Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity.

The RREB1::MRTFB (former RREB1::MKL2) fusion characterizes ectomesenchymal chondromyxoid tumors (EMCMT) of the tongue. Only five molecularly confirmed extra-glossal EMCMT cases have been reported recently; all occurring at head and neck or mediastinal sites. We herein describe five new cases including the first two extracranial/extrathoracic cases. The tumors occurred in three male and two female patients with an age ranging from 18 to 61 years (median, 28). Three tumors were located in the head and neck (jaw, parapharyngeal space, and nasopharyngeal wall) and two in the soft tissue (inguinal and presacral). The tumor size ranged from 3.3 to 20 cm (median, 7). Treatment was surgical without adjuvant treatment in all cases. Two cases were disease-free at 5 and 17 months; other cases were lost to follow-up. Histologically, the soft tissue cases shared a predominant fibromyxoid appearance, but with variable cytoarchitectural pattern (cellular perineurioma-like whorls and storiform pattern in one case and large polygonal granular cells embedded within a chondromyxoid stroma in the other). Two tumors (inguinal and parapharyngeal) showed spindled to ovoid and round cells with a moderately to highly cellular nondescript pattern. One sinonasal tumor closely mimicked nasal chondromesenchymal hamartoma (NCMH). Mitotic activity was low (0-5 mitoses/10 hpfs). Immunohistochemical findings were heterogeneous with variable expression of S100 (2/5), EMA (2/3), CD34 (1/4), desmin (1/4), and GFAP (1/3). Targeted RNA sequencing revealed the same RREB1::MRTFB fusion in all cases, with exon 8 of RREB1 being fused to exon 11 of MRTFB. This study expands the topographic spectrum of RREB1::MRTFB fusion-positive mesenchymal neoplasms, highlighting a significant morphological and phenotypic diversity. Overall, RREB1::MRTFB-rearranged neoplasms seem to fall into two subcategories: tumors with lobulated, chondroid, or myxochondroid epithelioid morphology (Cases 2 and 3) and those with more undifferentiated hypercellular spindle cell phenotype (Cases 1, 4, and 5). Involvement of extracranial/extrathoracic sites and the NCMH-like pattern are novel. The biology of these likely indolent or benign tumors remains to be verified in the future.

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection.

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Chondroblastoma of foot bones; a clinicopathological study of 29 cases confirming the diagnostic utility of H3K36M and H3G34W antibodies at an uncommon site.

OBJECTIVE: Chondroblastoma (CB) is a benign cartilaginous bone neoplasm which commonly occurs in long bones of adolescents. CB can uncommonly involve foot. Its mimics include both benign and malignant lesions. H3K36M immunohistochemical (IHC) stain is a helpful tool for establishing the diagnosis of CB in such challenging situations. In addition, H3G34W IHC stain helps to rule out giant cell tumor which is the closest differential of CB. Our objective was to describe the clinicopathological features and frequencies of H3K36M, H3G34W and SATB2 IHC stains in CB of foot. MATERIALS AND METHODS: We reviewed H&E slides and blocks of 29 cases diagnosed as "chondroblastoma" of foot at our institutions. RESULTS: Patient's age ranged from 6 to 69 (mean: 23.3 and median: 23) years. Males were almost 5 times more commonly affected than females. Talus and calcaneum were involved in 13 (44.8 %) cases each. Microscopically, tumors were composed of polygonal mononuclear cells and multinucleated giant cells and chondroid matrix. Other histological features included aneurysmal bone cyst-like (ABC-like) change (44.8 %), osteoid matrix (31 %), chicken-wire calcification (20.7 %), and necrosis (10.3 %). H3K36M was expressed in 100 % and SATB2 in 91.7 % cases. H3G34W was negative in all cases, where performed. One out of 11 patients with follow up information developed local recurrence after 48 months. CONCLUSION: CB in foot occur at an elder age and show more frequent ABC-like changes as compared to long bones. Males are affected ~5:1 as compared to 2:1 in long bones. H3K36M are H3G34W are extremely useful diagnostic markers for CB, especially elderly (aged or higher) patients and we report the largest series of foot CB cases confirmed by immunohistochemistry.

Utility of MUC4 in the diagnosis of secretory carcinoma of salivary glands.

Salivary gland tumors are diverse in morphology and both benign and malignant tumors may pose diagnostic challenges especially in small biopsies. Secretory carcinoma (SC) is histologically characterized by microcysts, follicles, solid growth pattern and occasional papillary structures, and absence of zymogen granules. SC is molecularly defined by the presence of novel gene fusion ETV6::NTRK3. Among the positive stains (S100 and mammaglobin), MUC4 is now another promising marker for the diagnosis of SC, that would enable the pathologists to exclude other morphologically close simulators. Aim of this study was to report clinicopathological features and assess utility of MUC4 in the diagnosis of SC. MUC4 was performed on 22 cases of SC. Glass slides were reviewed to record morphological patterns and staining of S100, mammaglobin, DOG1 and MUC4. Age ranged from 9 to 63 years with mean age of 34.41 ± 16.28 years. The male: female ratio was 72.7 %:27.3 %. The majority occurred in major salivary glands. A combination of patterns was seen; microfollicles were the most prevalent (90 %) followed by papillary-cystic and macrofollicles. MUC4 was positive in 19/21 (90 %) cases with almost equal number of 2+ and 3+ staining. MUC4 was negative in all cases of acinic cell carcinoma, polymorphous adenocarcinoma, adenoid cystic carcinoma, salivary duct carcinoma, myopepithelioma and myoeithelial carcinoma, cystadenoma and cribriform adenocarcinoma and all except 3 cases of mucoepidermoid carcinoma tested. Overall sensitivity of MUC4 was 95.4 %, specificity 90 %, p-value being <0.01, positive predictive value 87.5 % and negative predictive value 96.4 %. A characteristic cytoplasmic granular pattern was observed in 76.1 % tumors. S100 and mammaglobin were positive in all the performed cases. DOG1 was positive in 6/11 (28.5 %) tumors. In conclusion, MUC4 is a useful addition to a diagnostic immunohistochemical panel for SC, and to distinguish it from close potential mimickers such as acinic cell carcinoma, especially in practice settings where molecular testing is unavailable.

Automated Battery Making Fault Classification Using Over-Sampled Image Data CNN Features.

Due to the tremendous expectations placed on batteries to produce a reliable and secure product, fault detection has become a critical part of the manufacturing process. Manually, it takes much labor and effort to test each battery individually for manufacturing faults including burning, welding that is too high, missing welds, shifting, welding holes, and so forth. Additionally, manual battery fault detection takes too much time and is extremely expensive. We solved this issue by using image processing and machine learning techniques to automatically detect faults in the battery manufacturing process. Our approach will reduce the need for human intervention, save time, and be easy to implement. A CMOS camera was used to collect a large number of images belonging to eight common battery manufacturing faults. The welding area of the batteries' positive and negative terminals was captured from different distances, between 40 and 50 cm. Before deploying the learning models, first, we used the CNN for feature extraction from the image data. To over-sample the dataset, we used the Synthetic Minority Over-sampling Technique (SMOTE) since the dataset was highly imbalanced, resulting in over-fitting of the learning model. Several machine learning and deep learning models were deployed on the CNN-extracted features and over-sampled data. Random forest achieved a significant 84% accuracy with our proposed approach. Additionally, we applied K-fold cross-validation with the proposed approach to validate the significance of the approach, and the logistic regression achieved an 81.897% mean accuracy score and a +/- 0.0255 standard deviation.

Gliosarcoma in patients under 20 years of age. A clinicopathologic study of 11 cases and detailed review of the literature.

BACKGROUND: Gliosarcoma is a rare variant of IDH- wild type glioblastoma with both glial and mesenchymal differentiation. It accounts for approximately 2% of glioblastomas and has a poor prognosis similar to that of classic glioblastoma. It is seen mostly between 40 and 60 years of age with a mean age over 50 years. Pediatric gliosarcoma is even rarer than gliosarcoma in adults. We describe the clinicopathological features of gliosarcoma in patients under 20 years of age and determine whether there are significant differences from gliosarcoma in adults. We also present detailed review of published literature on pediatric gliosarcoma. METHODS: Slides of gliosarcomas in patients under 20 years of age were reviewed. Clinicopathological features were noted in detail and follow up was obtained. RESULTS: Eleven cases of gliosarcoma were reported in patients under 20 years of age. Ages ranged from three to 19 years (mean age 13 years). Frontal, parietal and temporal lobes were the commonest locations. Mean and median tumor size was six and five cm respectively. All 11 cases demonstrated the classic biphasic pattern. In 10 cases, glial component was astrocytic and was highlighted on GFAP. Sarcomatous component in most cases resembled fibrosarcoma and was high grade in 72.7%. Glial areas were reticulin poor while sarcomatous areas were reticulin rich. In over 45% cases, bizarre tumor giant cells were seen in the sarcomatous areas. In 1 case, sarcomatous areas showed extensive bone and cartilage formation. Other histologic features included hyalinized blood vessels, hemorrhage, infarction, gemistocytic cells, rhabdoid cells etc. Follow up was available in nine patients, five received chemoradiation post resection while three received radiotherapy only. Prognosis was dismal and eight patients died within one to 14 months following resection. CONCLUSIONS: Gliosarcomas in patients under 20 comprised 13% of all gliosarcomas reported during the study period. Frequency and mean age were higher compared to other published reports. Pathological features were similar to those described in literature. Clinicopathological features and prognosis of pediatric gliosarcomas were similar to adult gliosarcomas.

Concomitant bilateral mandibular cemento-ossifying fibroma and cementoblastoma: case report of an extremely rare occurrence.

BACKGROUND: Cemento-ossifying fibroma (COF) and cementoblastoma (CB) are rare benign odontogenic tumors with a predilection for the mandible. Cemento-ossifying fibroma is a fibro-osseous lesion that originates in the tooth bearing areas of jaw and shows cementum-like tissue in a fibrotic stroma. Cementoblastoma is classically related to roots of teeth with the presence of calcified cementum-like material. To date, only a single case of concomitant unilateral COF and CB has been reported in the literature. CASE PRESENTATION: We present an unusual case of a 37-year-old female who presented with two discrete bilateral swellings in the right and left mandible for 10 years. The larger tumor involved the left posterior mandible with extension anteriorly to the left and right anterior mandibles, and the smaller tumor was present in right posterior mandible. Radiology revealed two distinct lesions involving both sides of mandible. Histopathological examination showed characteristic features of cemento-ossifying fibroma in sections of the larger tumor and cementoblastoma in sections of smaller tumor. CONCLUSION: This case shows the very unique bilateral co-existence of COF and CB, the second case reported in literature to date.

Metachronous translocation renal cell carcinoma in a child with successfully treated medulloblastoma.

BACKGROUND: The most common primary CNS tumor in children is the medulloblastoma, which generally occurs in the posterior fossa and can spread through the CNS and spinal cord. Although the recurrence of renal cell carcinoma as a secondary tumor to neuroblastoma has been reported with successful anti-neoplastic treatment, the rare occurrence of a child who initially had medulloblastoma and then developed translocation renal cell carcinoma has never been reported before. CASE PRESENTATION: We report the case of a 12-year-old boy who initially presented with complaints of vomiting and headache. An MRI head confirmed the presence of 4 × 4 × 3 cm lesion which was resected completely and histopathology report confirmed the diagnosis of medulloblastoma Grade IV. Four years later, the child came for a follow-up visit and during routine screening, a CT scan showed heterogeneous lesion arising from the lower pole calyx of right kidney. The patient was referred to pediatric surgery for right radical nephrectomy involving the right adrenal gland. The histopathology report was consistent with the diagnosis of translocation renal cell carcinoma. CONCLUSION: Central nervous system (CNS) tumors remain the leading cause of death among pediatric neoplasms. We advise genetic testing of index cases and the establishment of an international tumor registry for a challenging disease.

Intra-abdominal Follicular Dendritic Cell Sarcoma (FDCS): Series of 18 cases of a rare entity from Pakistan.

OBJECTIVES: Follicular Dendritic Cell Sarcoma (FDCS) is a rare neoplastic proliferation of dendritic cells which are immune accessory cells found in both lymphoid and non-lymphoid organs. FDCS can thus occur in lymph nodes as well as non-lymphoid organs. Intraabdominal FDCS is even rarer. Our aim was to describe the clinical and morphological features of intra-abdominal FDCSs diagnosed in our practice and to review published literature on FDCSs including intra-abdominal FDCSs. METHODS: All cases of FDCSs diagnosed between January 1, 2008 and December 31, 2019 were included in the study. Slides of the cases were reviewed and clinical follow up was obtained. RESULTS: A total of 18 cases of intraabdominal FDCS were diagnosed during the study period. Age range was 17 to 55 years. Mean and median ages were 28 and 29 years respectively. Of the 18 patients, 11 were male and 7 were females. Colon was involved in 9 cases and appendix in 2 cases. 9 cases were received as resection specimens while 9 cases were received as slides and blocks for second opinion. Tumor size ranged from 2.7 to 26 cm. Average tumor size in these 9 cases was 8.2 cm and in 6 of these 9 cases, tumor size was greater than 6 cm in largest dimension. Grossly, tumors were nodular or polypoid and had a fleshy, grey white, homogeneous cut surface. Histologically, all 18 cases showed proliferation of plump to spindle shaped cells arranged in a fascicular or storiform pattern. Tumor cells had mild to moderately pleomorphic spindle to ovoid vesicular nuclei with fine chromatin and inconspicuous to variably conspicuous nucleoli, and moderate amount of pale eosinophilic cytoplasm. Mitotic activity was usually brisk. CD21 and CD23 were positive in all 18 cases. Resection margins were negative in all 9 resection specimens. Lymph nodes positive for metastases were seen in 4 cases. Follow up was available in 13 cases. Recurrence was seen in 6 patients, out of which 3 patients died of disease 15, 17- and 24-months following resection. 1 patient with appendiceal FDCS was free of disease almost 12 years after surgery but recently developed recurrence and is currently undergoing chemotherapy. 6 patients were alive and well at the time of follow-up 5 to 68 months after resection. None of them had developed recurrence or metastases at the time of follow up. 8 of the 13 patients received chemotherapy and/or radiotherapy post-surgical resection. CONCLUSION: Colon was involved in 9 of our 18 cases. Lymph nodes were positive for metastases in 4 out of 9 resection specimens. All cases were diagnosed based on morphology supported by positivity for immunohistochemical stains CD21 and CD23. Histological factors associated with aggressive behavior were seen in 14 cases. Majority of patients had an aggressive clinical course.

Spectrum of histological features of Denosumab treated Giant Cell Tumor of Bone; potential pitfalls and diagnostic challenges for pathologists.

OBJECTIVES: Denosumab is Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) inhibitor which is being used in the treatment of locally advanced, recurrent and metastatic Giant Cell Tumor of Bone (GCTB). It causes reduction in monocyte recruitment and Osteoclast-Like Giant Cell (OLGC) formation which limits bone destruction. After Denosumab treatment, GCTB exhibit diverse morphological features which can pose diagnostic challenge. Our aim was to study the spectrum of histologic features seen in Denosumab treated GCTB which could be helpful in establishing correct diagnosis. METHODS: We retrieved and reviewed H&E stained microscopic glass slides of 38 GCTB cases who received Denosumab as neoadjuvant treatment. These cases were treated at different institutes and diagnosed at our institute between January 2017 and October 2019. Morphologic features such as presence of residual OLGC, appearances of mononuclear stromal and bony components were assessed along with other non-specific features. RESULTS: Patients' median age was 29 years. Male to female ratio was 1.53:1. Femur was the most commonly involved bone. Microscopically, peripheral shell of reactive bone was observed in all cases. In 20 (52.6%) cases, there was complete elimination of OLGC. Mononuclear stromal cells were predominantly bland spindle shaped and arranged in fascicular and storiform patterns. Focal atypia was noted in 3 cases. Bony component manifested as trabeculae of woven bone with osteoblastic rimming and immature trabeculae of unmineralized osteoid with haphazardly present osteoblasts. Spectrum of stromal changes included cystic spaces, foamy macrophages, inflammatory infiltrate, hemangiopericytoma-like (HPC-like) vessels, hyalinization, edematous areas and hemosiderin pigment. The tumors showed areas which resembled other bony and soft tissue lesions such non-ossifying fibroma, fibrous dysplasia, osteoblastoma, sclerosing epithelioid fibrosarcoma and osteosarcoma. CONCLUSION: Denosumab treatment induces a variety of changes in GCTB. Clinical history and knowledge of these features are necessary for excluding differential diagnoses and avoiding misdiagnosis.

Tuberculosis of the flexor carpi radialis muscle - a case report.

Tuberculosis involving almost any organ of the body is a major problem in developing countries. The most commonly affected site in tuberculosis is the lung. Of the extra pulmonary tuberculosis, musculoskeletal involvement accounts for 1-5% of the cases. Muscular involvement in tuberculosis is a rare manifestation of extra pulmonary tuberculosis. Unusual presentations often go undetected and are associated with a diagnostic and therapeutic delay. This case report presents tuberculosis of the flexor carpi radialis.

Primitive myxoid mesenchymal tumor of infancy with brain metastasis: first reported case.

INTRODUCTION: Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a recently diagnosed entity, with only a handful of cases reported to date. CASE DESCRIPTION: Herein, we present the occurrence of this tumor in a 2-year-old boy, initially diagnosed as primitive neuroectodermal tumor of the extremity and treated with chemotherapy and surgical resection. He later presented with a cerebellar lesion, and biopsy was consistent with PMMTI. CONCLUSION: While there have been previous cases of PMMTI reported with loco-regional metastatic spread, to our knowledge, there is no known incidence of distant metastasis with involvement of the central nervous system, which makes this case the first of its kind.

Immunophenotypic characterisation of morphologically diagnosed cases of Acute Myeloid Leukaemia (AML).

OBJECTIVE: To determine immunophenotypic pattern in newly diagnosed cases of acute myeloid leukaemia by flow cytometry and its correlation with morphological findings. METHODS: This study was conducted at Haematology (Pathology) department, Army Medical College, in collaboration with Immunology Department Armed Forces Institute of Pathology, Rawalpindi from 16 November 2016 to 16 November 2017. One hundred and six patients of both genders and all age groups diagnosed as acute myeloid leukaemia were included in the study. Demographic data was noted. Complete blood counts, bone marrow examination and cytochemical stains were carried out and evaluated microscopically for blast percentage and morphology. Immunophenotyping was performed by flow cytometry using standard panel on peripheral blood or bone marrow samples. The surface and cytoplasmic antigens of interest were analysed and correlated with morphological findings. RESULTS: The most commonly expressed antigens were CD13, CD33, CD45 and HLA-DR. Almost all blasts expressed CD45 with no remarkable difference among the subtypes of AML. The mean positivity for CD13 among all AML subtypes was 57% and for CD33 was 67%. Aberrant expression of CD7 and CD19 were expressed in 26.4% and 1.1% of all cases respectively. There was concordance rate of 90% between morphology and FCM in our study. CONCLUSION: Flow cytometric analysis of acute leukaemia done by a combination of patterns and intensity of antigen expression improves diagnostic yield in AML. CD13, CD33 and CD45 are the most frequently expressed antigens in AML. Our findings suggest a 90% concordance between morphology and flow cytometry. It is pertinent to conclude that flow cytometry results interpreted with morphology are complementary.

Meningeal solitary fibrous tumor/hemangiopericytoma: Emphasizing on STAT 6 immunohistochemistry with a review of literature.

BACKGROUND: The 2016 central nervous system (CNS) World Health Organisation (WHO) Update has merged the entities of meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) into a single entity based on the presence of the nerve growth factor 1A (NGFI-A) binding protein 2 (NAB2)- signal transducer and activator of transcription 6 (STAT6) gene fusion in these tumors. Immunohistochemical (IHC) staining with STAT6 results in a strong nuclear positivity confirming the diagnosis. Meningeal SFT/HPCs are currently histologically graded according to a three-tiered system. Grade I (SFT phenotype) is benign, whereas grades II and III (HPC phenotype) are malignant and require radiotherapy in addition to gross total resection. OBJECTIVES: The objectives were to review the cases diagnosed as meningeal SFT or HPC between 2010 and 2017 and classify them into SFT (grade I) or HPC (grades II and III) phenotypes; to confirm the diagnosis by performing STAT6 immunohistochemistry; and to observe and record the histological features in detail and correlate the tumor grades with their behavior. The published literature on the subject was also reviewed. MATERIALS AND METHODS: A total of 21 cases diagnosed between 2010 and 2017 as meningeal SFT or HPC were included in the study. All cases were reviewed by the authors and were categorized and graded according to histologic phenotype and mitotic count. STAT6 immunohistochemistry was performed in all the cases. The epidemiological data and histologic findings in each case were recorded in detail. The follow-up of patients was obtained. RESULTS: Fifteen patients were males and six were females. The mean age was 43.5 years. The mean tumor size was 6.8 cm. The tumor specimens in 20 out of 21 cases corresponded to the HPC phenotype, of which 6 were in grade II while 14 were in grade III. Thus, over 95% cases had malignant lesions. The tumor in all the 21 cases recruited for the study showed immunohistochemical positivity for SAT6, while CD34 was positive in all the 18 tumor in which it was performed. The follow-up was available in 14 of the patients. Recurrence occurred in six patients who had either a grade II or a grade III tumor and three patients died (including one patient with a grade III tumor. This patient died a month after initial resection although there was no evidence of recurrence). Radiotherapy was given to only 4 out of 14 patients in whom follow-up was available. CONCLUSION: These rare tumors need to be accurately diagnosed and optimally treated (gross total resection and radiotherapy) to improve the prognosis.

Papillary craniopharyngioma: A clinicopathologic study of a rare entity from a major tertiary care center in Pakistan.

BACKGROUND: Papillary craniopharyngioma (PCP) are uncommon variants of craniopharyngiomas (CP), which are benign epithelial neoplasms of the sellar and suprasellar region. Histologically, PCPs are typically composed of well-differentiated stratified squamous epithelium; however, focal variations are not uncommon. A distinction from other lesions of the region, despite being difficult to achieve due to the overlapping radiological and clinical features, is important for adequate treatment to be administered. OBJECTIVE: Our aim was to study the clinical and histological features of PCP with emphasis on features that are helpful in its distinction from other lesions that are similar in appearance. MATERIALS AND METHODS: We reviewed 13 cases of PCP diagnosed in our institution between January 2010 and December 2015. RESULTS: The mean age at presentation was 30.76 years. Two of the patients belonged to the pediatric age group. Male-to-female ratio was 2.25:1. Suprasellar location (either alone or in combination with sellar region) was the most common tumor site. Microscopically, all of the cases showed stratified squamous epithelium with frequent pseudopapillae formation. Focal adamantinomatous epithelium and columnar epithelium with variable cilia and goblet cells were seen in 4 (30.7%) cases. Brain invasion was observed in 3 (23%) cases. Four patients died of their disease; 2 of the 7 patients with an available follow up, developed recurrences; and, 5 experienced severe postoperative morbidity. CONCLUSION: Majority of the PCPs exhibited typical features with minor variations. Knowledge of the variations in histologic features helps in reaching the correct diagnosis. These tumors can behave aggressively with a high recurrence rate and decreased overall survival.

Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic study of 11 cases.

Mammary analogue secretory carcinoma (MASC) is a recently described tumor sharing the histologic, immunohistochemical, and molecular profile of secretory carcinoma of breast. We aimed to evaluate the morphologic and histochemical features needed/required for the diagnosis of MASC without adjunct of molecular analysis. Six retrospective cases suspicious for MASC and 5 prospective cases reported as MASC were included in the study. Molecular analysis of ETV6 by fluorescence in situ hybridization was performed at the University of Pittsburg, USA. The ages of the patients ranged from 9 to 60 years (mean, 27.5 years). Histologically, all tumors showed mixed growth patterns including microcystic, macrocystic, papillary, tubular, and solid, papillary the being most common pattern. The tumor cells showed round to oval vesicular nuclei with small nucleoli, and eosinophilic to vacuolated cytoplasm. All cases demonstrated luminal and cytoplasmic mucin on periodic acid-Schiff with and without diastase digestion and alcian blue stain. ETV6 fusion gene rearrangement by fluorescence in situ hybridization was detected in 10 of 11 tumors. Recurrences occurred in 3 patients, and 1 patient died of disease 5 years after surgery. In conclusion, MASC is a relatively rare salivary gland malignancy exhibiting distinct histologic and histochemical features which can help to differentiate it from other mimics. Histologically, papillary-cystic and microcystic patterns are the main clues to diagnosis. The follicular pattern of acinic cell carcinoma might represent MASC, as 4 cases in our series had this pattern. Two patients in our series were 9 and 9½ years old respectively, which are the youngest ages ever recorded for MASC.

Cementum-like matrix in solitary bone cysts: a unique and characteristic but yet underrecognized feature of promising diagnostic utility.

Solitary bone cysts (SBCs) are benign, intraosseus, cystic lesions, which generally involve metaphysis of long bones during the period of skeletal immaturity. Histologic features are nonspecific, but identification of amorphous cementum-like material provides a significant diagnostic clue. This material is unique to SBC with reported frequency of 10% to 70% and has been described as an immature form of bone. We retrieved and reviewed 41 cases of SBC reported in the last 10 years. The ages of patients ranged from 4 to 64 years (mean, 16 years), with a male-to-female ratio of 3:1. Humerus and femur were the most common sites. Cementum-like matrix was observed in 26 cases (63.4%). This material was seen in different phases of deposition and progression, ultimately transforming into mature bone as seen in 4 cases. Cyst wall lining was observed in 70.7% of cases along with several other nonspecific histologic features including reactive bone formation, hemosiderin macrophages, hemorrhage, multinucleated giant cells, foamy macrophages, fibrin, cholesterol clefts, and granulation tissue. Cementum-like material in the wall of SBCs is a specific and fairly consistent finding of diagnostic significance in cases where cyst wall lining is deficient. We also histologically demonstrate, for the first time, transformation of cementum-like material into reactive and mature bone, which further validates the immature osteoid nature and finding of other authors.

Myoepithelial tumors of soft tissue and bone in children and young adults: A clinicopathologic study of 40 cases occurring in patients ≤ 21 Years of age.

Myoepithelial tumors of the soft tissue and bone occurring in patients 21 years of age and younger are rare, and their clinicopathologic features remain incompletely understood. We studied a well-characterized series of 40 such tumors. Cases were retrieved from our archives for the period 2009-2022 and re-reviewed. Available immunohistochemical and molecular genetic data was collected. Clinical information including available follow-up was obtained. The tumors occurred in 18 males and 22 females, ranging from 3 months to 21 years of age (median 11.5 years), and involved a wide variety of soft tissue (n = 36) and bone (n = 4) locations. Histologically benign myoepithelial tumors tended to occur in adolescents (median age 14.5 years; range 5-21 years), whereas myoepithelial carcinomas occurred in younger patients (median age 8.5 years; range 3 months-20 years). Microscopically, the tumors showed a complex admixture of epithelioid, plasmacytoid and spindled cells in a variably hyalinized, myxoid, chondroid or chondromyxoid background. Small subsets of histologically malignant tumors had rhabdoid or "round cell" features. Immunohistochemistry showed 35/40 (88%) cases to be positive with at least one keratin antibody. The 5 keratin-negative tumors were uniformly positive for S100 protein and/or SOX10 and expressed EMA (4 cases) and/or p63 (3 cases). EMA, SMA and GFAP were positive in 21/25 (84%), 13/21 (62%), and 8/21 (38%) tumors, respectively. SMARCB1 and SMARCA4 expression was retained in 29/31 (94%) and 22/22 (100%) of cases, respectively. FISH for EWSR1 gene rearrangement was positive in 6/18 (33%) tested cases. Two EWSR1-negative tumors were also FUS-negative. NGS identified EWSR1::POU5F1, FUS::KLF17, and BRD4::CITED1 gene fusions in 3 tested cases. Clinical follow-up (22 patients; median 23 months; range 1-119 months) showed 3 patients with local recurrences and 5 with distant metastases (lymph nodes, lung, and brain). Three patients died of disease, 3 were alive with recurrent or unresectable disease, and 16 were disease-free. Adverse clinical outcomes were seen only in patients with malignant tumors. We conclude that myoepithelial neoplasms of soft tissue and bone are over-repesented in patients ≤21 years of age, more often histologically malignant, and potentially lethal. Histologic evaluation appears to reliably predict the behavior of these rare tumors.

A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1-altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1- amplified Versus GLI1-rearranged Tumors.

GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.