Wide Morphologic Spectrum Research Articles

Clinicopathologic features and outcomes of hepatic inflammatory pseudotumour (IPT) and hepatic IPT-like lesions.

Hepatic inflammatory pseudotumours (IPTs) are nonneoplastic hepatic masses characterized by variably fibroblastic stroma and inflammatory infiltrate, hypothesized to arise as part of a response to infection or prior surgery. The aim of this study was to evaluate the clinicopathologic features and outcomes of biopsy-proven hepatic IPT as well as other cases with IPT-like histologic features. A database search at our institution identified cases with a pathologic diagnosis of hepatic IPT (n = 80) between 2000 and 2023. Histologic features (stromal quality, inflammatory cell components, granulomas, and necrosis) were evaluated. Past medical and surgical history, microbiologic studies, and outcomes were reviewed retrospectively. Patients frequently had a past medical history of malignancy (34%), biliary disease (15%), or prior intraabdominal surgery (24%), and often presented with multifocal hepatic lesions (36%). Variable inflammatory backgrounds were present, including histiocytic (36%), lymphoplasmacytic (34%), or neutrophilic (24%). Specific organisms were identified in 15% of cases, most commonly Klebsiella and Staphylococcus species. Most patients with available clinical follow-up demonstrated radiologic resolution and/or had repeat negative biopsy; a minority of patients (8%) were subsequently diagnosed with neoplastic hepatic lesions. No significant association was seen between histologic features and the subsequent clinical or pathologic diagnosis of hepatic neoplastic lesions. Hepatic IPT is a heterogeneous entity that can present in a variety of clinical scenarios and show a wide morphologic spectrum. These lesions often regress spontaneously or with antibiotics. A subset of cases with hepatic IPT-like histologic features were subsequently diagnosed with malignancy, emphasizing the need for continued follow-up and repeat biopsy depending on clinical and radiologic features.

HER2 amplification and PD-L1 expression in invasive stratified mucin-producing carcinoma of the cervix: a clinicopathological analysis of eighteen cases

Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.

Adult caudal fin shape is imprinted in the embryonic fin fold.

Appendage shape is formed during development (and re-formed during regeneration) according to spatial and temporal cues that orchestrate local cellular morphogenesis. The caudal fin is the primary appendage used for propulsion in most fish species, and exhibits a range of distinct morphologies adapted for different swimming strategies, however the molecular mechanisms responsible for generating these diverse shapes remain mostly unknown. In zebrafish, caudal fins display a forked shape, with longer supportive bony rays at the periphery and shortest rays at the center. Here, we show that a premature, transient pulse of sonic hedgehog a (shha) overexpression during late embryonic development results in excess proliferation and growth of the central rays, causing the adult caudal fin to grow into a triangular, truncate shape. Both global and regional ectopic shha overexpression are sufficient to alter fin shape, and forked shape may be rescued by subsequent treatment with an antagonist of the canonical Shh pathway. The induced truncate fins show a decreased fin ray number and fail to form the hypural diastema that normally separates the dorsal and ventral fin lobes. While forked fins regenerate their original forked morphology, truncate fins regenerate truncate, suggesting that positional memory of the fin rays can be permanently altered by a transient treatment during embryogenesis. Ray finned fish have evolved a wide spectrum of caudal fin morphologies, ranging from truncate to forked, and the current work offers insights into the developmental mechanisms that may underlie this shape diversity.

Development of a High-Throughput Pipeline to Characterize Microglia Morphological States at a Single-Cell Resolution.

As rapid responders to their environments, microglia engage in functions that are mirrored by their cellular morphology. Microglia are classically thought to exhibit a ramified morphology under homeostatic conditions which switches to an ameboid form during inflammatory conditions. However, microglia display a wide spectrum of morphologies outside of this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, which have been observed across brain regions, neurodevelopmental timepoints, and various pathological contexts. We applied dimensionality reduction and clustering to consider contributions of multiple morphology measures together to define a spectrum of microglial morphological states in a mouse dataset that we used to demonstrate the utility of our toolset. Using ImageJ, we first developed a semiautomated approach to characterize 27 morphology features from hundreds to thousands of individual microglial cells in a brain region-specific manner. Within this pool of features, we defined distinct sets of highly correlated features that describe different aspects of morphology, including branch length, branching complexity, territory span, and circularity. When considered together, these sets of features drove different morphological clusters. Our tools captured morphological states similarly and robustly when applied to independent datasets and using different immunofluorescent markers for microglia. We have compiled our morphology analysis pipeline into an accessible, easy-to-use, and fully open-source ImageJ macro and R package that the neuroscience community can expand upon and directly apply to their own analyses. Outcomes from this work will supply the field with new tools to systematically evaluate the heterogeneity of microglia morphological states across various experimental models and research questions.

Abstract 4632: Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer

Abstract Bladder cancers display a wide spectrum of morphologies that frequently co-exist within individual tumors. Several histologic variants, including plasmacytoid, neuroendocrine, and micropapillary subtypes, are associated with an increased bladder cancer recurrence risk and cancer-specific mortality. The molecular basis and therapeutic implications of this phenotypical plasticity remain poorly understood. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has also emerged as a new standard-of-care for metastatic bladder cancer patients, but the association between lineage plasticity as manifested by morphologic heterogeneity in bladder cancer, Nectin-4 expression and ADC response remains poorly defined. Previous DNA-based molecular profiling studies of histologic variants revealed that CDH1 mutations were the pathognomonic molecular alteration in plasmacytoid urothelial carcinoma, but no recurrent driver mutations have been found to be unique to the aberrant histology regions of other mixed histology subtypes. Thus, to explore the molecular basis for the lineage plasticity of bladder cancers with aberrant histology and to define the association between lineage plasticity manifested as morphologic heterogeneity and the expression of Nectin-4, HER2 and other potential ADC targets, we performed RNA-seq of pure urothelial carcinomas (n=118, not otherwise specified, UC-NOS) and bladder tumors with divergent differentiation or histologic subtypes (n=199). Our cohort included a subset of tumors in which RNA-seq was performed on microdissected UC-NOS and variant histology regions of the same tumor. Tumors with neuroendocrine, sarcomatoid and squamous histology had the lowest Nectin-4 expression, whereas histologic subtypes that retained a luminal transcriptional profile such as micropapillary, plasmacytoid and nested histology had higher levels of Nectin-4 expression. In mixed histology tumors, Nectin-4 and/or HER2 expression was often restricted to only one of the two histologic components. Gene Set Enrichment Analysis noted enrichment of distinct oncogenic pathway gene sets in different histologic variants. Preliminary investigation into the mechanism(s) of Nectin-4 regulation using bladder cancer cell lines and patient-derived organoids (PDOs) has identified targetable pathways which when inhibited revert lineage plasticity and induce Nectin-4 expression. In sum, lineage plasticity manifested as heterogenous histomorphologies was associated with heterogeneous Nectin-4 expression in some but not all histologic variants of bladder cancer. Ongoing studies using PDOs from bladder cancer patients with mixed histology will seek to identify molecular pathways whose inhibition leads to increased expression of Nectin-4 or other ADC targets such as HER2 and thus increased sensitivity of ADCs targeting these cell surface proteins. Citation Format: Jiaqian Luo, Sizhi P. Gao, Fengshen Kuo, Gamze Gokturk Ozcan, Merve Basar, Florestan Koll, Jacob E. Tallman, Syed M. Alam, Carissa E. Chu, Ziyu Chen, Eugene J. Pietzak, Gopakumar Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat Al-Ahmadie. Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4632.

Genomic analysis of primary epithelial neoplasms of the seminal vesicle identifies a subset of mucinous cystic tumours driven by KRAS mutations.

Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored. In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes). The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian-type clear cell phenotype, two mucinous tumours resembling low-grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post-radiation mucinous adenocarcinoma had genomic findings consistent with bi-allelic inactivation of TP53, as well as multiple copy-number changes with regional and chromosomal arm-level copy-number losses. The Müllerian-type clear cell carcinoma exhibited a complex copy-number profile with numerous regional and arm-level copy-number changes, as well as focal amplification events, including copy-number gain of 8q and amplification of a region within 20q13. Both low-grade mucinous tumours resembling LAMN harboured hot-spot gain-of-function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma. Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparablephenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.

Surface Reconditioning of Lithium Metal Electrodes by Laser Treatment for the Industrial Production of Enhanced Lithium Metal Batteries

AbstractIncorporating lithium metal anodes in next‐generation batteries promises enhanced energy densities. However, lithium's reactivity results in the formation of a native surface film, affecting battery performance. Therefore, precisely controlling the chemical and morphological surface condition of lithium metal anodes is imperative for producing high‐performance lithium metal batteries. This study demonstrates the efficacy of laser treatment for removing superficial contaminants from lithium metal substrates. To this end, picosecond‐pulsed laser radiation is proposed for modifying the surface of lithium metal substrates. Scanning electron microscopy (SEM) revealed that different laser process regimes can be exploited to achieve a wide spectrum of surface morphologies. Energy‐dispersive X‐ray spectroscopy (EDX) confirmed substantial reductions of ≈80% in oxidic and carbonaceous surface species. The contamination layer removal translated into interfacial resistance reductions of 35% and 44% when testing laser‐cleaned lithium metal anodes in symmetric all‐solid‐state batteries (ASSBs) with lithium phosphorus sulfur chloride (LPSCl) and lithium lanthanum zirconium oxide (LLZO) solid electrolytes, respectively. Finally, a framework for integrating laser cleaning into industrial battery production is suggested, evidencing the industrial feasibility of the approach. In summary, this work advances the understanding of lithium metal surface treatments and serves as proof of principle for its industrial applicability.

Solitary fibrous tumor occurring at unusual sites: A clinico-pathological series of 31 cases with emphasis on its wide morphological spectrum

Solitary fibrous tumor (SFT) is a relatively rare mesenchymal fibroblastic tumor occurring most commonly in adults with no gender predilection. Although the pathological diagnosis of SFT is usually straightforward, some difficulties may occasionally arise mainly due to the wide morphological spectrum exhibited by this tumor. In the present paper we aimed to evaluate the unusual clinicopathological features in a series of 31 SFTs arising from parenchymal organs, superficial soft tissues and deep soft tissues. Our results emphasize that SFTs may occur anywhere, including unusual sites such as periosteum of the thoracic spine, mesorectal tissue, hepatic hilum, paravescial space, kidney and breast. Moreover, a wide morphological spectrum was observed in tumors included in our series. The most striking morphological features observed included: extensive lipomatous component, myxoid stromal changes, epithelioid cell component, metaplastic mature bone, neurofibroma-like, myxofibrosarcoma-like and pseudoalveolar-like areas. Additionally, multinucleated giant cells and sarcomatous dedifferentiation were also identified.Our paper emphasizes that SFT may occur in unusual anatomical locations and exhibits a wide morphological spectrum. Pathologists must be aware of these features to avoid confusion with other benign and malignant neoplasms that may show overlapping morphological features.

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Cytologic features of meningioma: An analysis of common and uncommon subtypes and diagnostic difficulties during intraoperative procedures.

Despite common histogenesis meningiomas have a wide morphologic spectrum, and the World Health Organization (WHO) recognizes 15 subtypes. They are the most common brain tumour in adults and typically have an extra-axial location. Although there have been important advances in the molecular biology of meningiomas its diagnosis is based on histopathologic features. The great majority are benign WHO grade 1 tumours. There are specific criteria for assigning WHO grade 2 and 3 that can be applied to all meningioma subtypes. Regardless of these criteria, chordoid and clear cell morphologic subtypes are considered grade 2. WHO grade 3 tumours exhibit a very high mitotic index, frank anaplasia or specific molecular abnormalities. The impressive morphologic diversity shown by meningiomas makes them a diagnostic challenge, which can be even greater in intraoperative studies. The focus of this article is to describe and illustrate their main cytologic features, with emphasis on the most infrequent subtypes.

High-grade vulvar intraepithelial neoplasia: comprehensive characterization and long-term vulvar carcinoma risk.

Adequate diagnosis of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population-based series of vulvar lesions, originally reported as high-grade VIN, and assessed the cancer risk. Baseline high-grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16INK4a , p53, Ki-67) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV-associated lesions (77.0% HSIL, 10.9% low-grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV-independent lesions (6.1% HPV-independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16INK4a block-positivity in 99.0%, increased Ki-67 in ≥2/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid-epithelial staining pattern was common (51.6%) while this was not observed in HPV-independent lesions. HPV-independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated ('HPV-associated-like', in 41.3%). Kaplan-Meier analyses showed a 10-year cancer risk of 8.0% in HPV-associated HSIL, 67.4% in HPV-independent VIN/p53mutant, and 27.8% in HPV-independent VIN/p53wildtype. Strikingly, the 10-year cancer risk was 73.3% in HPV-independent VIN with nondifferentiated ('HPV-associated-like') morphology. Immunohistochemistry by p16INK4a and p53 is highly recommended for optimal categorization into HPV-associated and HPV-independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV-independent VIN underscores the need for surgical treatment and close follow-up, especially in case of a p53 mutant pattern and/or nondifferentiated morphology.

Malignant peripheral nerve sheath tumor: a clinicopathological analysis

Objective: To investigate the clinicopathological, immunophenotypic, and genetic features of malignant peripheral nerve sheath tumor (MPNST). Methods: Twenty-three cases of MPNST were diagnosed at the Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University), China, between January 2012 and December 2022 and thus included in the study. EnVision immunostaining and next-generation sequencing (NGS) were used to examine their immunophenotypical characteristics and genomic aberrations, respectively. Results: There were 10 males and 13 females, with an age range of 11 to 79 years (median 36 years), including 14 cases of neurofibromatosis type I-associated MPNST and 9 cases of sporadic MPNST. The tumors were located in extremities (7 cases), trunk (4 cases), neck and shoulder (3 cases), chest cavity (3 cases), paraspinal area (2 cases), abdominal cavity (2 cases), retroperitoneum (1 case), and pelvic cavity (1 case). Morphologically, the tumors were composed of dense spindle cells arranged in fascicles. Periphery neurofibroma-like pattern was found in 73.9% (17/23) of the cases. Under low magnification, alternating hypercellular and hypocellular areas resembled marbled appearance. Under high power, the tumor cell nuclei were irregular, presenting with oval, conical, comma-like, bullet-like or wavy contour. In 7 cases, the tumor cells demonstrated marked cytological pleomorphism and rare giant tumor cells. The mitotic figures were commonly not less than 3/10 HPF, and geographic necrosis was often noted. Immunohistochemically, tumor cells were positive for S-100 (14/23, 60.9%) and SOX10 (11/23, 47.8%). The loss of the CD34-positive fibroblastic network encountered in neurofibromas was observed in 14/17 of the MPNST cases. The loss of H3K27me3 expression was observed in 82.6% (19/23) of the cases. Moreover, SDHA and SDHB losses were presented in one case. NGS revealed that NF1 gene loss of function (germline or somatic) were found in all 5 cases tested. Furthermore, four cases accompanied with somatic mutations of SUZ12 gene and half of them had somatic mutations of TP53 gene, while one case with germline mutation in SDHA gene and somatic mutations in FAT1, BRAF, and KRAS genes. Available clinical follow-up was obtained in 19 cases and ranged from 1 to 67 months. Four patients died of the disease, all of whom had the clinical history of neurofibromatosis type Ⅰ. Conclusions: MPNST is difficult to be differentiated from a variety of spindle cell tumors due to its wide spectrum of histological morphology and complex genetic changes. H3K27me3 is a useful diagnostic marker, while the loss of CD34 positive fibroblastic network can also be a diagnostic feature of MPNST. NF1 gene inactivation mutations and complete loss of PRC2 activity are the common molecular diagnostic features, but other less commonly recurred genomic aberrations might also contribute to the MPNST pathogenesis.

Early Carboniferous coiled nautiloids from the Anti-Atlas (Morocco)

Viséan coiled nautiloids from North Africa are only poorly known. From the Mougoui Ayoun, Zrigat and Hamou-Rhanem formations of the eastern Anti-Atlas, we describe coiled nautiloids, which belong to the genera Rineceras, Stroboceras, Temnocheilus, Vestinautilus, Maccoyoceras, Endolobus, Epidomatoceras, Liroceras, Ephippioceras, and Solenochilus. The new species Temnocheilus imazighenorum sp. nov., Temnocheilus aubrechtovae sp. nov., Vestinautilus kesslerae sp. nov., Endolobus rota sp. nov., Epidomatoceras ebbighausenorum sp. nov., Liroceras vermis sp. nov., Liroceras karaouii sp. nov., Ephippioceras pygops sp. nov., Solenochilus lucynae sp. nov. and Solenochilus pohlei sp. nov. are described; six taxa are kept in open nomenclature. The assemblage is composed of the three superfamilies Trigonoceratoidea, Clydonautiloidea and Aipoceratoidea and shows a wide spectrum of conch morphologies, ranging from widely umbilicate compressed forms to involute compact forms, reflecting a broad ecological variation.

Morphological Characteristics of Various Cells in Esophageal Squamous Dysplasia: Extremely Wide Morphological Spectrum.

The WHO classification of esophageal tumors divides esophageal squamous intraepithelial dysplasia into high and low grades, but does not specify its morphological spectrum. Here, the morphological characteristics of various cells were investigated in esophageal squamous (high-grade) dysplasia, and a morphological spectrum and terminology for this lesion were proposed to avoid misdiagnosis. The clinicopathological data of 540 patients with esophageal squamous dysplasia were analyzed retrospectively. According to the unique cytomorphological characteristics of the lesions and the predominant cell type, the esophageal squamous dysplasia was divided into the following morphological groups: classic type (34.6%, 187/540), basaloid subtype (10.7%, 58/540), spindle-cell subtype (4.6%, 25/540), differentiated subtype (48.9%, 264/540), and verrucous subtype (1.1%, 6/540). Gender, age, and lesions location did not differ among the subtypes (P > 0.05), while Paris classification and lesions diameter significantly differed among the subtypes (P < 0.01). Classic-type cells showed severe atypia. In the basaloid subtype, the cells were small, and resembled basal cells; most of these lesions were of the 0-IIb type with small lesion diameter. In the spindle-cell subtype, the cells and nuclei were spindle-shaped or long and spindle-shaped and arranged in parallel. Differentiated-subtype showed well-to-moderately differentiated cells, and epithelial basal cells were mature. Verrucous-subtype showed well-differentiated cells, and were characterized by verrucous or papillary structures. Esophageal squamous dysplasia has extremely wide morphological spectrum. Awareness of the spectrum of morphological presentations of this lesion, specifically the basaloid subtype, spindle-cell subtype, differentiated subtype, and verrucous subtype, is important for accurate diagnosis.

BI02 Disseminated toxoplasmosis presenting as panniculitis in an immunocompromised patient

Abstract Inflammatory dermatoses and inflammatory reaction patterns to underlying systemic disease are relatively uncommon in immunosuppressed organ transplant recipients (OTRs) and infection should always be suspected as a possible cause. We present an OTR with biopsy-proven panniculitis resulting from disseminated toxoplasmosis, only identified after extensive histological analysis. A 45-year-old Nigerian woman who was profoundly immunocompromised through a combination of a kidney transplant 12 months earlier, hyposplenism due to sickle cell anaemia and a CD4+ count 74 × 106 cells L–1 (&amp;gt; 455 × 106 L–1) presented with a 3-month history of &amp;gt; 20 painful, red–purple and hyperpigmented subcutaneous nodules and plaques up to 2 cm in diameter limited to her legs, associated with fatigue and weight loss. She only had childhood contact with cats. There was no lymphoedema or lymphadenopathy, and she was HIV negative. Urgent skin biopsy excluded Kaposi sarcoma and demonstrated a lobular, necrotizing panniculitis, a mixed inflammatory cell infiltrate and evidence of vasculitis. The cause was unclear; cultures for mycobacterial, fungal and bacterial infections were negative. However, on rereview of histology, within areas of inflammation and necrosis in the subcutaneous fat, there were a few scattered structures (10–30 μm in diameter) consisting of small basophilic periodic acid–Schiff-positive ‘dots’ within bright eosinophilic cytoplasm, raising the possibility of toxoplasmosis. Toxoplasma immuno­staining was positive. Further tertiary review of histology and immunostaining by the Hospital for Tropical Diseases agreed that there was no other causative organism and the panniculitis and vasculitis were consistent with active toxoplasmosis. The diagnosis of toxoplasma reactivation was supported by positive toxoplasma IgG on pretransplant bloods. Magnetic resonance imaging of the head was consistent with cerebral toxoplasmosis. She received treatment with clindamycin, pyrimethamine and folinic acid and, thereafter, long-term cotrimoxazole prophylaxis. Cutaneous toxoplasmosis is rare, with only three reported cases over the last 10 years. Historically, a wide spectrum of clinical morphologies has been described, including maculopapular rashes, nodules, ulcers, dermatomyositis and even mimicry of varicella and graft-versus-host disease. Most cases affect immunocompromised patients. In our patient, this was the result of reactivation of latent infection, which is more common in West Africa, coinciding with profound immunosuppression. In our case, a diagnosis was only made after extensive histological review. Given the varied morphologies of clinical presentations, it is possible that this condition may be easily missed, with potentially serious consequences. In summary, we highlight the importance of maintaining a high index of suspicion for infection and the need for careful clinicopathological correlation in OTRs presenting with apparently atypical inflammatory skin lesions.

PA21 A rare case of diffuse infantile fibromatosis

Abstract Fibromatoses are a heterogeneous collection of tumours of the skin and soft tissue with a large variability in presentation. We present a case of diffuse infantile fibromatosis in a 17-day-old infant boy. He was born at 40 + 7 weeks gestation with a vacuum-assisted delivery following an uncomplicated pregnancy. On physical examination, there were two well-circumscribed circular plaques that coalesced centrally on his left elbow. The plaque measured 2 × 1 cm and was firm, nontethered and nontender. Full skin examination was otherwise normal. Histopathological examination showed hyperkeratotic skin with an attenuated epidermis overlying a dermally based bland-appearing spindle cell proliferation. The lesion was infiltrative throughout the dermis and was arranged in short fascicles and interdigitated with subcutaneous fat, which was extensively trapped by spindle cells. There was no significant atypia and mitotic activity was identifiable but not brisk. Immunohistochemical stains showed strong and diffuse reactivity for smooth muscle actin. Infantile fibromatosis is the childhood counterpart of musculoaponeurotic fibromatosis. It is a benign mesenchymal tumour of infancy and early childhood with diffuse proliferations of oval-to-spindled fibroblasts that infiltrate regional structures. There is a male predominance and in most cases is noted within the first 8 years of life. Clinically, it presents as an asymptomatic, white-yellowish mass that is nontethered to the overlying skin. Although any site may be involved, the majority of cases affect the upper limbs, head and neck region. Histological findings include a wide morphological spectrum. In infants, small oval cells appearing between primitive mesenchymal cells and fibroblasts are in a myxoid background. The cells are loosely arranged and infiltrate skeletal muscle and other regional structures. Peripheral lymphocytic inflammation blends with more cellular proliferation composed of spindle-shaped fibroblasts arranged in bundles and fascicles. There is no well-documented immunohistochemical profile. An important differential diagnosis to exclude is congenital/infantile fibrosarcoma, which, characteristically, has high cellularity, uniform herringbone pattern, high mitotic rate, and zones of haemorrhage and necrosis. In terms of management, as there is a high likelihood of local recurrence in 65% of cases, evidence supports complete excision with documented margins. Where the lesion is diffusely infiltrative, a partial resection to maintain the best postoperative function is recommended.

Parasites observed in urine sediments: A learning from incidental rare species

Parasitic infection becomes an unsolved problem in using of automated instruments for urinalysis. Most common parasitic infections described in literature are Trichomonas vaginalis, Schistosoma hematobium and Microfilaria. Other rare organisms are Balantidium coli and Paramecium. The main purpose of this article is to raise the awareness in pathologists and clinicians on the importance of cytological evaluation of urine. This study was done to find the associations between the age and point prevalence of organisms in our zone in the last 6 years. Identification of parasites in centrifuged deposits of urine sediment is a relatively rare occurrence in clinical practice. A fairly wide morphological spectrum of parasites may be diagnosed through microscopic examination of centrifuged urine sediment. They may present with symptoms like pyuria, hematuria, diarrhoea, burning micturition, itching and morphological awareness helps in prompt and effective management in most cases.

Wide morphological spectrums of renal neoplasms with TSC/mTOR, NF2, or monoallelic MUTYH germline mutation

Advances in molecular biology techniques have led to the recognition of more molecularly defined renal entities. However, some molecular-defined renal cell carcinomas (RCC) exhibit heterogeneous morphologies. In recent years, TSC/mTOR and NF2 alterations in renal cancers have attracted considerable attention from pathologists, including several renal tumors that have been validated as different entities. The monoallelic MUTYH germline mutation has also recently been demonstrated to be a driver of tumorigenesis, which is relatively enriched in renal cancers and may predict the risk of metastasis. In the current study, we presented seven cases with TSC/mTOR alterations (two with fibromyomatous stroma, one concomitant with ELOC mutation, three eosinophilic solid and cystic RCC, and two RCC, NOS), four cases with NF2 mutations (one concomitant with FH mutation, one biphasic hyalinizing psammomatous RCC, and two RCC, NOS), and two cases with monoallelic MUTYH germline mutations (one collecting duct carcinoma and one papillary RCC). We observed that renal cancers harboring these mutations had a wide morphological spectrum. Renal neoplasms with TSC/mTOR mutations may have an indolent outcome. NF2-mutated RCC appeared to display calcification and sclerotic stroma. The identification of these renal cancers can help reduce the number of tumors diagnosed as RCC, NOS. However, whether they can be grouped into TSC/mTOR, NF2, or MUTYH -associated RCC requires further validation.

Generating in vitro models of NTRK-fusion mesenchymal neoplasia as tools for investigating kinase oncogenic activation and response to targeted therapy

The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has led to new personalized therapies in oncology. Recent studies investigating NTRK fusions among mesenchymal neoplasms have identified several emerging soft tissue tumor entities displaying various phenotypes and clinical behaviors. Among them, tumors resembling lipofibromatosis or malignant peripheral nerve sheath tumors often harbor intra-chromosomal NTRK1 rearrangements, while most infantile fibrosarcomas are characterized by canonical ETV6::NTRK3 fusions. However, appropriate cellular models to investigate mechanisms of how kinase oncogenic activation through gene fusions drives such a wide spectrum of morphology and malignancy are lacking. Progress in genome editing has facilitated the efficient generation of chromosomal translocations in isogenic cell lines. In this study we employ various strategies to model NTRK fusions, including LMNA::NTRK1 (interstitial deletion) and ETV6::NTRK3 (reciprocal translocation) in human embryonic stem (hES) cells and mesenchymal progenitors (hES-MP). Here, we undertake various methods to model non-reciprocal, intrachromosomal deletions/translocations by induction of DNA double strand breaks (DSBs) exploiting either the repair mechanisms of homology directed repair (HDR) or non-homologous end joining (NHEJ). Expression of LMNA::NTRK1 or ETV6::NTRK3 fusions in either hES cells or hES-MP did not affect cell proliferation. However, the level of mRNA expression of the fusion transcripts was significantly upregulated in hES-MP, and phosphorylation of the LMNA::NTRK1 fusion oncoprotein was noted only in hES-MP but not in hES cells. Similarly, an NTRK1-driven transcriptional profile related to neuronal and neuroectodermal lineage was upregulated mainly in hES-MP, supporting the importance of appropriate cellular context in modeling cancer relevant aberrations. As proof of concept of the validity of our in vitro models, phosphorylation was depleted by two TRK inhibitors, Entrectinib and Larotrectinib, currently used as targeted therapy for tumors with NTRK fusions.

HISTOPATHOLOGICAL APPROACH TO THE DIAGNOSIS OF BENIGN PERIPHERAL NERVE SHEATH TUMORS AT UNCOMMON LOCATION

Peripheral nerve sheath tumors are relatively common lesions that exhibit a wide morphological and biological spectrum. In the presence of classical morphological and immunohistochemical features, the histological diagnosis is usually straightforward, but they may represent diagnostic challenges. Schwannoma is a slow growing encapsulated tumor of neuroectodermal derivation that originates from the Schwann cells of the neural sheath. Most commonly presents as cerebellopontine angle mass but extracranial sites are known and needs to be considered in the differential diagnosis. Intraparotid and penile schwannomas are extremely rare. Their diagnosis could be missed on cytology due to cystic changes. Isolated plexiform neurofibroma of the tongue is again a rare tumor. Plexiform pattern recognition is important for the pathologist as these varients might show malignant transformation. Overall Fine needle aspiration cytology though inconclusive at times, help a lot initially to delineate between benign Vs malignant lesions. Moreover its minimally invasive so can be performed easily at the uncommon locations. Histopathology remains the gold standard. Clinicopathological and imaging correlation is must for definite diagnosis and treatment.