Distinct Histological Variant Research Articles

Clinical features, surgical management and outcome of squamous and basal cell carcinoma in squamates and chelonians.

Squamous cell carcinoma (SCC) is one of the most commonly diagnosed neoplastic disorders in reptiles. Recently, however, it has been demonstrated that basal cell carcinomas (BCCs) are frequently misclassified as SCCs. Several histological SCC and BCC variants have been characterised and their classification may allow the establishment of appropriate prognosis estimation and treatment approaches. To describe the clinical features and surgical outcomes of SCCs and BCCs diagnosed between 2010 and 2022 in reptiles. Thirty-three captive reptiles (21 squamates and 12 chelonians). Detailed clinical history, including staging and surgical outcomes, were performed. Statistical analysis assessed significant factors using Prism (v8.2.1). While SCC was predominantly diagnosed in lizards, BCC was most commonly diagnosed in chelonians, and both neoplasms mainly occurred in adult to aged, male individuals. Although the gross pathological findings were highly comparable between SCC and BCC, considerable variation could be seen according to the primary location (oral, cutaneous or epidermis of the shell). Humane euthanasia or noncurative intent surgeries were performed in a minority of the cases. Curative intent surgeries were successful in 19 of 27 cases during a 1- to 7-year follow-up period, yet recurrence was seen in 8 cases. The results of this study allowed the identification of significant high-risk prognostic factors for SCC and BCC in reptiles. This study contributes to predicting the clinical behaviour and prognosis of distinct SCC and BCC histological variants, and selecting the most appropriate treatment protocol.

Inflammatory Giant Cell Carcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Next-generation Sequencing Study of 14 Cases.

A distinctive histological variant of poorly differentiated, sarcomatoid, non-small cell lung carcinoma characterized by a discohesive population of giant tumor cells associated with prominent interstitial inflammatory cell infiltrates is described. The tumors occurred in 7 women and 7 men, 42 to 72 years of age (mean: 56y). They predominantly affected the upper lobes and measured 1.3 to 9cm in greatest diameter (mean: 4.6cm). The tumor cells were characterized by large pleomorphic nuclei with prominent nucleoli, ample cytoplasm, and frequent abnormal mitoses, and were surrounded by a dense inflammatory cell infiltrate, often associated with emperipolesis. Immunohistochemical stains were positive in the tumor cells for cytokeratin AE1/AE3 and CK8/18 and negative for TTF1, napsin A, p40, and CK5/6. Next-generation sequencing was performed in all cases using the Oncomine Precision Assay; the most common abnormalities found included TP53 mutations (9 cases) and AKT1 amplification (8 cases), followed by KRAS mutations (4 cases) and MAP2K1/2 mutations (4 cases). Clinical follow-up was available in 13 patients. Three patients presented with metastases as the initial manifestation of disease; 8 patients died of their tumors from 6 months to 8 years (mean: 2.7y); 3 patients were alive and well from 4 to 6 years; and 2 patients had metastases when last seen but were lost to follow-up thereafter. The importance of recognizing this distinctive and aggressive variant of non-small cell lung carcinoma lies in avoiding confusion with a sarcoma or other types of malignancy.

Pure Foamy Gland Carcinoma of Prostate - A Series of Rare Cases

Foamy gland carcinoma (FGC) is a distinct histological variant of prostatic acinar adenocarcinomas. It was first described by Epstein and Nelson in 1996. It is characterized by abundant xanthomatous cytoplasm, pyknotic nuclei, and intermediate Gleason grade. However, FGC with a high Gleason grade exists. FGC is found admixed with conventional acinar adenocarcinoma in 17 to 22% of needle biopsies and 13 to 22% of radical prostatectomy specimens and only rarely found in pure form. We report six cases of pure foamy gland carcinoma of prostate. The mean age in our study was 62.83 years and 5 out of the 6 cases presented with an elevated serum PSA level. Histopathological examination of our cases showed tumor cells with abundant foamy cytoplasm and low nucleo-cytoplasmic ratio. This deceptively benign-looking morphology can mimic nonneoplastic prostatic glands, Cowper’s gland, mucinous metaplasia, and xanthomatous prostatitis and hence often pose diagnostic challenges, especially in core needle biopsies. PNI was detected in two of our cases. PSA and AMACR staining was positive in all our cases (100%). p63 Staining was negative in all four cases where it was performed. Three, two, and one of our cases had a Gleason score of 7, 8, and 6 respectively. The prognosis depends on the Gleason score and the presence or absence of PNI or extraprostatic extension. Three of the cases presented with bony metastasis. We report this case series in view of the rarity and also to raise awareness of this entity which is often missed on small biopsies. Keywords: Foamy gland carcinoma, Gleason score, Prostate

Histological Variants of Squamous and Basal Cell Carcinoma in Squamates and Chelonians: A Comprehensive Classification.

In the present study, the histological characteristics of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) obtained from 22 squamate and 13 chelonian species were retrospectively evaluated. While the examined tissues were originally diagnosed as 28 SCCs and 7 BCCs based on histological evaluation by a specialty diagnostic service, eight SCCs could be re-classified as BCCs and three SCCs proved to be non-neoplastic lesions. In addition, all SCCs and BCCs were classified into distinct histological variants. The SCCs could be categorized as one SCC in situ, three moderately differentiated SCCs, seven well-differentiated SCCs, and six keratoacanthomas. BCCs were classified as five solid BCCs, four infiltrating BCCs, five keratotic BCCs, and one basosquamous cell carcinoma. In addition, the present study reports the occurrence of BCCs in seven reptile species for the first time. In contrast to what has been documented in humans, IHC staining with the commercially available epithelial membrane antigen and epithelial antigen clone Ber-EP4 does not allow differentiation of SCCs from BCCs in reptiles, while cyclooxygenase-2 and E-cadherin staining seem to have discriminating potential. Although the gross pathological features of the examined SCCs and BCCs were highly similar, each tumor could be unequivocally assigned to a distinct histological variant according to the observed histological characteristics. Based on the results of this study, a histopathological classification for SCCs and BCCs is proposed, allowing accurate identification and differentiation of SCCs and BCCs and their histological variants in the examined reptile species. Presumably, BCCs are severely underdiagnosed in squamates and chelonians.

Contrast-Enhanced Imaging Features and Clinicopathological Investigation of Steatohepatitic Hepatocellular Carcinoma

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinctive histologic variant of HCC for the presence of steatohepatitis. This study intended to evaluate the contrast-enhanced imaging features and clinicopathological characteristics of 26 SH-HCCs in comparison with 26 age-and-sex-matched non-SH-HCCs. The frequency of obesity (34.6%, p = 0.048) and type 2 diabetes mellitus (23.1%, p = 0.042) were significantly higher in SH-HCC patients. As seen via B-mode ultrasound (BMUS), SH-HCCs were predominantly hyperechoic (65.4%, p = 0.002) lesions, while non-SH-HCCs were mainly hypo-echoic. As seen via contrast-enhanced ultrasound (CEUS), 96.2% of SH-HCCs exhibited hyperenhancement in the arterial phase. During the portal venous and late phase, 88.5% of SH-HCCs showed late and mild washout. Consequently, most SH-HCCs and all non-SH-HCCs were categorized as LR-4 or LR-5. As seen via magnetic resonance imaging (MRI), a signal drop in the T1WI opposed-phase was observed in 84.6% of SH-HCCs (p = 0.000). Notably, diffuse fat in mass was detected in 57.7% (15/26) SH-HCCs (p < 0.001). As seen via contrast-enhanced MRI (CEMRI), most of the SH-HCCs and non-SH-HCCs exhibited heterogeneous hyperenhancement in the arterial phase (80.8% versus 69.2%, p = 0.337). During the delayed phase, 76.9% SH-HCCs and 88.5% non-SH-HCCs exhibited hypo-enhancement. Histopathologically, the rate of microvascular invasion (MVI) was significantly lower in SH-HCCs than non-SH-HCCs (42.3% versus 73.1%, p = 0.025). The frequency of hepatic steatosis >5% in non-tumoral liver parenchyma of SH-HCCs was significantly higher than in non-SH-HCCs (88.5% versus 26.9%, p = 0.000). Additionally, the fibrotic stages of S0, S1 and S2 in SH-HCCs were significantly higher than in non-SH-HCCs (p = 0.044). During follow-up, although the PFS of SH-HCC patients was significantly longer than non-SH-HCC patients (p = 0.046), for the overall survival rate of SH-HCC and non-SH-HCC patients there was no significant difference (p = 0.162). In conclusion, the frequency of metabolism-related diseases in SH-HCC patients was significantly higher than in non-SH-HCC patients. The imaging features of SH-HCCs combined the fatty change and typical enhancement performance of standard HCC as seen via CEUS/CEMRI.

Invasive micropapillary carcinoma: a rare and aggressive breast cancer

Invasive micropapillary carcinoma of the breast is a rare and distinct histological variant of breast cancers, accounting for less than 3% of all breast carcinomas. It is characterized by a pejorative prognosis due to heavy lymph node involvement and the presence of numerous vascular and lymphatic emboli. We here report the case of a 63-year-old woman presenting with left mastodynia evolving for two months. Physical examination revealed breast asymmetry with skin retraction and multiple suspected lymph nodes in the left axilla. Mammography objectified a spiculated mass in the left breast classified as ACR5. Breast microbiopsy showed invasive micropapillary carcinoma. The patient underwent left Patey’s mastectomy with ipsilateral axillary dissection. Macroscopically, the tumor was grayish-white with spiculated margins located at the union of the two external quadrants and measuring 13 x 8 cm (Panel A). Histological examination of the surgical specimen revealed invasive carcinomatous proliferation arranged in clusters, nests, micropapillae, morules and glands with reversed polarity within a fibro-inflammatory stroma retracted around the carcinomatous structures (Panel B, C). Histoprognostic grading (SBR grade) modified according to ELSTON and ELLIS was 3. Several peritumoral vascular emboli were detected as well as lymph nodes metastases 20N+/20N. Immunohistochemistry using EMA showed reversed polarity (Figure D). Molecular classification of the tumor was luminal B. The postoperative course was simple. The patient underwent adjuvant chemoradiotherapy. Currently, the patient is systematically monitored on an outpatient basis.

Long noncoding RNA landscapes specific to benign and malignant thyroid neoplasms of distinct histological subtypes

The main types of thyroid neoplasms, follicular adenoma (FA), follicular thyroid carcinoma (FTC), classical and follicular variants of papillary carcinoma (clPTC and fvPTC), and anaplastic thyroid carcinoma (ATC), differ in prognosis, progression rate and metastatic behaviour. Specific patterns of lncRNAs involved in the development of clinical and morphological features can be presumed. LncRNA landscapes within distinct benign and malignant histological variants of thyroid neoplasms were not investigated. The aim of the study was to discover long noncoding RNA landscapes common and specific to major benign and malignant histological subtypes of thyroid neoplasms. LncRNA expression in FA, FTC, fvPTC, clPTC and ATC was analysed with comprehensive microarray and RNA-Seq datasets. Putative biological functions were evaluated via enrichment analysis of coexpressed coding genes. In the results, lncRNAs common and specific to FTC, clPTC, fvPTC, and ATC were identified. The discovered lncRNAs are putatively involved in L1CAM interactions, namely, pre-mRNA processing (lncRNAs specific to FTC); PCP/CE and WNT pathways (lncRNAs specific to fvPTC); extracellular matrix organization (lncRNAs specific to clPTC); and the cell cycle (lncRNAs specific to ATC). Known oncogenic and suppressor lncRNAs (RMST, CRNDE, SLC26A4-AS1, NR2F1-AS1, and LINC00511) were aberrantly expressed in thyroid carcinomas. These findings enhance the understanding of lncRNAs in the development of subtype-specific features in thyroid cancer.

Genomic characterization of bladder cancer with variant histology.

470 Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology. The presence of variant histology may be associated with more advanced stage at presentation and a poorer response to systemic therapy. While histomorphologic assessment provides important prognostic information, genomic analysis of tumors can provide important insight into the biology of disease and inform treatment. In this analysis we performed genomic sequencing of tumors from patients with bladder cancer with variant histology. Methods: Our prospectively generated institutional cohort of molecularly profiled bladder and upper tract tumors contains over 2,000 samples including nearly 300 primary bladder tumor samples from patients with variant histology. Targeted sequencing with MSK-IMPACT was used to identify alterations in cancer-associated genes and to describe trends across variant subtypes. To explore and compare tumor and immune cell heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on a subset of specimens. Results: Our cohort included patients with pure urothelial carcinoma not otherwise specified (NOS), as well as squamous, small cell, pure adenocarcinoma and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid variants. Compared with urothelial carcinoma NOS, nearly all small cell tumors had mutations in TP53, RB1, and TERT. Squamous tumors had similar mutational frequencies as urothelial carcinoma NOS. Pure adenocarcinoma had frequent mutations in TP53, KRAS, and PIK3CA, resembling colorectal adenocarcinomas, while urothelial carcinoma with glandular differentiation resembled NOS. Micropapillary variant commonly had ERBB2 amplifications. Nested variant was more commonly found to have RHOA mutations and FOXA1 amplifications. Finally, nearly all plasmacytoid variants had pathognomonic alterations in CDH1. To further explore heterogeneity in tumor and immune cell populations, scRNA-seq was performed on four samples from patients with urothelial carcinoma NOS, squamous, micropapillary, and nested variants, showing distinct tumor cell clusters and varying contributions of immune cells from each variant. Conclusions: While the distribution of oncogenic mutations differed among distinct histologic variants, a pathognomonic DNA alteration was not found for most variant histologic subtypes. Within the context of a larger effort to characterize bladder cancer with variant histology, scRNA-seq may reveal differences in immune cell population infiltrates. Further efforts will aim to characterize these cohorts with whole exome sequencing and mutational signatures, and increase the number of samples per histology and representation of variant histologies for scRNA-seq.

Efficacy of enfortumab vedotin in advanced urothelial cancer: Retrospective analysis of the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) Study.

443 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is FDA approved for patients (pts) with treatment-refractory advanced urothelial cancer (aUC). The activity of EV in pt subsets of interest such as those with distinct histological variants has not been well defined. Methods: A retrospective study of pts with aUC treated with ≥1 dose of EV as standard of care (SOC) or on a clinical trial (if trial results already reported) at 12 US sites was undertaken. Objective response rate (ORR) was investigator-assessed for pts with at least one post-baseline scan or clear evidence of clinical progression. ORR was compared across subsets of interest using proportion test. Results: A total of 184 patients with aUC were included; median age at diagnosis 70, 20% women and 60% with definitive surgery. Most common primary sites included bladder (70%) and upper tract (28%). Majority of pts (72%) had pure urothelial histology (UH) per local review, but 26% had at least a component of variant histology (VH), most commonly squamous (14%), micropapillary (8%) or plasmacytoid (3%). EV was given as monotherapy in 84% and as SOC in 58%; and 81% had ≥ 1 prior treatment in the metastatic (met) setting. ECOG PS was ≥2 in 15%; 37% had baseline neuropathy, 15% diabetes and 9% had GFR≤30. At median follow-up of 37.0 (IQR: 20.5-60.2) months from initial diagnosis, median time from met diagnosis to EV start was 11.7 (IQR: 4.3 – 20.5) months. Median duration of EV was 5.5 (IQR: 1.4 – 6.7) months, and 84% of pts were evaluable for response. ORR for evaluable pts was 53% (8% CR, 45% PR); 25% had SD and 21% PD. Median PFS and OS were not yet reached. At data cutoff in 9/2020, 55% had stopped EV (36% due to PD, 19% intolerance) and 65% were alive. Comparison of ORR in subgroups of interest for 127 evaluable pts treated with EV monotherapy is shown in the table below. Notably, among 31 pts with FGFR3 alterations, 26 were evaluable and ORR was 46%. Conclusions: In a large, retrospective, multi-institutional cohort, responses to EV were observed across a broad range of aUC pts, including pts with variant histology component, FGFR3 alterations and also in populations previously excluded from clinical trials such as pts with GFR&lt;30 and significant baseline comorbidities. No significant differences in ORR were demonstrated for patient subsets of interest. [Table: see text]

Treatment at an Academic Cancer Center Confers Better Survival by Stage for Signet-Ring Cell and Non-signet-Ring Cell Gastric Cancer.

The literature lacks large-scale population studies comparing survival outcomes between signet-ring cell gastric carcinoma (SRGC) and non-SRGC (NSRGC) when treatment is delivered at academic versus community cancer centers. The National Cancer Database (NCDB) from 2004 to 2016 was queried to examine the association between treatment facility category and overall survival of patients who underwent gastrectomy for resectable gastric adenocarcinoma (GAC). The study investigated 22,871 patients. Upstaging of resectable GAC to pathologic stage 4 was more evident at community centers (3.5%) than at academic centers (2.8%) for the NSRGC variant (p = 0.211), whereas it was comparable between the two facility categories for the SRGC variant (5.9% vs 6%, respectively). Patients with pathologic stage 1 or 3 NSRGC who underwent gastrectomy at academic programs had better overall survival (OS) (hazard ratio [HR], 0.68; p < 0.0001) than those who underwent gastrectomy at community centers (HR, 0.79; p < 0.0065). Similarly, patients with stage 2 SRGC had better OS when treated at academic versus community centers (HR, 0.54; p = 0.0019). No statistically significant improvement in OS was observed between patients with stage 2 NSRGC (HR, 0.84; p = 0.083) and those with stage 3 SRGC (HR, 0.78; p = 0.054) who were treated at academic centers. No survival benefit was demonstrated for stage 1 SRGC when academic and community centers were compared (p = 0.56). This is the first study based on a large-scale database in the Western population that addressed the overall survival-by-stage of two distinct GAC histologic variants. Treatment at academic centers was associated with significant improvements in OS.

Primary mucinous carcinomas of the lung: Clinical characteristics and treatment outcomes.

Introduction:Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct histologic variant of adenocarcinomas comprising about 2%–10% of lung adenocarcinomas. A large proportion of IMAs carry KRAS mutations and only rarely epidermal growth factor receptor (EGFR) mutations or ALK/ROS translocations; thus, most cases are not amenable for targeted therapy at present. This study was conducted to elicit the unique clinicopathological characteristics of IMA.Materials and Methods:Medical records of patients diagnosed with IMA by needle biopsy at Kidwai Cancer Institute, Bangalore, from 2013 to 2018, were retrieved and reviewed. Statistical analysis was performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA).Results:Four hundred and ninety cases of needle biopsy of the lung were diagonosed at our institute between January 2013 and December 2018. Nine cases (1.8%) were diagnosed as IMA. The median age of presentation was 59 years. Six (66.7%) were current smokers with pack-year > 20. Three (33.3%) of the cases were initially misdiagnosed as pneumonia in view of computed tomography findings. The lung was the most common site of metastasis (77.8%). Serum Carcinoembryonic Antigen (CEA) was elevated in six cases (66.7%). None of the cases had any driver mutations in EGFR gene or ALK and ROS1 translocations. All cases were treated with pemetrexed–carboplatin doublet followed by pemetrexed maintenance till progression. The median progression-free survival (PFS) was 15 months (range: 5–18 months). Docetaxel was given as the second-line chemotherapy in all progressed patients. Best response noted was stable disease, seen in 4 (57.1%) cases. The median PFS for docetaxel was 6 months (range: 3–8 months). The median overall survival was 22 months (range: 9–27 months). Patients with initially raised CEA at progression had a serial rise in serum CEA.Conclusions:IMA is rarely diagnosed on needle biopsies due to insufficient tissue. They mimic pneumonia on imaging, thus delaying diagnosis. EGFR mutations, ALK, and ROS1 translocations are usually negative making them ineligible for tyrosine kinase inhibitors. Response to chemotherapy is modest.

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) disclose similar epigenetic signatures but different transcriptional profiles

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Methylation profiling revealed "infant" and "children" SHH MB clusters but neither DNMB nor MBEN composed separate epigenetic cohorts, and their profiles were intermixed within the "infant" cluster. In contrast, RNA-based transcriptional profiling disclosed that expression signatures of all MBEN were clustered separately from most of DNMB and a set of differentially expressed genes was identified. MBEN transcriptomes were enriched with genes associated with synaptic transmission, neuronal differentiation and metabolism, whereas DNMB profiling signatures included sets of genes involved in phototransduction and NOTCH signaling pathways. Thus, DNMB and MBEN are distinct tumor entities within the SHH MB family whose biology is determined by different transcriptional programs. Therefore, we recommend a transcriptome analysis as an optimal molecular tool to discriminate between DNMB and MBEN, which may be of benefit for patients' risk stratification in clinical trials. Molecular events identified in DNMB by RNA sequencing could be considered in the future as potent molecular targets for novel therapeutic interventions in treatment-resistant cases.

Microcystic/reticular schwannoma of the adrenal gland: a case report and literature review

Microcystic/reticular schwannoma is a recently described, rare, distinctive histological variant of schwannoma with a predilection for the gastrointestinal tract [1]. Unlike classic Schwannoma, most microcystic/reticular Schwannoma had an incomplete fibrous capsule, two distinctly different areas - hypercellular areas and myxoid areas, Microcystic/reticular schwannoma occurs in the internal organs, especially in the digestive tract and a rare case occurs in the adrenal glands [1–3]. Herein, we report a case of microcystic/reticular schwannoma of the adrenal gland, in a 60-year-old male with 7.0 cm × 6.0 cm × 5 cm mass in the left adrenal gland. The tumor showed a vague multinodular appearance with a pushing border and arranged in a microcystic and reticular growth pattern with anastomosing and intersecting strands of spindle cells in a myxoid or collagenous/hyalinized stroma. Tumor cells showed diffuse nuclear and cytoplasmic positivity for S-100.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

SUMMARYGenomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

Solitary diffuse neurofibroma of buccal mucosa

Neurofibroma (NF) is a benign peripheral nerve sheath tumor, arising from the mixture of Schwann cells and perineural fibroblasts. Diffuse NF (DNF) is an uncommon but distinct histological variant of NF. It typically involves skin and subcutaneous tissues, occurring primarily in children and young adults. DNF is seen either as a sporadic (solitary) lesion or as part of neurofibromatosis, usually type 1-NF1 (von Recklinghausen's disease of skin). Involvement of oral cavity is rare with isolated reports in the literature. Clinically, it appears as pedunculated or sessile nodular mass, exhibiting slow growth and mostly without pain. Histologically it differs from the conventional NF in that it has a very uniform matrix of fine-fibrillary collagen. Sheets or cords of neoplastic Schwann cells in the matrix are less elongated and has short fusiform or round contour. A characteristic feature is the presence of clusters of laminated Wagner–Meissner-like bodies, scattered throughout tumor mass, which distinguishes DNF from NF. A case of solitary DNF of buccal mucosa in a 23-year-old female patient is presented.

Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse.

Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well-differentiated HCC. However, the clinicopathological features and pathogenesis of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC. A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow-up was 45.5 (range: 0.2-166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein-1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin-like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks [diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%)], underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha-fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non-anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism. Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse.

Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas

Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 μg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1–9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2–171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature ‘silent’ for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as ‘poorly differentiated Pit-1 lineage adenomas’.

Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.

Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.

A rare case report: atypical epithelioid leiomyosarcoma of urinary bladder

Background Benign and malignant mesenchymal tumours of the urinary bladder are rare. Non-epithelial tumours account for 1–2% of all primary urinary bladder neoplasms. Among them, leiomyosarcoma is the most common type, representing only 0.1% of bladder cancers. It has three distinct histological variants: the classical spindle cell subtype, the myxoid subtype and the rare epithelioid subtype.1 Case report A 54-year-old female became increasingly symptomatic with urge incontinence and gross haematuria associated with significant weight loss. Abdominal ultrasound showed a large mass in urinary bladder. Core biopsy and then radical cystectomy show sheets of atypical cells which are mostly epithelioid or polygonal in shape. The main differentials include epithelioid leiomyosarcoma, sarcomatoid carcinoma and other sarcomas. Immunostains for smooth muscle markers, calponin, h-caldesmon, SMA, cytokeratin stains, S100 stains, HMB45, c-kit and myoglobin stain were performed. Other immunomarkers of epithelioid tumours were also checked. Overall features are consistent with an epithelioid leiomyosarcoma with urinary bladder involvement. Discussion Epithelioid leiomyosarcoma is a very rare tumour of the urinary bladder. The use of immunohistochemical staining is of value in assisting diagnosis.

Basaloid squamous cell carcinoma of the maxillary gingiva: A case report and review of the literature.

Basaloid squamous cell carcinoma (BSCC) is a rare, but distinct histologic variant of squamous cell carcinoma in the head and neck region. It is considered to have a poor prognosis due to its aggressive behavior and tendency to metastasize. The usual sites of BSCC are the floor of the mouth, hypopharynx and base of the tongue, and according to the English-language literature its presentation in the gingiva is somewhat uncommon. In the current report, the unusual case of a 40-year-old male is presented; the patient exhibited a painless irregular mass in the maxillary gingiva, which infiltrated the maxillary sinus, as observed by computed tomography. Hematoxylin and eosin-stained sections revealed a diagnosis of BSCC with typical central necrosis in the cancer nests, which contained basaloid and squamous cells. Immunohistochemistry revealed that p63 was weakly positive, high molecular weight cytokeratin (CK) was focally positive, and S-100, CK7, CK14 and vimentin were negative. It must be noted that histopathology results may be incorrectly interpreted as adenoid cystic carcinoma, undifferentiated carcinoma and basal cell adenocarcinoma.