Distinct Histopathological Features Research Articles

Squamous Cell Carcinoma of the Gallbladder Masquerading as Complicated Cholecystitis: A Case Report and Review

In summary, squamous cell carcinoma (SCC) of the gallbladder, although rare, poses significant diagnostic and therapeutic challenges. We report the case of a 51-year-old woman with no previous medical history, with SCC discovered during complicated cholecystitis with cholangitis, treated by palliative chemotherapy, underscoring the difficulty in early detection and the poor prognosis associated with advanced-stage diagnosis. Treatment options are limited, with palliative chemotherapy often being the primary recourse for unresectable tumors. Gallbladder cancers, including SCC, share risk factors with adenocarcinomas, but their distinct histopathological features and clinical presentations warrant careful consideration. Despite recent advancements in treatment modalities, including adjuvant therapy, optimal management strategies remain elusive, highlighting the need for further research to improve outcomes for patients with this aggressive malignancy.

Desmoplastic Melanoma

Desmoplastic melanoma is a rare fibrosing variant of melanoma. It typically affects elderly patients but can occasionally affect young or middle-aged individuals. Desmoplastic melanoma is relevant as a diagnostic pitfall for pure tumor variants' distinct histopathologic and clinical features. The latter includes a lower regional lymph node involvement frequency and a more favorable prognosis among thick melanomas. Classic cases of desmoplastic melanoma tend to carry a high mutation burden. Patients with metastases from those tumors tend to respond favorably to novel immunotherapies.

Lymphatic and blood vessels in parathyroid tumors: Immunohistochemical study with LYVE-1 and von Willebrand factor.

Parathyroid tumors exhibit distinct histopathological features that differentiate benign from malignant lesions. This study aimed to study characteristic distribution of lymphatic and blood vessels in normal parathyroid gland and parathyroid tumors to distinguish cancer from benign tumors. Immunohistochemical staining for lymphatic and blood vessels and parathyroid hormone was performed with parathyroid proliferating lesions including adenoma, multiglandular multiple adenomas, atypical tumor, and carcinoma. Lymphatic vessels were immunostained with lymphatic vessel endothelial receptor 1 (LYVE-1) and blood vessels were immunostained with von Willebrand factor (vWf). Normal parathyroid gland contained several round blood vessels with less linear lymphatic vessels. The less parathormone-immunostained adenomas weighing less than 2 g revealed larger blood vessels with perivascular small linear lymphatic vessels, and the larger adenomas contained proportionally larger blood vessels. Smaller multiglandular multiple adenomas were like smaller adenomas with less parathormone staining and contained larger, round blood vessels with perivascular small linear lymphatic vessels. Larger multiglandular multiple adenomas weighing more than 4 g and one atypical tumor contained nodular pattern consisted of alternating strongly parathormone-positive lobes and negative lobes with numerous, dilated blood vessels and perivascular linear lymphatic vessels. Both primary and metastatic carcinomas were strongly and diffusely positive for parathyroid hormone with numerous lymphatic and blood vessels at the invading margin. Thus, normal parathyroid has rich blood vessels which provide accessibility of minced tissues seeding for auto-transplantation. Immunostaining patterns of parathyroid hormone, lymphatic and blood vessels help to distinguish carcinoma from benign parathyroid proliferating lesions. The negative immunohistochemical staining for parafibromin will detect carriers of hyperparathyroidism-jaw tumor (HPT-JT) syndrome and would help in diagnosing parathyroid cancer in both HPT-JT carriers and sporadic patients.

Conjunctival keratoacanthoma: a clinical and histopathological case series

ObjectiveTo present a series of conjunctival keratoacanthomas and provide clinical, histopathological, immunohistochemical, and imaging results that characterize this rare entity. MethodsA retrospective chart review of records from 2005 to 2023 from the Florida Lions Ocular Pathology Laboratory was conducted. Nine patients with histologically proven conjunctival keratoacanthoma were identified. Data extracted includes demographics, clinical history, diagnostic testing, histopathological and immunohistochemical testing, treatment modalities, and recurrences. ResultsPatients’ mean age was 55.2 ± 21.1 years (range: 22–83). 77.8% (7/9) of patients were male. 55.6% (5/9) were Hispanic. 55.6% of lesions (5/9) were in right eyes. 55.6% of lesions (5/9) were on the temporal, bulbar conjunctiva. The lesions were rapidly growing, with mean onset time of 4.71 ± 3.30 weeks (range: 2–12). High-resolution anterior segment optical coherence tomography of three lesions revealed hyper-reflective, thickened epithelium with abrupt transition between normal and abnormal epithelium. Underlying disorganized subepithelial tissue was noted. However, the overlying abnormal epithelium caused considerable shadowing, which obscured subepithelial structures. Prominent, keratin-filled, cup-shaped lesions with faulty maturational sequencing that extend full thickness, variably pale cytoplasm, and foci of dyskeratosis and hyperkeratosis were present on all lesions’ histopathology.All lesions were surgically excised, but two demonstrated partial spontaneous resolution before surgery. Two patients were lost to follow-up; the remaining seven had no signs of recurrence at a of mean of 36.9 ± 45.4 months (range: 3 to 141 months) of follow-up. ConclusionsConjunctival keratoacanthomas are rare lesions of the ocular surface with distinct clinical, histopathologic, and diagnostic features.

A case report of de novo histoid leprosy in a Nigerian male: A diagnostic dilemma.

Histoid leprosy is an uncommon variant of lepromatous leprosy. It poses a diagnostic challenge because of its distinctive clinical and histopathological features. It presents as smooth papules and nodules that rarely ulcerate. We present the case of a 22-year-old Nigerian man with a 2-year history of multiple, dome-shaped papules and nodules on the skin with necrotic centres. General examination showed right axillary lymphadenopathy, non-pitting oedema, foot ulcer, and glove and stocking sensation loss. Despite previous misdiagnoses, histopathological examination showed dermal expansion by histiocytes arranged in a storiform pattern. Slit skin smear yielded abundant bacilli. The patient was started on WHO multidrug treatment, resulting in the improvement of his lesions. This case emphasises the importance of increased awareness of this rare presentation of leprosy.

Understanding Nuchal Type Fibroma: A Rare Case Report with Comprehensive Discussion

Introduction and Aim: Nuchal-type fibroma (NTF) is a rare benign fibrous proliferation primarily originating from the dorsocervical neck region. Enzinger and Weiss first characterized it in 1988, highlighting its distinct histopathological features. Description of the Case Report: We present a case of 71-year-old South Asian male patient with painless swelling over the nape of neck, highlighting the challenges in diagnosis of NTF. Clinical examination, imaging, and cytological findings initially suggested a lipomatous lesion. Histopathological evaluation revealed characteristic features consistent with NTF, emphasizing the importance of histopathological assessment for accurate diagnosis. Despite its benign nature, vigilance is essential due to the potential for recurrence. Conclusion: This case underscores the need for a comprehensive understanding of NTF's clinical and histopathological features to facilitate optimal management and improve patient outcomes.

Papillary tumor of the pineal region: analysis of DNA methylation profiles and clinical outcomes in 76 cases

Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR’s, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.

Prediction of molecular subclasses of uveal melanoma by deep learning using routine haematoxylin-eosin-stained tissue slides.

Uveal melanoma has a high propensity to metastasize. Prognosis is associated with specific driver mutations and copy number variations, and these can only be obtained after genetic testing. In this study we evaluated the efficacy of patient outcome prediction using deep learning on haematoxylin and eosin (HE)-stained primary uveal melanoma slides in comparison to molecular testing. In this retrospective study of patients with uveal melanoma, 113 patients from the Erasmus Medical Centre who underwent enucleation had tumour tissue analysed for molecular classification between 1993 and 2020. Routine HE-stained slides were scanned to obtain whole-slide images (WSI). After annotation of regions of interest, tiles of 1024 × 1024 pixels were extracted at a magnification of 40×. An ablation study to select the best-performing deep-learning model was carried out using three state-of-the-art deep-learning models (EfficientNet, Vision Transformer, and Swin Transformer). Deep-learning models were subjected to a training cohort (n = 40), followed by a validation cohort (n = 20), and finally underwent a test cohort (n = 48). A k-fold cross-validation (k = 3) of validation and test cohorts (n = 113 of three classes: BAP1, SF3B1, EIF1AX) demonstrated Swin Transformer as the best-performing deep-learning model to predict molecular subclasses based on HE stains. The model achieved an accuracy of 0.83 ± 0.09 on the validation cohort and 0.75 ± 0.04 on the test cohort. Within the subclasses, this model correctly predicted 70% BAP1-mutated, 61% SF3B1-mutated and 80% EIF1AX-mutated UM in the test set. This study showcases the potential of the deep-learning methodology for predicting molecular subclasses in a multiclass manner using HE-stained WSI. This development holds promise for advanced prognostication of UM patients without the need of molecular or immunohistochemical testing. Additionally, this study suggests there are distinct histopathological features per subclass; mainly utilizing epithelioid cellular morphology for BAP1-classification, but an unknown feature distinguishes EIF1AX and SF3B1.

Dermatological Enigma Unveiled: A Rare Case Report on Dowling-Degos Disease

Abstract Dowling-Degos disease (DDD) is an extremely rare hereditary skin condition characterized by the development of painless, small-sized pigmented patches known as macules or keratotic papules. Typically inherited in an autosomal dominant manner, DDD primarily manifests in adulthood, with onset occurring between the ages of 30 and 40 years, and a higher prevalence among females. Although DDD shares clinical similarities with other reticulated pigmentary disorders such as dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria, and reticulate acropigmentation of Kitamura, its distinctive histopathological features set it apart. A 50-year-old female patient presented with hyperpigmented lesions since infancy, predominantly located in flexural areas, prompting consideration of endogenous eczema or DDD. Despite the absence of a family history and normal laboratory test results, a biopsy confirmed the diagnosis based on characteristic histological findings. The identification of DDD underscores the importance of considering rare dermatological entities in differential diagnosis, especially when clinical presentation aligns with established criteria. Further research and awareness are essential for enhancing our understanding and management of this intriguing skin condition.

A hybrid case of eosinophilic folliculitis and eosinophilic cellulitis associated with hypereosinophilic syndrome

AbstractEosinophilic cellulitis or Wells syndrome encompasses distinct histopathological features but can also be associated with eosinophilic related conditions like hyper eosinophilic syndrome (HES) or eosinophilic granulomatosis with polyangiitis (EGPA) (Churg–Strauss syndrome). We report a case of a Turkish 41‐year‐old female who presented in clinic with pruritus and tenderness on her chest and breasts, having received several courses of antibiotics for recurrent abscess formation. A year before she had been diagnosed with HES with multiorgan involvement that included biopsy proven eosinophilic folliculitis, and prompted further investigation including bone marrow aspiration that revealed T cell clonality. Biopsy of her rash revealed eosinophilic infiltration of the dermis with flame figures. Ongoing respiratory symptoms and a history of childhood asthma were suggestive of EGPA. This case highlights important associations that should be considered in the investigation of Wells syndrome.

Comprehensive genomic and transcriptomic profiling of pulmonary nodules in synchronous multiple primary lung cancer.

e20022 Background: Synchronous Multiple Primary Lung Cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients. Methods: We performed targeted sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others. Results: For the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency demonstrated notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Conclusions: This study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.

Ependymomas of the spinal region in adults: Clinical and pathological features and MYCN expression levels in spinal ependymomas and myxopapillary ependymomas

BackgroundEpendymomas (EPNs) of the spinal region are a heterogeneous group of tumors that account for 17.6 % in adults. Four types have been recognized: subependymoma, spinal ependymoma (Sp-EPN), myxopapillary ependymoma (MPE), and Sp-EPN-MYCN amplified, each with distinct histopathological and molecular features. MethodsThis study investigated the clinical and pathological characteristics and MYCN expression levels of 35 Sp-EPN and MPE cases diagnosed at a tertiary university hospital over a decade-long period. ResultsTwenty-five cases were Sp-EPN and 10 cases were MPE, and were graded as WHO grade 2, except for 1 Sp-EPN case with grade 3 features. The most common symptoms were lower back pain and difficulty in walking. Radiology showed different tumor sizes and locations along the spinal cord, with MPEs exclusively in the lumbosacral region. Surgery was the main treatment, and gross total resection was achieved in all cases except for one. Immunohistochemistry showed low Ki-67 proliferation indices in all cases, and no MYCN expression. During follow-up, 3 (8.6 %) cases recurred and/or metastasized and 5 cases (14.3 %) died. No significant difference was found in disease-free survival or overall survival between Sp-EPN and MPE cases. However, 3 cases with grade 2 histology demonstrated recurrence and/or metastasis, despite the lack of MYCN expression. ConclusionOur results underscore the multifactorial nature of tumor aggressiveness in EPNs of the spinal region. This study enhances our knowledge of the clinical and pathological features of Sp-EPNs and MPEs and highlights the need for better diagnostic and prognostic markers in these rare tumors.

Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma

Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics’ specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.

Erythema Multiforme-Like Fixed Drug Eruption During Azathioprine and Hydroxychloroquine Treatment for Systemic Lupus Erythematosus Mimicking Rowell Syndrome: A Rare and Challenging Clinical Scenario.

Background. Fixed drug eruption and Rowell syndrome stand as intriguing entities with overlapping clinical and pathological features. Case Presentation. A 32-year-old female patient presented with a tender and pruritic rash on the left upper chest for 3 days. Clinical examination revealed a flaring rash on the chest, under her left eye, tongue, and lips. The patient had a significant past medical history of systemic lupus erythematous with positive (ANA, Sm, dsDNA, ribosomalP, RNP) antibodies, hypocomplementemia, inflammatory arthritis, discoid lupus, leukopenia, thrombocytopenia, and immune thrombocytopenic purpura, and avascular necrosis affecting both hips and her right knee. At the time of presentation, the patient was on azathioprine 150 mg daily and hydroxychloroquine 200 mg twice daily. Skin biopsy of the left upper chest revealed interface dermatitis with necrotic keratinocytes at the dermal-epidermal junction. Superficial and, in some areas, deep perivascular and peri adnexal lymphocytic infiltrates were observed, accompanied by eosinophils. CD123 staining highlighted 16% of the inflammatory cells. Direct Immunofluorescence for IgG, IgA, IgM, C3, and fibrinogen revealed positive linear basement membrane staining for IgG and fibrinogen, with no significant staining for the remaining immunoreactants. Considering the patient's history of medicine usage, and negative SS-A and SS-B antibody, a fixed drug eruption was favored. Discussion. This article discusses the clinical presentations, pathophysiological mechanisms, and diagnostic criteria for fixed drug eruption and Rowell syndrome. Conclusion. Awareness of the distinct clinical and histopathologic features of fixed drug eruption and Rowell syndrome, particularly when sharing cutaneous manifestations, underscores the importance of a comprehensive diagnostic approach and laboratory testing.

Epidermodysplasia verruciformis-associated eccrine neoplasm: a rare entity with distinctive clinical and histopathologic features.

Most tumors are caused by inherited or acquired genetic changes. However, a subset of tumors is driven by viral infection including Kaposi sarcoma, nasopharyngeal carcinoma, and others. Human papillomavirus (HPV) is an especially common cause of epithelial cancers and hyperplasias. Epidermodysplasia verruciformis (EDV) is a rare type of HPV infection with characteristic histopathologic features and a unique spectrum of HPV subtypes. We report here a distinctive form of EDV-associated eccrine neoplasia. Seven tumors from two patients were analyzed and show highly uniform features including multiple clustered clinical lesions, multifocal epidermal origin, eccrine differentiation with close association with the acrosyringium, an anastomosing growth pattern, and a bland monotonous poroid-to-basaloid cytomorphology. Clinical follow-up for one patient has been benign to date. These tumors show strong similarity to two previously reported cases, suggesting that this type of EDV-associated eccrine neoplasia may represent a rare but reproducible form of skin adnexal tumor with distinctive clinicopathologic features.

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis.

Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.

Extra-Ocular Sebaceous Carcinoma in Situ of the Arm of an Elder Male: An Unusual Presentation in an Atypical Location.

Background. Sebaceous carcinoma in situ outside the ocular region is an exceedingly uncommon. It is an intraepidermal neoplasm originating from sebaceous glands limited to the epidermis with no invasion into the underlying dermis or beyond. Although sebaceous carcinoma in situ is predominantly observed in ocular regions, particularly the eyelids, instances of its occurrence in extraocular locations are infrequent, with only a limited number of examples reported in the literature. Case Presentation. A 63-year-old man presented with a left posterior arm lesion. Microscopic examination revealed a proliferation of poorly differentiated atypical neoplastic sebocytes confined to the epidermis with pleomorphic nuclei, prominent nucleoli, and clear cell changes. The neoplastic cells demonstrated positive staining for adipophilin, androgen receptor, epithelial membrane antigen, P63, BerEP4, and keratin 7. Microsatellite instability markers showed preserved nuclear staining for MLH1, PMS2, MSH2, and MSH6. A definitive diagnosis of sebaceous carcinoma in situ was rendered. Discussion. The distinctive histopathologic characteristics typically involve the presence of atypical sebaceous cells confined within the epidermis. Atypical cells often exhibit enlarged nuclei, increased mitotic activity, and prominent nucleoli. A panel of epithelial membrane antigen, adipophilin, and androgen receptors is essential for ensuring an accurate diagnosis. Conclusion. This report underscores the importance of considering sebaceous carcinoma in situ in diagnosis in atypical locations, emphasizing the need for a comprehensive histopathologic examination and immunohistochemical staining panel. This article aims to demonstrate the rarity of sebaceous carcinoma in situ in extraocular sites to broaden our understanding of its diverse clinical presentations.

Comparative genomic analysis to identify a signature of sporadic colorectal cancer development in young adults.

208 Background: Young-onset sporadic CRC is an important yet understudied heterogeneous group of aggressive cancers with distinct clinical and histopathological features. There is a steady increase in the incidence of cancer in this group of patients and currently, there are no screening guidelines to identify these patients due to a lack of understanding of the molecular mechanisms driving cancer in this patient group. Introduction: Despite screening guidelines and recent advances in cancer treatment, colorectal cancer (CRC) remains the second most diagnosed cancer and the second and third leading cause of cancer-related mortality in Canadian men and women, respectively [Canadian Cancer Statistics 2017.]. More striking is the rise in incidence of CRC in young adults in the United States [Siegel, R.L., et al, Bailey, C.E., et al., Dozois, E.J., et al., Deen, K.I., et al.], and the expectation that by the year 2030, the incidence rate will increase by 90% in this patient population. Data from the Surveillance and Cancer registry at Cancer Care Ontario shows a similar trend with increased rates in younger adults (ages 30 to 49) by 5.2 per cent per year between 2005 and 2012 [Ontario, C.C., Cancer Fact.]. Moreover, these younger patient groups are often diagnosed with aggressive forms and advanced stages of the disease [Ontario, C.C., Cancer Fact.]. Methods: In this study, using a total of 30 colorectal cancer patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions/deletions, copy number variants in over 500 genes that are implicated in cancer. Mean age of the patients in this study was 44 years and only patients without any personal or family history of colon cancer /other malignancies or IBD were enrolled in the study. Results: While identifying previously known colorectal cancer associated genetic variants, our preliminary data shows distinct missense mutations in several genes potentially contributing to the development and progression of cancer in these patients. In addition to showing pathogenic mutations in colorectal cancers associated genes, such as PIK3CA (H1047R, E545K, E545G, R93W, V344A), KRAS (G12V, G12D, A146T) and APC, our study showed recurring missense mutations in several genes including AXIN2, ALK, CDKN1A, MAP3K1, ROS1, EPCAM, KDM5A and AURKA in over 50% of our samples. Conclusions: The genomic profiling performed using biopsies from young colorectal cancer patients through this study provides a unique ability to identify the potential “genomic triggers” for the development and progression of cancer in young sporadic colorectal cancer patients. This information can not only be used to develop targeted treatment options for these patients but also to design new screening protocols as well as optimal surveillance strategies.

"Hemispheric pilocytic astrocytoma" revisited: A comprehensive clinicopathological and molecular series emphasizing their overlap with other glioneuronal tumors.

Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.

The use of cultured human alveolar basal cells to mimic honeycomb formation in idiopathic pulmonary fibrosis

BackgroundHoneycomb cysts (HC) within the alveolar region are distinct histopathological features in the lungs of idiopathic pulmonary fibrosis (IPF) patients. HC are lined with a single-or stratified layer of basal cells (BC), or with a bronchiolar-like epithelium composed of basal-, ciliated- and secretory epithelial cells. By using cultured IPF patient-derived alveolar BC, we aimed to establish an in vitro- and in vivo model to mimic HC formation in IPF. We (1) optimized conditions to culture and propagate IPF patient-derived alveolar BC, (2) cultured the cells on an air liquid interface (ALI) or in a three dimensional (3D) organoid model, and (3) investigated the cells` behavior after instillation into bleomycin-challenged mice.MethodsAlveolar BC were cultured from peripheral IPF lung tissue and grown on tissue-culture treated plastic, an ALI, or in a 3D organoid model. Furthermore, cells were instilled into bleomycin-challenged NRG mice. Samples were analyzed by TaqMan RT-PCR, immunoblotting, immunocytochemistry/immunofluorescence (ICC/IF), or immunohistochemistry (IHC)/IF. Mann–Whitney tests were performed using GraphPad Prism software.ResultsCultured alveolar BC showed high expression of canonical basal cell markers (TP63, keratin (KRT)5, KRT14, KRT17), robust proliferation, and wound closure capacity. The cells could be cryopreserved and propagated for up to four passages without a significant loss of basal cell markers. When cultured on an ALI or in a 3D organoid model, alveolar BC differentiated to ciliated- and secretory epithelial cells. When instilled into bleomycin-challenged mice, human alveolar BC cells formed HC-like structures composed of human basal-, and secretory epithelial cells within the mouse parenchyma.ConclusionIPF patient-derived alveolar BC on an ALI, in 3D organoids or after instillation into bleomycin-challenged mice form HC-like structures that closely resemble HC within the IPF lung. These models therefore represent powerful tools to study honeycomb formation, and its potential therapeutic inhibition in IPF.