VM but complete absence in CT. Histologically, the case exhibited typical features of CHM including trophoblast hyperplasia and severe nuclear atypia, but was unusual in the presence of gestational membranes identified ultrasonographically and histologically. Ploidy determination by FISH and genotyping by short tandem repeat analyses showed that this was a diploid gestation with variable allelic ratios and with an androgenetic lineage, similar to previously reported p57 VM/CT-discordant cases.

Russell bodies are accumulation of immunoglobulin in plasma cells forming intracytoplasmic inclusions. Russell body colitis is rare with only 3 cases described in the English literature up to date. We report a 78-year-old male with cirrhosis showing prominent cecal infiltration of Russell body containing plasma cells. Plasma cells showed no nuclear atypia or mitoses, and no evidence of light chain restriction. In this article, we report a fourth case of Russell body colitis, that is unique in being localized to the cecum in contrast to the other 3, 1 of which was in an inflammatory polyp in the sigmoid colon, 1 in a rectal tubulovillous adenoma and 1 as part of diffuse gastrointestinal disease. This is therefore the first report of localized Russell body typhlitis, occurring in a cirrhotic patient in whom an adjacent erosion was likely nonsteroidal anti-inflammatory drug-associated, a combination that may have facilitated the formation of Russell bodies.

Background Intraductal papillary mucinous neoplasm (IPMN) constitutes up to 20% of all pancreatic resections, and has been increasing in recent years. Histomorphological findings of IPMN are well established; however, there are not many published papers regarding the cytological findings of IPMN on fine needle aspiration (FNA) specimens. We review the cytomorphological features, molecular profile, imaging findings, and prognosis of IPMN. Methods The English literature was thoroughly searched with key phrases containing IPMN. Observations IPMN is a rare entity, affecting men and women equally and is usually diagnosed at the age of 60-70 years. The characteristic imaging features include a cystic lesion with associated dilatation of the main or branch pancreatic duct, and atrophy of surrounding pancreatic parenchyma. Cytomorphological features of IPMN include papillary fragments of mucinous epithelium in a background of abundant thick extracellular mucin, a hallmark feature. IPMNs should be evaluated for high-grade dysplasia, which manifests with nuclear atypia, nuclear moulding, prominent nucleoli, nuclear irregularity, and cellular crowding. Molecular profiling of IPMN along with carcinoembryonic antigen and amylase levels is useful in predicting malignancy or high-grade dysplasia arising in IPMN. Overall, the prognosis of IPMN is excellent except in those cases with high-grade dysplasia and malignant transformation. Postoperative surveillance is required for resected IPMNs. Conclusion IPMN requires a multidisciplinary approach for management. Cytomorphological findings of IPMN on FNA, in conjunction with tumour markers in pancreatic fluid cytology and imaging findings, are of paramount importance in clinical decision-making for IPMN.

We report 10 cases of a previously undescribed lesion within ovarian teratomas which we designate bronchus-like structures. The lesions occurred in patients aged 16 to 56 yr (mean: 36) and involved the left ovary (n=5) or right ovary (n=5). Nine cases were mature teratomas (dermoid cysts/mature cystic teratomas or mature solid teratomas), 1 with somatic malignant transformation, and 1 was an immature teratoma. The bronchus-like structures ranged in size from 2.5 to 10 mm and were unifocal (7 cases) or multifocal (3 cases). The morphology was relatively constant in all cases and characterised by a well-formed bronchus surrounded by glandular structures, some of which were dilated, separated by stroma containing a variable amount of smooth muscle. In all but 1 case, a proportion of the glands contained abundant foamy cytoplasm. There was little or no nuclear atypia or mitotic activity. At low-power, the glands often had a somewhat "infiltrative" appearance and one case was originally diagnosed as a "pulmonary-type" adenocarcinoma arising in a dermoid cyst. In all cases, there was diffuse staining of the bronchus and glands with TTF1 and Napsin A, confirming the cell lineage. Follow-up in 4 cases (18-130 mo; median: 64 mo) showed no evidence of recurrence; 1 patient died from an unrelated malignancy. In reporting this apparently rare but possibly underrecognized benign lesion arising within ovarian teratomas, we discuss the differential diagnosis and stress that pathologists should be aware of this phenomenon in order to avoid an erroneous diagnosis of malignancy.

BACKGROUND Appropriate surgical treatment of epithelial ovarian tumors is reliant on intraoperative diagnosis. A retrospective study to compare the diagnostic accuracies of imprint cytology (IC) with frozen section histology (FSH) in these tumors was performed. METHODS About 78 cases of IC-based and FSH-based diagnoses against the final histopathologic diagnoses in terms of both histologic subtype (serous, mucinous, endometrioid, or clear cell tumor) and behavioral type (benign, borderline, or malignant) were compared. The cytomorphologic features of the tumor cells (nuclear atypia, papillary clusters, adenoma cells, and necrosis) in relation to behavioral types were also evaluated. RESULTS While the diagnostic accuracy of IC and FSH were similar with respect to behavioral type (87% and 88%, respectively), the diagnostic accuracy of IC was superior to that of FSH with respect to histologic subtype (83% and 74%, respectively). Among histopathologically confirmed malignant tumors, the diagnostic accuracy of IC (62/64; 97%) was superior to that of FSH (58/64; 91%). The presence of necrosis and absence of adenoma cells were significantly more prevalent among malignant group than among borderline and benign groups (P

Uterine leiomyosarcoma (LMS) is a rare but deadly disease. Due to poor understanding of the molecular and genetic causes of the disease, the diagnosis of LMS has been based primarily on histology. Nuclear atypia is one of hallmarks in LMS, however, it also occurs in 2 clinically benign variants, including smooth muscle tumors with fumarate hydratase alteration (SMT‐FH) and leiomyoma with bizarre nuclei (LM‐BN). In addition to nuclear atypia, many well recognized biomarkers used for LMS are also frequently overexpressed in LM‐BN, and the histogenesis and molecular natures for LM‐BN and LMS remain largely unknown. To characterize the molecular profiling of LMS, SMT‐FH, and LM‐BN, we performed integrated comprehensive genomic profiling including whole‐genome sequencing (WGS) and RNA sequencing and genomic microarray analyses to assess genome‐wide copy number alterations (CNAs) and immunohistochemistry (IHC) in all 3 tumor types. We found that both LM‐BN and LMS showed genomic instability and harbored extensive CNAs throughout the whole genome. By contrast, the SMT‐FH presented its characteristic 1q43‐44 deletions in all cases tested, with minimal CNAs in the rest of genomic regions. Further analyses revealed that LMS and LM‐BN groups showed similar patterns of CNAs that are tended to cluster together and separated from the SMT‐FH group. The integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM‐BN and LMS. Our study suggests that LM‐BN, despite having similar nuclear atypia to SMT‐FH, showed similar genomic instability but distinct genomic alterations with its malignant counterpart of LMS. The integrated molecular profiling is of clinical importance in characterizing these rare uterine smooth muscle tumors., Leiomyosarcoma and 2 benign mimics (leiomyoma with FH alteration [SMT‐FH] and leiomyoma with bizarre nuclei [LM‐BN]) have characteristic nuclear atypia and often cause diagnostic challenge. LM‐BN and LMS are highly genomically unstable and harbor extensive CNAs in the genome, whereas SMT‐FH shows simple 1q43‐44 deletions. Integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM‐BN and LMS.

Breast cancer is the most common malignancy in female patients with Li–Fraumeni syndrome (LFS), a rare autosomal dominant hereditary syndrome characterized by germline TP53 mutations. Recent studies have shown that the majority of these tumors are estrogen receptor (ER) positive with frequent HER2 co-expression. However, the morphologic features of these tumors have not been as well studied as other germline-associated breast cancers. We evaluated the pathologic features of 27 invasive and in situ carcinomas from patients with known germline TP53 mutations collected through the Li–Fraumeni Consortium. Overall, 60% of cases were HER2 positive and 44% showed ER co-expression. Most DCIS was high nuclear grade with central necrosis and associated periductal fibrosis and lymphocytic response. Invasive carcinomas were mostly of ductal type (NOS), modified Scarff–Bloom–Richardson (mSBR) high grade, with marked nuclear atypia and high mitotic rate. Prominent tumor infiltrating lymphocytes, syncytial growth pattern, or pushing borders were not seen in these tumors. High p53 IHC expression was seen in tumors from individuals with germline TP53 missense mutations whereas little or no protein expression (

Three cases of primary giant cell tumors of the lung akin to those described in the soft tissues are presented. The patients are 3 men between the ages of 43 and 54 years who presented with nonspecific symptoms of cough, chest pain, and shortness of breath. None of the patients had any prior history of malignancy anywhere else. Diagnostic imaging disclosed the presence of an intrapulmonary mass. All the patients underwent lobectomy. Grossly, the tumors were described as solid, slightly hemorrhagic, and measuring between 1.8 and 2.4 cm in greatest diameter. Histologically, the tumors were characterized by a dual population of multinucleated giant cells admixed with a mononuclear proliferation. Nuclear atypia was mild to moderate, and mitotic activity varied but was under 5 mitotic figures per 10 high power fields. Immunohistochemical stains showed positive staining for vimentin, CD68, and cathepsin K, whereas the tumors were negative for keratin, TTF-1, p40, S-100 protein, and SABT-2. Clinical follow-up was obtained in 2 patients who have remained alive and without evidence of recurrence or metastasis up to 12 months after surgery. One patient was lost to follow-up. The current neoplasms represent a tumor that to the best of our knowledge has not been reported as a primary neoplasm of the lung. The cases herein described represent an unusual occurrence and should be maintained in the differential diagnosis of primary pulmonary tumors rich in multinucleated giant cells.

The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic, and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non-ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of ten Spitz nevi and seven Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency toward spindle cell cytomorphology, low grade nuclear atypia, and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.

While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naïve TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had “LGSC-like” morphology (i.e. Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these “usual HGSC-like” tumors often showed evidence of p53 dysfunction, including downregulation of expression (‘null’ or equivocal immunohistochemical p53 staining in 9/14, 64%) and/or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

There is a lack of consensus regarding the prognostic value of grading endocervical adenocarcinomas and currently, no universally applied, validated system for grading exists. Several grading schemes have been proposed, most incorporating an evaluation of tumor architecture and nuclear morphology and these are often based on the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, although some schemes modify the proportion of solid tumor required to separate grades 1 and 2 from 5% to 10%. In the absence of a validated system, we endorse this approach for most human papillomavirus-associated endocervical adenocarcinomas and, based on the available evidence, recommend that tumors with ≤10% solid growth be designated grade 1, 11% to 50% solid growth grade 2 and >50% solid growth grade 3. Tumors should be upgraded in the presence of marked nuclear atypia involving the majority (>50%) of the tumor. Grading is not recommended for human papillomavirus-independent adenocarcinomas, since no validated system has been suggested and most of these neoplasms exhibit intrinsically aggressive behavior regardless of their morphologic appearance. Importantly, grading should not be performed for gastric-type adenocarcinomas, particularly as these tumors may appear deceptively "low-grade" yet still exhibit aggressive behavior. Recently devised, validated and reproducible etiology and pattern-based tumor classification systems for endocervical adenocarcinomas appear to offer more effective risk stratification than tumor grading and, in the future, these systems may render the provision of a tumor grade redundant.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease in terms of morphological characteristics, protein expression profiles, genetic abnormalities, and potential for progression. Molecular heterogeneity has been extensively studied in DCIS. Yet morphological heterogeneity remains relatively undefined. This study investigated morphological intratumor heterogeneity in a series of 51 large DCIS. Nuclear atypia, DCIS architecture, necrosis, calcifications, stromal architecture, and stromal inflammation were assessed in one biopsy slide and three representative slides from each corresponding resection. For each histopathological feature, a histo-score was determined per slide and compared between the biopsy and the resection, as well as within a single resection. Statistical analysis comprised of Friedman tests, post hoc Wilcoxon tests with Bonferroni corrections, Mann-Whitney U tests, and chi-square tests. Despite substantial morphological heterogeneity in around 50% of DCIS, the histopathological assessment of the biopsy did not statistically significantly differ from the resection. Morphological heterogeneity was not significantly associated with patient age, DCIS size, or type of surgery, except for a weak association between heterogeneous stromal inflammation and smaller DCIS size. At the group level, the degree of heterogeneity did not significantly affect the representativity of a biopsy. At the individual patient level, however, the presence of necrosis, intraductal calcifications, myxoid stromal changes, and high-grade nuclear atypia was underestimated in a minority of DCIS patients. This study confirms the presence of morphological heterogeneity in DCIS for all six evaluated histopathological features. This should be kept in mind when taking biopsy-based treatment decisions for DCIS patients.

Clear cytoplasm is a major characteristic feature of most malignant renal neoplasms. Benign clear cells in the renal parenchyma, usually histiocytes, can occasionally be found, but they are infrequently of an epithelial nature. We report histological, immunohistochemical, ultrastructural, and cytogenomic features of clear epithelial cell clusters incidentally found in four kidney specimens. Multiple microscopic clear cell clusters were present in the cortex, often in subcapsular location. They were composed of large epithelial cells with strikingly clear cytoplasm, without nuclear atypia, arranged in solid nests, and some tubules with narrow lumina. Immunohistochemically, they were positive for AE1AE3, PAX 8, EMA, kidney-specific cadherin, cytokeratin 7, E cadherin, and CD117, with focal immunoreactivity for CD10. Carbonic anhydrase IX, vimentin, and markers related to apoptosis and proliferation were negative. Ultrastructurally, the cytoplasms were enlarged and poor in organelles, showing ballooning degeneration. Array comparative genomic hybridization showed no chromosomal gains or losses. Clear cell clusters constitute a rare finding in the kidney and must be differentiated from benign lesions (ectopic adrenal tissue, osmotic tubulopathy, histiocytic clusters, renal adenomas) and renal cell carcinomas. Clear cell clusters appear to be generated from "endocrine-type" atrophic tubules whose cells are enlarged due to intracellular oedema. Immunohistochemistry shows a distal nephron phenotype with a limited expression of a proximal marker, CD10. Coexisting chronic renal disease or ischemic conditions seem to be related to the development of clear cell clusters. Pathological, ultrastructural, and cytogenomic features do not support a preneoplastic nature of this lesion, at least in the cases studied here.

A woman in her 30s, who was clinically diagnosed with tuberous sclerosis complex, underwent lung transplantation due to lymphangioleiomyomatosis with concomitant multifocal micronodular pneumocyte hyperplasia (MMPH). Histologically, MMPH lesions demonstrated variety in histology; some showed homogenous cells with mild nuclear atypia and elastic fibers proliferation, and the others showed enlarged nuclei without elastic fibers. Because the natural history of MMPH is not well characterized, we used next-generation sequencing to perform a comprehensive genetic analysis for the MMPH lesions to explore their malignant potential. Regardless of their histological variety, three of four lesions had BRAF missense mutations, especially the types frequently detected in atypical adenomatous hyperplasia that is considered to be benign rather than a precursor of adenocarcinoma. None of them had major driver mutations of lung adenocarcinoma, except for BRAF mutations. In conclusion, our study of the lesions from this patient indicated the benign characteristic of MMPH.

Background: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites. Case Presentation: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT. Conclusion: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.

The histopathological diagnosis of prostatic adenocarcinoma is challenged by the existence of numerous benign mimics. Most of these lesions have no clinical significance and many do not need to be reported. Their clinical relevance lies in the risk that they are misinterpreted as cancer. This review presents the histopathological features of benign mimics and discusses their distinction from cancer. The lesions that are most often misdiagnosed as cancer are atrophy and its variants, including simple atrophy, partial atrophy and post-atrophic hyperplasia. Benign proliferations are a group of lesions with crowded small glands with no or little nuclear atypia. The most problematic entity of this group is adenosis, which may have a more alarming architecture than some cancers. A diagnostic problem with atrophy and several of the benign proliferations is that the glands often have a discontinuous or absent basal cell layer. Hyperplastic and metaplastic lesions include basal cell hyperplasia. Basal cell hyperplasia may especially mimic prostate cancer with its small dark glands, variable nuclear atypia and a pseudoinfiltrative pattern, which may be present. The anatomical structure that most often causes diagnostic problems is the seminal vesicle. The mucosa of the seminal vesicle contains small acini, often with very pronounced nuclear atypia that may be misinterpreted as cancer. Pathologists need to be familiar with these mimics, as a false positive diagnosis of prostate cancer may lead to unnecessary radical treatment.

Low-grade myofibroblastic sarcoma (LGMS) is a mesenchymal tumor of myofibroblasts that occurs more frequently in adults. A series of three cases is presented to illustrate that LGMS may also occur within the oral cavity in children and adolescents. The first case (Case 1) occurred intra-osseously in the mandible, while the remaining two presented as gingival swellings and were purely restricted to soft tissue (Cases 2 and 3). The intra-osseous lesion arose in a 7-year-old girl, whereas the gingival lesions were observed in a 12-year-old girl (Case 2) and a 13-year-old boy (Case 3). Histopathologically, all cases were composed of spindle shaped cells arranged into long fascicles showing mild to moderate degree of nuclear atypia. Ki-67 (MIB-1) proliferation activity was relatively low, amounting to 3–5% in all cases. Immunohistochemically, all cases showed smooth muscle actin (SMA) positivity in spindle cells, while desmin, beta catenin, cytokeratin, and CD34 were negative, resulting in a diagnosis of LGMS. In conclusion, current series of three cases of LGMSs that occurred in the oral cavity in a child and two adolescent patients is presented to highlight an emerging disease that requires additional data for further characterization.

The reticulin stain is a critical diagnostic aide used to differentiate benign hepatocellular proliferations from well differentiated hepatocellular carcinoma. Rarely, however, hepatocellular carcinomas do not show definitive loss of reticulin in liver biopsy specimens. In order to study this group of tumors, 11 HCC with no reticulin loss in 10 patients were collected and studied. Analysis of demographics showed a typical enrichment for men with a typical age for HCC presentation of 69± 7 years for adults. The background livers showed advanced fibrosis or cirrhosis in 6/6 cases with available information. The tumors were all well differentiated. Cytological atypia was mild and consisted of very mild nuclear atypia (8 cases), mild increase in N:C ratio (3 cases), and pseudorosette formation (4 cases). The cytological/architectural atypia was insufficient in isolation to diagnose HCC. Additional studies, however, showed an increased Ki-67 proliferative rate (N= 10/10 stained cases). The Ki-67 proliferative rate was estimated to be between 5–10% in all tested cases and was clearly increased from adjacent liver at low power. Glypican 3 positivity (4 tumors) and alpha fetoprotein (1/8 stained cases) positivity also helped make the diagnosis of HCC. Morphologically, the HCC had conventional morphology with five showing steatosis / steatohepatitic features and one showing intratumoral fibrosis. A control group of macroregenerative/dysplastic nodules showed no increase in Ki-67 proliferation and no staining for glypican 3. These findings highlight an important diagnostic pitfall: rare HCC show no reticulin loss on biopsy. In these challenging cases, additional findings are useful to make a diagnosis of HCC: increased Ki-67, and positive staining for aberrant expression of proteins such as glypican 3 or alpha fetoprotein (AFP).

Aims Very limited data are available concerning the clinicopathological and molecular features of early subungual melanoma (SM), especially with regard to the Asian population. The aim of this study was to investigate the clinical, histological, immunohistochemical and chromosomal features of early SM. Methods and results Fifty-two in-situ and 13 thin (Breslow thickness ≤1.0 mm) SM cases were retrospectively reviewed. All patients presented with longitudinal melanonychia involving a single digit, and the thumb was the most affected digit (35 of 65, 53.8%). Microscopically, most cases showed small to medium nuclear enlargement (58 of 65) and mild to moderate nuclear atypia (57 of 65). Hyperchromatism and irregular contours of nuclei were persistent features in all cases. The variation of melanocyte count (the number of melanocytes per mm dermal-epithelial junction) ranged from 31 to 255. Intra-epithelial mitoses were identified in 34 cases (52.3%). Statistically, features of in-situ lesions including higher melanocyte count (>70), presence of multinucleated melanocytes, inflammatory infiltrate and cutaneous adnexal extension, were associated with early invasion. Melan-A, human melanoma B (HMB)45, mouse monoclonal melanoma antibody (PNL2) and SOX10 antibodies (>95.0%) showed superior diagnostic sensitivity to S-100 protein (83.1%). Fluorescence in-situ hybridisation (FISH) results were positive in 15 of 23 successfully analysed cases. Conclusions To the best of our knowledge, this is the largest single-institution study of early SM in an Asian population, and the largest cohort tested by FISH. Early SM mainly showed small to medium nuclear enlargement and mild to moderate nuclear atypia. High melanocyte count, hyperchromatism and irregular contours of nuclei and intra-epithelial mitoses are crucial diagnostic parameters. Immunohistochemistry, especially SOX10 staining, and FISH analysis are valuable in the diagnosis of SM.

Misdiagnosis of endocervical adenocarcinoma (EAC) as endometrial endometrioid carcinoma (EEC) is one of the major concerns when evaluating endometrial curettage specimens. It is difficult to differentiate EAC involving the endometrium from EEC, particularly when the specimens have only a few small tumor fragments. We report a case of endocervical adenocarcinoma in situ (AIS) with multifocal microscopic involvement of the endometrium. The endometrial curettage specimen obtained from an 82-year-old woman consisted of a large volume of blood and fibrin, with small endometrial tissue fragments showing microscopic foci of atypical glandular proliferation. Based on the presence of complex glands with stratified mucin-poor columnar epithelium and intermediate-grade nuclear atypia, a preoperative diagnosis of grade 1 EEC was made. However, the hysterectomy specimen revealed an endocervical AIS involving the endocervix and low uterine segment. Frequent mitotic figures and apoptotic bodies, characteristic of AIS, were present. The endometrium showed a few microscopic foci of atypical glandular proliferation involving the surface only. Their histological features were similar to those of the endocervical AIS. Immunohistochemically, the atypical glands exhibited block p16 positivity. The final diagnosis was a superficially spreading endocervical AIS with multifocal microscopic involvement of the endometrial surface epithelium. In summary, small tumor tissues in an endometrial curettage may lead to misdiagnosis of AIS or EAC as EEC, especially when the pathologists are unaware of the possibility of microscopic endometrial involvement of AIS or EAC. The origin of the tumor can be correctly determined based on a combination of histological features and immunostaining. Endocervical AIS involving the endometrium should be included in the differential diagnosis of neoplastic glandular lesions in endometrial curettage specimens. An accurate diagnosis in these cases is important because of its significant implications for clinical management.

Objectives: The aims of this study were to evaluate if digital quantification of proliferation marker Ki-67 and mitotic marker phosphohistone H3 (PHH3) can reliably distinguish leiomyosarcoma (LMS) from smooth muscle tumors of uncertain malignant potential (STUMP), leiomyoma with bizarre nuclei (LMBN), and leiomyoma (LM), and if digital quantification of these markers correlates with clinical outcomes. Methods: Cases of LMS, STUMP, LMBN, and LM for which paraffin-embedded tissue was available were identified from a single institution. Manual evaluation of mitotic count was performed using hematoxylin and eosin (H&E) evaluation on 50 high powered fields (5 mm2). Immunohistochemical staining for Ki-67 and PHH3 was performed on one section from each case, and a high throughput digital quantification system was used to calculate an average percent stain. Receiver operating characteristic (ROC) curves for the ability of Ki-67 and PHH3 to predict LMS versus the other diagnostic groups were generated. Univariate Cox regression assessed for associations between each marker and progression-free survival (PFS) among patients with available follow-up. Results: A total of 39 cases (17 LMS, 5 STUMP, 10 LMBN, and 7 LM) were included. Mitotic count, Ki-67, and PHH3 were significantly correlated. When comparing the LMS group to the STUMP, LMBN, and LM groups combined, LMS showed a significantly greater digital quantification of Ki-67 (median 10.6% versus 0.4%, p Download : Download high-res image (67KB) Download : Download full-size image Conclusions: This study provides preliminary evidence that digital quantification of Ki-67, and possibly PHH3, can aid in a fast and reliable diagnosis of LMS versus other uterine smooth muscle tumors.

The current World Health Organization (WHO) classification of adenocarcinoma of the urinary tract including the urethra includes uncommon Mullerian-derived carcinomas such as clear cell and endometrioid adenocarcinomas. The concept of primary mesonephric (Wolffian-derived) adenocarcinoma (MA) in the urethra (and urinary tract in general) is currently regarded as controversial as the term "mesonephric" had been also inaccurately applied in the past to label Mullerian-derived carcinomas, particularly clear cell adenocarcinoma. Further, pathologically well-documented or bona fide urethral MAs have not yet to be reported. Herein, we describe 2 examples of MA in elderly females that primarily presented in the urethra and manifested clinically with obstructive lower urinary tract symptoms. Both tumors exhibited histology similar to those in MAs of the female genital tract including the distinctive tubular proliferations with luminal eosinophilic materials. The first case, in addition, showed a variety of patterns including ductal (glandular), solid, fused/sieve-like tubules, dilated tubules, and spindled cells. The second case also showed a transition to the more irregular and poorly formed tubular proliferation of cells with greater nuclear atypia and with a desmoplastic response. Both tumors showed positivity for PAX8, GATA3, and luminal CD10, and 1 tumor analyzed harbored KRAS and ARID1A mutations. One patient received neoadjuvant chemotherapy and underwent resection but had local tumor recurrence and metastasis to the lungs and lumbar spine 12 months after presentation. In conclusion, MA, similar to those occurring in the female genital tract and distinct from the recognized Mullerian-derived carcinomas, may present primarily as urethral tumors. MA in the urethra probably shares a common pathogenesis with vaginal MA as both may originate from the same caudal loci of mesonephric remnants along the closely apposed anterior vaginal and posterior urethral walls. MA should be considered in future classifications for urethral tumors and we recommend that the confusing term "mesonephroid adenocarcinoma" should no longer be used.

Minimal uterine serous carcinomas (MUSCs) include serous carcinomas with invasion confined to the endometrium (superficial serous carcinoma) and those without stromal invasion (serous endometrial intraepithelial carcinoma). Although these tumors are confined to the endometrium proper, they have highly metastatic potential for disseminating to extra-uterine sites. We report here a case of MUSC that was initially misdiagnosed as early-stage low-grade endometrioid carcinoma but later metastasized to the abdominopelvic peritoneum. The patient was a 61-year-old woman who was diagnosed with grade 1 endometrioid carcinoma of the endometrium and underwent total hysterectomy. Because the tumor was confined to the endometrium (International Federation of Gynecology and Obstetrics stage IA), no further treatment was performed. However, several metastatic tumor masses were detected in the vaginal stump and abdominopelvic peritoneum 7 years after the surgery. Histologically, the metastatic tumor tissues showed high-grade carcinoma. A review of previous hysterectomy slides showed multiple separate foci of atypical glandular proliferation measuring up to 0.8 cm in the greatest dimension and consisting of markedly atypical cells involving the surface and atrophic glands. The tumor showed a predominantly glandular architecture without evident papillary growth or stromal invasion. However, it had large, pleomorphic nuclei showing a high nuclear-to-cytoplasmic ratio, conspicuous eosinophilic nucleoli, and numerous mitotic figures. Characteristically, the tumor showed marked nuclear atypia immediately appreciated at low magnification in the background of well-formed glandular structures, indicating a significant discordance between nuclear and architectural features. On immunostaining, both the uterine and metastatic tumor tissues exhibited diffuse and strong p16 expression and mutant pattern of p53 expression, confirming the diagnosis of serous carcinoma. In summary, the case findings support that failure to preoperatively recognize high-risk endometrial carcinoma is associated with worse outcomes. Complete surgical staging and accurate pathological diagnosis are critical for patients with serous carcinoma even at the early clinical stage.

A 35-year-old male, presented with a slow growing painless cutaneous nodule of 1.5 cm size of 6-month duration. On local examination, single well defined, freely mobile, non-tender skin nodule was found over the dorsum of right hand. Fine needle aspiration of the swelling yielded particulate material. The cytosmears were highly cellular and showed three population of cells comprising of cohesive clusters of larger cells, discretely lying larger cells and smaller lymphocyte like cells. (Figure 1) The cohesive cells were larger with round nuclei, pale chromatin and moderate amount of cytoplasm. Focal rosette like arrangement were noted. The larger scattered cells were in the form of naked nuclei with fragile cytoplasm giving a glycogenated appearance to the background. The third population of cells comprised of smaller cells with a coarsely clumped clock face appearing chromatin resembling lymphocytes. There was no mitosis, nuclear atypia or necrosis. (Figure 2).

Cellular fibromas represent ~10% of ovarian fibromas. Mitotically active cellular fibromas show mild nuclear atypia but ≥4 mitoses/10 high-power fields: the clinical course is usually uneventful but literature review is lacking. A 34-yr-old woman underwent left oophorectomy for a 9-cm ovarian mitotically active cellular fibroma at another hospital. The tumor was cellular (spindle cells in fascicular and storiform patterns) revealing mild atypia and 4 nonatypical mitoses/10 high-power fields without necrotic areas. After 16 yr, the tumor recurred as a 5-cm peritoneal nodule on the anterior sigmoid wall near the sigmoid-rectal junction. Frozen section revealed a spindle cell tumor invading the intestinal tunica muscularis propria: a gastrointestinal stromal tumor was favored as previous history was unavailable at that time. Intestinal resection was performed: no residual tumor was found. The patient was followed-up for 8 yr without further recurrences. The peritoneal nodule showed 2 mitoses/10 high-power fields and pericellular reticulin staining. The tumor was variably positive for vimentin/bcl-2/melan-A/CD56/ER/PR/α-inhibin/CD10/calretinin, focally positive for desmin, negative for pan-cytokeratin/actin/EMA/CD34/HMB45/CD117/CD99/S100/synaptophysin. The Ki67-index was ~9%. To our systematic literature review, 7 additional recurrent cases were reported. We describe a mitotically active cellular fibroma recurring after the longest interval of time. Extensive sampling of difficult cases should exclude malignant areas. Moderate nuclear atypia, tumor rupture, adhesions to pelvic/abdominal organs, infarction with extraovarian involvement, and incomplete excision may lead to relapse but there are conflicting data: prolonged follow-up can be suggested in these cases.

Background: It has been known that the “atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)” category is the most problematic category in Bethesda system due to its highly heterogeneous morphological features. Recently, it has been reported that aspirates including nuclear atypia in the AUS/FLUS category have a higher risk of malignancy. Aims: This study aimed to assess each nuclear property in aspirates with cytological atypia and also to determine the relationship with the risk of malignancy. Material and Methods: We reviewed 980 AUS/FLUS fine-needle aspirations (FNAs) performed between '2012 and 2019' at a single institution. We classified these aspirates into four groups: AUS-N (nuclear atypia), AUS-A (architectural atypia), AUS-H (Hurthle cell change), and AUS-O (other). Nuclear features were detailed sub-classified; size and shape (enlargement, elongation, and overlapping), membrane irregularities (irregular contours, grooves, pseudoinclusion), and chromatin characteristics (pale chromatin). The estimated risk of malignancy (ROM) was calculated for each subgroup. Results: Of 980 AUS/FLUS cases, follow-up histological outcome data were available for 209 cases. Among these cases, the estimated ROM was 27.8%. The ROM were 26.4%, 15.4%, and 22.5% for AUS-N, A, and H, respectively. The most common nuclear findings associated with ROM were nuclear groove (67.9%); irregular contours (76.9%) suspected pseudoinclusion (100%) and overlapping (56%) (P < 0,001). But nuclear findings such as nuclear enlargement, mild pleomorphism, or pale chromatin have a similar ROM as architectural atypia. Conclusion: Although it is known that the presence of cytological atypia in an AUS/FLUS nodule increases the estimated risk of malignancy, all nuclear properties are not equally effective in predicting malignancy risk. Emphasizing nuclear atypia details in reports of AUS case may be a more sensitive way to identify nodules with a high risk of malignancy.

Endometriosis is a relatively common condition in which endometrial tissue is established in locations outside the uterus where, like the eutopic endometrium, it responds to hormonal stimuli and develops internal bleeding, inflammation, and fibrosis. These changes are associated with chronic and often debilitating cyclic pain and infertility. The pathogenesis of endometriosis is multifactorial, and several theories have been proposed to explain it. These include retrograde menstruation, celomic metaplasia, embryologic rests, and lymphovascular spread. Hormones, immunologic status, and genetic factors may also play a role. In most patients, the disease involves pelvic organs, but rarely it may also extend to a large variety of distant locations in the body. Patients with ovarian endometriosis are at higher risk for developing ovarian carcinomas including endometrioid and clear cell carcinomas. Some of these carcinomas may arise in a background of structural and/or nuclear atypia within the endometriotic foci. There is no known cure for endometriosis and treatment mostly consists of managing chronic pain or infertility.

Embryonal rhabdomyosarcoma of the uterine cervix is a rare neoplasm which is almost invariably associated with pathogenic somatic or germline DICER1 mutations; patients with germline mutations have DICER1 syndrome. We report 2 subtle cervical embryonal rhabdomyosarcoma, one occurring in a 21-yr-old woman with a known history of DICER1 syndrome and the other in a 19-yr-old woman with no history of DICER1 syndrome or DICER1-associated neoplasms. Both neoplasms focally involved otherwise benign endocervical polyps and were characterized histologically by subtle areas of increased stromal cellularity, nuclear atypia and mitotic activity; there was focal nuclear staining of these areas with the skeletal muscle markers myogenin and myoD1. In both cases, demonstration of a somatic DICER1 RNase IIIb mutation in the tumor was instrumental in establishing the diagnosis. We believe these neoplasms represent the earliest discernible phase of cervical embryonal rhabdomyosarcoma. Pathologists should have a high index of suspicion when atypical stromal elements are present in endocervical polyps and immunohistochemistry together with DICER1 sequencing will assist in diagnosis.

The objective of this study is to investigate the signal changes and optimal scanning concentration of MRI in tumor tissues of tumor-bearing nude mice by SPIO-shRNA molecular probes. 30 BALB/c tumor-bearing nude mice were randomly divided into 5 groups with 6 mice in each group. At the given scanning time (before and 27 h after injection), the caudal vein was respectively injected with iron content of 6 mg·kg−1, 12 mg·kg−1, 18 mg·kg−1, 24 mg·kg−1, and 30 mg·kg−1, and MR examination was simultaneously performed to measure signal intensity changes of tumor tissue and contralateral muscle tissue in each concentration group. After each examination above, the nude mice were sacrificed immediately, and the tumor and muscle tissues were removed for HE and Prussian blue staining,and observed under light microscope. Nude mice in 6 mg, 12 mg and 18 mg groups all survived after probe injection, but some nude mice died in 24 mg and 30 mg groups after probe injection or during scanning. The signal changes of T2WI and T2*WI sequences were the most obvious in MR scanning sequences. Compared with other groups, the signal intensity of the tumor tissue in 18 mg, 24 mg and 30 mg groups were most obvious (P 0.05 ); HE staining indicated that structural disorder of tumor tissue as well as increase of nuclear atypia. Prussian Blue staining showed that blue-stained iron particles were present in each experimental group,and the most densely distributed were in 18 mg,24 mg and 30 mg groups. Tumor tissue could be well labeled with SPIO-shRNA molecular probes, and the optimal MR scanning concentration (iron content) is 18 mg·kg−1.

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3mm; malignant LCTs, mean 44mm) (P&nbsp

We demonstrated the clinicopathological findings of 13 myoepitheliomas of soft tissue and bone (MESTBs) and two myoepithelioma-like tumors of the vulvar region (MELTVRs), focusing on the association between nuclear atypia and clinical course, and the utility of immunohistochemistry (IHC) of pleomorphic adenoma gene 1 (PLAG1) for the pathological diagnosis of these tumors. Of the 13 MESTBs, eight, one and four cases exhibited mild, moderate and severe nuclear atypia, respectively. Two cases with venous invasion showed severe nuclear atypia and both died of advanced disease. Two MELTVR cases showed moderate nuclear atypia and had no evidence of disease after surgery. On IHC, 12 of 13 (92.3%) MESTBs showed PLAG1 immunoreactivity and none of the MELTVRs expressed PLAG1. In addition, MELTVRs showed loss of INI1 expression. In contrast, all MESTBs retained INI1 expression. Fluorescence in situ hybridization detected EWSR1, FUS and PLAG1 rearrangement in 5 (38.5%), 0 (0%) and 2 (15.4%) of the 13 MESTBs, respectively. No EWSR1, FUS and PLAG1 rearrangement were observed in the METLVRs. In conclusion, MESTBs with both severe nuclear atypia and venous invasion would be indicative of malignant potential. PLAG1 might be a useful IHC marker in MESTB diagnosis.

Giant cell tumor of bone is a locally aggressive, rarely metastasizing neoplasm. Evidence suggests that the neoplastic cells may be osteoblastic in differentiation. Standard treatment is surgical removal, but medical therapy with denosumab, an inhibitor of receptor activator of nuclear factor-κβ ligand, has become a component of patient management in select cases. Denosumab-treated giant cell tumor of bone (DT-GCTB) shows drastic morphologic changes including the presence of abundant bone. To further determine the relationship of the neoplastic cells to osteoblast phenotype, we performed a morphologic and immunohistochemical study on a series of DT-GCTB. Cases of DT-GCTB were retrieved from surgical pathology files, available slides were reviewed, and immunohistochemistry for H3.3 G34W, SATB2, and p63 was performed. The cohort included 31 tumors from 30 patients (2:3 male:female), ages 15 to 73 years (median=36 y). The morphology of post-denosumab-treated tumors ranged from tumors composed of an abundant bone matrix with few spindle cells to spindle cell-predominant tumors. Five had focal residual classic CGTB, and 2 manifested mild nuclear atypia. The majority expressed all markers: 86.2% for H3.3 G34W, 96.7% for SATB2, and 100% for p63. All markers stained the various tumor components including spindle cells and the cells on the surface of and within the treated tumor bone matrix. Most markers were also positive in reactive-appearing woven bone adjacent to tumor: 84.6% for H3.3 G34W, 100% for SATB2, and 68% for p63. These findings suggest that denosumab treatment of giant cell tumor of bone results in osteoblastic differentiation with bone production.

Pure intravascular growth of epithelioid hemangioma (EH) is exceptional. Herein, we report a series of 21 intravascular EHs, representing a potential serious diagnostic pitfall by mimicking malignant vascular neoplsms with epithelioid morphology. The tumors developed in 12 males and 4 females, aged from 11 to 71 years (mean age 40.2 years) with a predilection for the extremities (13 of 21, 61.9%), followed by the head and neck (8 of 21, 38.1%). Lesions ranged in size from 2 to 30 mm (mean size 13 mm). The most common presenting feature was a slowly growing nodule. Most neoplasms were solitary (13 of 16 patients, 81.2%) but three patients developed more than one intravascular EH (3 of 16, 18.8%). Treatment consisted of complete surgical excision and was generally curative. Follow-up was available for 13 lesions that had developed in ten patients (range 4-72 months, mean 27.3 months). No recurrences or development of additional tumors were observed. All 21 lesions developed in subcutaneous veins. Two morphological patterns of intravascular epithelioid endothelial cell proliferation were observed: (1) a lobular capillary hemangioma-like proliferation with variable formation of open vascular lumina and (2) a solid proliferation generally lacking open vascular spaces. A lobular capillary hemangioma-like pattern was the sole pattern in nine lesions, a mixed lobular hemangioma-like pattern, and solid pattern in eight and a pure solid pattern in four intravascular EHs. Mitotic activity in epithelioid endothelial cells ranged from 0 to 7 mitoses per 10 high-power field (mean 2.1 mitoses per 10 HPFs). Six lesions displayed brisk mitotic activity of five or more mitoses per 10 HPF (6 of 21, 28.5%). The number of mitoses was usually more prominent in areas with solid growth. Atypical mitoses were not observed. No intratumoral necroses were seen. Cytological atypia was mild (20 out of 21 cases). By immunohistochemistry, all tumors were positive for CD31 (14 out of 14) and ERG (5 out of 5). While all tested cases were FOS negative by immunohistochemistry (6 out of 6), one out of six cases (case 6) displayed FOSB nuclear positivity in about 30% of the lesional endothelial cells. Eight cases were analysed by FISH for the presence of FOS and FOSB gene rearrangements. While all cases were negative for FOSB rearrangements, a single case proved positive for FOS gene break-apart. In conclusion, intravascular growth of EH is not associated with adverse biological behavior. Solid intravascular proliferations of endothelial cells can mimic a malignant vascular tumor with epithelioid morphology. Nevertheless, intravascular EHs display mild cytological atypia coupled with low mitotic activity, and a lack of atypical mitoses, pronounced nuclear atypia, multilayering or tumor necrosis. Finally, the FOS gene is infrequently rearranged, and there are no FOSB gene abnormalities in this subset of EHs, suggesting a potential distinct pathogenesis than most classic EHs.

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine-needle aspiration biopsies. The MV-FTC diagnosis is instead suggested following histological investigation, in which malignant attributes, most commonly capsular invasion, are noted. The bulk of MV-FTCs described in the literature arise in younger female patients and carry an excellent prognosis. A recent coupling to mutations in the DICER1 tumor suppressor gene has been proposed, possibly indicating aberrancies in micro-RNA (miRNA) patterns as responsible of the tumorigenic process. We describe the cytological, histological and molecular phenotype of a 35 mm large MV-FTC arising in the right thyroid lobe of a 33-year-old female with a family history of multinodular goiter. The tumor was encapsulated and strikingly inconspicuous in terms of cellularity and atypia, but nevertheless displayed multiple foci with capsular invasion. A next-generation molecular screening of tumor DNA revealed missense variants in DICER1 (p. D1709N) and MET (p. T1010I), but no established fusion gene events. After sequencing of germline DNA, the DICER1 mutation was confirmed as somatic, while the MET variant was constitutional. The patient is alive and well, currently awaiting radioiodine treatment. This MV-FTC mirrors previous publications, suggesting that these tumors carry a favorable prognosis and predominantly arise in younger females. Moreover, DICER1 mutations should be considered a common driver event in the development of MV-FTCs.

Intracranial anaplastic hemangiopericytoma (AHPC) is a rare and malignant subset of solitary fibrous tumor/hemangiopericytoma (SFT/HPC) as per the WHO 2016 Classification of Tumors of the Central Nervous System. AHPC portends a poor prognosis and is associated with higher rates of recurrence/metastasis in comparison with SFT/HPC. Accordingly, it is critical to continue to define the clinical course of patients with AHPC and in so doing further refine clinicopathologic/immunohistochemical (IHC) criteria needed for definitive diagnosis. Herein, we describe clinical/histological characteristics of six patients with AHPC. In addition, we reviewed and analyzed the expression of various IHC markers reported within the literature (i.e., a total of 354 intracranial SFT/HPCs and 460 meningiomas). Histologically, tumors from our six patients were characterized by a staghorn-like vascular pattern, mitotic cells, and strong nuclear atypia. Immunohistochemically, all tumors displayed positive nuclear staining for STAT6; other markers, including CD34 and Bcl-2, were expressed only in three patients. Analysis of IHC expression patterns for SFT/HPC and meningioma within the literature revealed that nuclear expression of STAT6 had the highest specificity (100%) for SFT/HPC, followed by ALDH1 (97.2%) and CD34 (93.6%). Of note, SSTR2A (95.2%) and EMA (85%) displayed a high specificity for meningioma. Anaplastic SFT/HPC is a tumor with poor prognosis that is associated with higher rates of recurrence and metastasis in comparison with SFT/HPC. Given that anaplastic SFT/HPC requires more aggressive treatment than meningioma despite of a similar presentation on imaging, it is crucial to be able to distinguish between these tumors.

A challenge in the diagnosis of prostate pathology is the numerous benign mimics of prostatic adenocarcinoma. Most of these lesions have no clinical significance but may be misinterpreted as cancer in biopsy specimens. In this review we describe the features of some of the more common benign mimics and discuss how they can be distinguished from carcinoma. The diagnostic entities most commonly associated with a false positive diagnosis of cancer are the atrophic group of lesions that include simple atrophy, partial atrophy and post-atrophic hyperplasia. Benign proliferations exhibit architectural atypia, often with closely packed small glands, but with no or little nuclear atypia. The most common diagnostic pitfall of this group is adenosis, which may have an even more atypical architecture than some cancers. A common denominator of atrophy and benign proliferations is that they consist of small glands that may have a patchy or absent basal cell layer, which adds to the diagnostic difficulties. Amongst hyperplastic and metaplastic lesions, basal cell hyperplasia may be misinterpreted as cancer because of its dark basophilic glands that sometimes display a certain degree of nuclear atypia and occasionally exhibit a pseudoinfiltrative pattern. The most important extraprostatic anatomical structure causing diagnostic difficulties is the seminal vesicle. The closely clustered small glands and often strikingly atypical nuclei of seminal vesicle epithelium may be misinterpreted as cancer. Awareness of these mimics is of paramount importance for the practicing pathologist as a false positive diagnosis of prostate cancer may lead to unnecessary radical therapy.

Spindle cell lipoma is a rare variety of lipoma that usually appears in subcutaneous tissue, for example, the posterior neck, shoulders, and back region, in middle-aged and older males. We reported a rare case of spindle cell lipoma of the floor of mouth. A 68-year-old man had a painless swelling of the floor of mouth. Clinical and image examination revealed that the mass was encapsulated, well-circumscribed, smooth-surfaced, and soft. Inside of the lesion was the same signal as adipose tissue, and the mass showed high signals at T1 and T2 weighted sequence in magnetic resonance imaging. However, the internal properties were non-uniform, and the vascular pattern was observed. Therefore, biopsy was performed before removal operation, and the mass was diagnosed as no malignancy. The encapsulated yellow mass was removed under general anesthesia. The histopathology showed that the well-demarcated mass was composed of mature adipocytes and spindle cells with bundles of collagen fibers. The size of mature adipocytes was uniform, and nuclear atypia was not observed. In immunohistochemical staining, the adipocytes were positive to S-100, and the spindle cells showed positive for CD34 and bcl-2 but S-100 negative. Based on the pathological features, the diagnosis was spindle cell lipoma. Differentiation of spindle cell lipoma includes solitary fibrous tumors, neurofibromas, subcutaneous fibrous malignancies, and well differentiated lipomas. S-100, CD34, and bcl-2 was able to differentiate these tumors and was very useful for the diagnosis of spindle cell lipoma. There were no signs of recurrence after 1-year follow up since the operation.

Background Spinal schwannomas are benign nerve sheath neoplasms that constitute about 30% of extramedullary spinal cord tumors. They are usually small, well-encapsulated tumors with low mitotic activity and concurrently carry a low risk of recurrence. Here, we report a case of atypical histologic variant of spinal schwannoma that had higher cellular density, nuclear atypia, and lack of encapsulation. To our best knowledge, no such cases of this atypical variant with regards to lumbar spine have been reported in the literature. Case Description A 66-year-old male had an incidental left-sided paraspinal mass discovered while undergoing workup for cholecystitis. On examination, the patient was neurologically intact. Imaging revealed the presence of a contrast-enhanced, partially cystic mass arising from the L3-4 intervertebral foramen and causing left psoas muscle displacement. A minimally invasive left L3-4 posterior extracavitary resection was done. Histopathologic examination revealed a partly unencapsulated tumor with higher than usual cellular density and nuclear atypia, resulting in a diagnosis of “atypical schwannoma.” Imaging at 6 months' follow-up showed stable postsurgical changes and residual tumor with no evidence of progression/recurrence. Conclusions Atypical schwannoma has higher cellular density and nuclear atypia and lacks encapsulation. A review of the literature suggests an increased risk of recurrence when compared with typical variants, and complete tumor removal should be attempted.