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Context.—: Human epidermal growth factor (HER2/neu) gene amplification, a poor prognostic factor in invasive breast cancer, has shown substantial utility as a predictive marker, with significantly improved survival following anti-HER2 therapies like trastuzumab. Dual-color dual in situ hybridization (D-DISH), a recently introduced fully automated assay for HER2/neu evaluation on light microscopy, has several advantages over fluorescence in situ hybridization (FISH)., Objective.—: To standardize and validate the D-DISH assay using FISH as the gold standard and assess interobserver reproducibility in interpreting the D-DISH assay., Design.—: D-DISH was performed using the latest HER2 Dual ISH DNA Probe Cocktail assay (Ventana Medical Systems Inc, Tucson, Arizona) in 148 cases of invasive breast cancer. The same block was used for performing immunohistochemistry by Ventana PATHWAY anti-HER2/neu (4B5) antibody and FISH assay by ZytoLight SPEC ERBB2/CEN17 Dual Color Probe. D-DISH was separately interpreted by 4 pathologists blinded to FISH results., Results.—: Concordance of 98.65% and a Cohen κ value of 0.97 were observed between FISH and D-DISH. Intraclass correlation coefficient (0.93-0.97) and κ values (0.98-1.0) for interobserver reproducibility showed almost perfect agreement by D-DISH. Interobserver reproducibility was also evaluated for genomic heterogeneity, HER2 group categorization, and polysomy (κ values 0.42-0.74, 0.89-0.93, and 0.98-1.0, respectively)., Conclusions.—: We successfully validated the latest version of D-DISH assay as a substitute for FISH in predicting HER2 gene status with significant interobserver reproducibility, concluding that this D-DISH assay may be introduced in routine diagnostic services as a reflex test to ascertain HER2 gene status., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is an uncommon extranodal lymphoma that accounts for more than 95% of all the CNS lymphomas. Unlike its systemic/nodal counterpart, which is currently subtyped into cell-of origin (COO) subtypes, its feasibility and utility are largely debatable in PCNS-DLBCL., Objectives: To classify PCNS-DLBCL into COO-subtypes based on immunohistochemical algorithms by Hans and Choi and evaluate concordance between the two. A further aim is to investigate the clinicoradiological and histomorphological parameters of the subtypes thus obtained., Materials and Methods: As many as 143 cases of primary CNS lymphoma were evaluated by immunohistochemistry for CD10, BCL6, MUM1, GCET, and FOXP1 and based on which the said 143 cases were further classified into COO subtypes using Hans and Choi algorithms., Results: Mean age was 53.8 years with marginal male preponderance and predominantly centroblastic morphology (75.5%). CD 10 was positive in 8.9% of the cases, BCL6 in 58.6%, MUM1 in 89.9%, GCET in 32.9%, and FOXP1 in 79.5%. As much as 84.9% cases were of non-germinal center B-cell (GCB) subtype and 15.1% cases were of GCB subtype as determined based on Hans algorithm. Furthermore, 90.7% cases were of activated B-cell (ABC) subtype and 9.3% cases were of GCB subtype according to Choi algorithm. A 91.8% concordance was observed between Hans and Choi algorithms. Among the 6 discordant cases, 5 cases were subtyped as GCB by Hans and ABC by Choi and 1 case as ABC by Hans and GCB by Choi., Conclusion: Most of PCNS-DLBCLs are of non-GCB/ABC COO subtype, but inconsistences abound in the utility of IHC algorithms in PCNS-DLBCL COO subtypes., Competing Interests: None

Background: The programmed cell death protein - 1 (PD-1) - programmed cell death ligand - 1 (PD-L1) axis is emerging as a promising target for immunotherapy in triple-negative breast cancers (TNBC)., Aims: We analyzed the expression of PD-L1 in TNBC cases, with special emphasis on lymphocyte-predominant tumors along with correlation of the same with clinicopathological features and outcome., Settings and Design: Tissue microarrays (TMA) were prepared from resection specimens of TNBC cases diagnosed from 2004 to 2008., Subjects and Methods: Immunohistochemical staining was performed on the TMA using the ventana PD-L1 antibody (Clone SP 263)., Statistical Analysis: Chi-square test was used for correlation of PD-L1 positivity in tumor and immune cells with clinicopathological features. Univariate and multivariate survival analyses were carried out using the Kaplan Meir and Cox Regression methods, respectively., Results: Overall, PD-L1 staining was seen in 35.9% (66 out of 184) tumors. PD-L1 positivity of tumor cells was seen in 14.7% (27 out of 184 cases), whereas stromal immune cell expression was observed in 21.2% (39 out of 184) cases. Lymphocyte-predominant tumors showed statistically significant expression of PD-L1 in both tumor (P < 0.0001) and immune cells (P 0.036). On univariate analysis, PD-L1 in immune cells was associated with good overall survival (P 0.05) as well as disease-free survival (P 0.013). On multivariate analysis, the same was associated with a significantly decreased risk for recurrence (P 0.018)., Conclusion: PD-L1 expression in stromal immune cells proved to be a significant prognostic factor for TNBC. This data can serve as a baseline to plan clinical trials with anti-PD-L1 drugs for TNBC in the Indian setting.

Ultrasound (US) lexicon of the Breast Imaging Reporting and Data System (BI-RADS) defines an echogenic breast mass as a lesion that is hyperechoic in comparison with subcutaneous adipose tissue. However, at sonography, only 0.6 to 5.6% of breast masses are echogenic and the majority of these lesions are benign. approximately, 0.5% of malignant breast lesions appear hyperechoic. The various benign pathologic entities that appear echogenic on US are lipoma, hematoma, seroma, fat necrosis, abscess, pseudoangiomatous stromal hyperplasia, galactocele, etc. The malignant diagnoses that may present as hyperechoic lesions on breast US are invasive ductal carcinoma, invasive lobular carcinoma, metastasis, lymphoma, and angiosarcoma. Echogenic breast masses need to be correlated with mammographic findings and clinical history. Lesions with worrisome features such as a spiculated margin, interval enlargement, interval vascularity, or association with suspicious microcalcifications on mammography require biopsy. In this article, we would like to present a pictorial review of patients who presented to our department with echogenic breast masses and were subsequently found to have various malignant as well as benign etiologies on histopathology., Competing Interests: Conflict of InterestFinancial Support and Sponsorship The authors declare no conflict of interest. Nil., (Indian Radiological Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Context: HER2/neu testing in breast cancer is a mandate due to availability of trastuzumab, a monoclonal antibody targeted against this biomarker. Dual-color dual-hapten in situ hybridization (D-DISH) is a new test for assessment of HER2/neu gene overexpression on light microscopy., Aims: This was a validation study for D-DISH in our laboratory and was conducted to study the concordance between fluorescence in situ hybridization (FISH) and D-DISH for HER2/neu testing in breast cancer., Materials and Methods: In all, 150 cases of invasive breast carcinoma requested for FISH analysis were selected. Immunohistochemistry by Ventana PATHWAY anti-HER2/neu (4B5) antibody, FISH by ZytoLight SPEC ERBB2/CEN17 Dual Color Probe, and D-DISH using the Ventana INFORM HER2 Dual ISH DNA Probe Cocktail Assay was carried out., Statistical Analysis: Cohen's kappa coefficient was used to calculate concordance between FISH and D-DISH assays. The ratios and average number of signals were compared with Lin's concordance correlation coefficient., Results: About 93.1% of the cases showed concordance between FISH and D-DISH results. Cohen's kappa correlation coefficient was 0.836, indicating almost perfect level of agreement. Lin's concordance correlation coefficient (ρc) showed moderate strength of agreement for HER2/chromosome 17 ratios between FISH and D-DISH assays (ρc 0.9452). As per the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 updated guidelines, four of the cases that were nonamplified on FISH showed low-level amplification on D-DISH due to counting errors caused by faint signals or background dust. Genomic heterogeneity and larger red chromosome 17 signals on D-DISH led to discordance of the six cases amplified by FISH. D-DISH failure rate was 3.33%., Conclusion: Overall, D-DISH showed good concordance with FISH but needs expertise for reporting.

Background: The incidence of non neoplastic lesions are much more common in epididymis. Clinically, epididymal nodules are easily accessible to fine needle aspiration cytology (FNAC) procedure. There are very few literature reports documenting the role of cytology in evaluation of epididymal nodules. Thus, we studied patients presenting with palpable epididymis nodules in the out patient department (OPD) from a tertiary care general hospital., Aim: This study is aimed to put forth the diagnostic utility of FNAC in palpable lesions of epididymis., Materials and Methods: A total of 40 palpable epididymal nodules were aspirated as a routine OPD procedure as part of this study. Smears were fixed in isopropyl alcohol and air dried. In all the cases, wet fixed papanicoloau stained and air dried giemsa stained smears were studied. Zeihl Neelsen stain was performed in cases which yielded caseous aspirate., Results: Except for two cases of adenomatoid tumor of epididymis all other lesions were nonneoplastic and included 14 cases (35%) of tuberculous granulomatous inflammation, 10 (25%) cystic nodules (9 spermatoceles and 1 encysted hydrocele), 5 (12.5%) of nonspecific inflammations, 3 (7.5%) filarial infection, 3 (7.5%) sperm granulomas and 3 (7.5%) adenomatous hyperplasia of rete testes. Except for the two tumors, one adenomatous hyperplasia and one tuberculous lesion, no other lesion was excised. Follow up and response to therapy was available in 78% patients and resolution indicated appropriateness of the diagnosis, Conclusions: Thus, as most of the lesions in epididymis are non neoplastic responding to medical line of treatment and FNAC served to aid diagnosis of non specific inflammation and avoid surgical excision in most cases.

Background: An accurate recognition of a lymphoma at an extranodal site is essential to avoid unnecessary excisions. Fine needle aspiration cytology (FNAC) has been recognized as a useful tool in the primary diagnosis of soft tissue tumors. An anaplastic large cell lymphoma (ALCL), occurring in soft tissues, poses a diagnostic challenge. We present the cytomorphology of 2 cases of anaplastic lymphoma kinase (ALK)+ ALCL that displayed a perivascular arrangement, thereby mimicking a sarcoma., Cases: The patients were aged 16 and 9 years. While the former presented with multiple nodular soft tissue and bony lesions over the body, the latter complained of an axillary lump. FNAC smears in both cases showed pleomorphic cells, arranged in loosely cohesive groups around blood vessels and scattered singly, with prominent nucleoli and abundant, finely vacuolated cytoplasm. Interspersed were a few cells with embryoid nuclei. Differential diagnoses included a rhabdomyosarcoma and a lymphoma. On biopsy and immunohistochemistry, tumor cells were positive for vimentin, LCA, EMA, CD30 and ALK., Conclusion: ALCL should be considered in the differential diagnosis of pediatric soft tissue tumors, especially in cases with multifocal involvement. The presence of cohesive, perivascular arrangements on FNAC should not detract a cytologist for keeping this possibility in mind. Further, a careful search for the typical "hallmark" cells should be made.

Solitary fibrous tumour (SFT) is a rare spindle cell neoplasm arising at pleural and extrapleural sites. Five cases of SFT diagnosed at our institution over a five year period were reviewed. Haematoxylin and eosin stained histological sections, immuno-histochemical markers including CD34 and electron microscopy were the different methods used to study these tumours. Three histological features were consistently observed in all the tumours: the tumours were composed of short spindle cells separated by dense collagen bands and arranged in alternate hypocellular and hypercellular areas. CD34 positivity was seen in all the cases. SFT's have been reported to behave in an unpredictable fashion and hence prolonged follow up is essential. Histology, CD34 positivity and electron microscopy are useful tools in diagnosing SFT. While the pleural tumours can be diagnosed based on histology, this must be substantiated by ancillary techniques in case of extrapleural tumours.

This study highlights the rare presentation of anaplastic large cell lymphoma as primary bone and soft tissue tumour. Twelve cases were studied. Clinical impression was non Hodgkin's lymphoma in 4 cases, sarcoma in 6 (osteosarcoma-2, Ewing's/primitive neuroectodermal tumour-1, and sarcoma NOS-3), and tuberculosis of thoracic spine in 1 and the last case involving the rib had a differential diagnosis of tuberculosis and NHL. Histology revealed round cells with eosinophilic cytoplasm and pleomorphic nuclei. Immunohistochemically all tumours were CD30 positive and 8 of 9 cases (88.9%) showed ALK-1 positivity. The pleomorphic cytomorphology ofALCL leads to confusion with the more frequent bone and soft tissue sarcomas affecting the musculoskeletal system. A high index of suspicion is necessary to initiate the correct panel of immunohistochemical markers to first confirm the lymphomatous nature of this tumour and to subsequently subclassify. This alone will lead to an accurate recognition of ALCL and the appropriate chemotherapy.

Background: Fibromatosis-like metaplastic carcinoma is a newly described metaplastic breast tumor, literature on which is still evolving., Case Presentation: A 77-year-old lady presented with a 2 x 2 cm mass with irregular margins in the upper and outer quadrant of left breast. Fine needle aspiration cytology (FNAC) from the lump was inconclusive. A lumpectomy was performed and sent for frozen section, which revealed presence of spindle cells showing mild atypia in a sclerotic stroma. The tumor cells revealed prominent infiltration into the adjacent fat. A differential diagnosis of a low-grade sarcoma vs. a metaplastic carcinoma, favoring the former, was offered. Final histology sections revealed an infiltrating tumor with predominant spindle cells in a collagenous background, simulating a fibromatosis. Adjacent to the tumor were foci of benign ductal hyperplasia and a micropapilloma. Immunohistochemistry (IHC) showed diffuse co-expression of epithelial markers i.e. cytokeratins (CK, HMWCK, CK7) and EMA along with a mesenchymal marker i.e. vimentin in the tumor cells. Myoepithelial markers (SMA and p63) showed focal positivity. A diagnosis of a low-grade fibromatosis-like carcinoma breast associated with a micropapilloma was formed., Conclusion: Fibromatosis-like carcinoma is a rare form of a metaplastic breast tumor. This diagnosis requires an index of suspicion while dealing with spindle cell breast tumors. The importance of making this diagnosis to facilitate an intra operative surgical planning is marred by diagnostic difficulties. In such cases, IHC is imperative in forming an objective diagnosis.

A 12-year-old male child born of non-consanguineous parents presented with multiple skin lesions, hoarseness of voice, and episodes of epilepsy since early childhood. The findings of characteristic beaded eyelid margins, patchy alopecia of the scalp, hoarseness of voice, and epilepsy were consistent with a rare clinical diagnosis, lipoid proteinosis. Skin biopsies obtained from representative skin lesions were subjected to histology and electron microscopy. Light microscopy demonstrated PAS-positive diastase-resistant material in the papillary dermis of skin. Ultrastructure revealed granulo-filamentary aspect of the accumulated material. Although this rare autosomal recessive disorder has been described in the literature, its occurrence is rare in India.

Rosette formation is a rare, recently reported variation in osteogenic sarcoma and is thought to be associated with a poor prognosis. We report two cases of rosette forming osteosarcoma, one with poor response and other with total necrosis following chemotherapy. Pathologists should be aware of rosette formation in osteosarcoma to avoid misdiagnosis as other rosette forming tumors of bone especially PNET/Ewings sarcoma. In our opinion rosettes in an osteosarcoma should be documented both from a differential diagnostic point of view and also to elucidate definitive prognostic implications.

Objective: To analyze fine needle aspirates from tubular adenomas of the breast and elucidate cytologic features unique to these tumors., Study Design: Fine needle aspiration (FNA) cytology smears from eight tubular adenomas were reviewed, with special attention given to architectural features and individual cell characteristics. Smears were then compared with those from 25 fibroadenomas and 2 tubular carcinomas for analyzing the distinguishing features., Results: Aspirates from tubular adenomas revealed cells arranged as small, three-dimensional balls or clusters, tubules of different shapes and less frequently as closely approximated acini. Cells were uniform, with pale cytoplasm, which showed magenta granules in the Giemsa smears from two tumors. Straight tubules, closely approximated acini and intracytoplasmic granules were not seen in aspirates from fibroadenomas. The tubules in tubular adenomas always showed myoepithelial cells and were more open than the angulated tubules of tubular carcinoma., Conclusion: Tubular adenomas on FNA cytology specifically show cells arranged as small, three-dimensional balls, tubules or closely approximated acini. Cells are uniform and sometimes show intracytoplasmic granules in Giemsa-stained smears.

Fourteen autopsy cases of neonatal hepatitis have been studied. Of these seven cases were due to infections viz.: cytomegalovirus infection (four cases), probable cases of congenital syphilis (two cases) and neonatal herpes (one case). The remaining seven cases were of Idiopathic Neonatal Hepatitis (INH) with giant cell change in six cases. Even in these cases (INH) there was a high index of suspicion of intrauterine or acquired infection in view of severe mononuclear inflammation in the pancreas, alimentary tract and lungs. Most of these neonates with INH had low birth weight and two were preterm pointing towards a prenatal insult. The orcein stain and Periodic Acid Schiff (PAS) with diastase in all the cases were negative making hepatitis B virus infection and infinity 1 antitrypsin deficiency less likely. These autopsies represent the tip of the iceberg and only the severe cases of infection. The fatal outcome could have been prevented by maternal screening for infections and earlier clinical diagnosis.

The mammary hamartoma is a poorly recognised benign breast neoplasm. For diagnosis one usually correlates the clinical, mammographic, gross and histologic features. This study of fifteen cases emphasises the histomorphologic criteria for diagnosis especially in the absence of mammographic picture, viz. a clinically palpable, well encapsulated mass which on histology shows normal breast epithelium admixed with fat, fibrous tissue and other mesenchymal elements. The epithelium in the hamartomas studied showed changes seen in normal breast especially in the progestational phase of the menstrual cycle. The stroma was either densely collagenous, hyalinised or cellular and admixed with fat in various proportion in thirteen cases, muscle in two cases and thick muscular arteries in four cases. It also showed pseudoangiomatous hyperplasia in seven cases. The importance of this change and probable evolution is discussed therein.

We report a patient with gastric adenocarcinoma presenting with a cauliflower-like large papillomatous cutaneous metastases on the nape of the neck.