Nodular lymphocyte-predominant Hodgkin lymphoma: advances in disease biology, risk stratification, and treatment.

Recent updates have detailed how patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) may be better risk stratified using prognostic scoring systems. Most patients with NLPHL present with early-stage disease and have an indolent disease course. To reflect these differences from classic Hodgkin lymphoma, nomenclature has been updated to recognise nodular lymphocyte predominant B-cell lymphoma as an alternative to NLPHL. The Global NLPHL One Working Group have published their pivotal dataset in 2024 which challenges the prognostic significance of variant immunoarchitectural (IAP) patterns and proposes a new prognostic scoring system. Key identified prognostic factors include age >45 years, stage III-IV disease, haemoglobin.

Cutaneous Involvement by Refractory Celiac Disease Type 2 Histologically Mimicking Mycosis Fungoides.

ABSTRACT: Refractory celiac disease (RCD) is a rare condition characterized by persistent malabsorptive symptoms and villous atrophy despite a gluten-free diet. While RCD type 1 has a normal intraepithelial lymphocyte phenotype, RCD type 2 is defined by the presence of immunophenotypically aberrant and monoclonal intraepithelial T lymphocytes, with a high propensity to transform to enteropathy-associated T-cell lymphoma (EATL). Although dermatological manifestations of celiac disease are common, presentation with cutaneous involvement by abnormal lymphocytes of RCD type 2 or EATL is rare, with few histologic descriptions in the literature. We describe the case of a 66-year-old man with a history of celiac disease presenting with a generalized, erythematous papular rash over his torso, upper arms, and legs. Biopsy of his skin lesions showed prominent hyperkeratosis with underlying spongiosis and interface change. Increased intraepithelial (epidermotropic) lymphocytes were observed, out of proportion to the level of spongiosis, but not overly atypical in appearance. Immunohistochemistry revealed an aberrant T-cell immunophenotype (CD3/2/7 positive; CD5/4/8 negative), raising suspicion for a cutaneous T-cell lymphoproliferative disorder. A duodenal biopsy demonstrated total villous atrophy with a morphologically bland population of epitheliotropic T lymphocytes showing the same aberrant immunophenotype. Similar cells were also identified by flow cytometry in the peripheral blood. In conjunction with the history of celiac disease, a diagnosis of RCD type 2 or 'EATL in situ' with cutaneous involvement was made. Cutaneous RCD type 2 or EATL should be considered as differential diagnoses in patients with a history of celiac disease and histopathology reminiscent of epidermotropic forms of cutaneous T-cell lymphoma.

Inter- and intrapatient heterogeneity of indoleamine 2,3-dioxygenase expression in primary and metastatic melanoma cells and the tumour microenvironment.

AIMS: Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumours and promotes tumour progression. IDO inhibitors with and without additional anti-PD-1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumours, and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy-naive metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases. METHODS AND RESULTS: Here, we evaluated IDO expression using immunohistochemistry in 99 melanoma tumour samples from 43 immunotherapy-naive patients with metastatic melanoma to determine patterns of expression in primary melanomas (n = 29), locoregional metastases (n = 36) and distant metastases (n = 34). Thirty-seven per cent of patients demonstrated tumour IDO expression in at least one specimen. Twelve of 35 patients (34%) with longitudinal specimens (i.e. two or more separate specimens from different disease stages in the same patient) displayed heterogeneous IDO staining between samples. Tumour IDO expression positively correlated with tumour-infiltrating lymphocyte (TIL) score as well as the number of IDO-expressing mononuclear cells in the primary melanoma (P < 0.0001 and P = 0.0011, respectively) and nodal metastases (P = 0.049 and P = 0.037, respectively), but not in distant metastases. Furthermore, tumour IDO expression correlated positively with PD-L1 expression by melanoma cells among all specimens (P = 0.0073). CONCLUSIONS: Therefore, while assessment of tumour IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by intertumoral heterogeneity.

Early Barrett esophagus-related neoplasia in segments 1 cm or longer is always associated with intestinal metaplasia.

The assumption that intestinal metaplasia is a prerequisite for intraepithelial neoplasia/dysplasia and adenocarcinoma in the distal esophagus has been challenged by observations of adenocarcinoma without associated intestinal metaplasia. This study describes our experience of intestinal metaplasia in association with early Barrett neoplasia in distal esophagus and gastroesophageal junction. We reviewed the first endoscopic mucosal resection of 139 patients with biopsy-proven neoplasia. In index endoscopic mucosal resection, 110/139 (79%) cases showed intestinal metaplasia. Seven had intestinal metaplasia on prior biopsy specimens and three had intestinal metaplasia in subsequent specimens, totaling 120/139 (86%) patients showing intestinal metaplasia at some point supporting the theory of sampling error for absence of intestinal metaplasia in some cases. Those without intestinal metaplasia (13%) were enriched for higher stage disease (T1a Stolte m2 or above) supporting the assertion of obliteration of intestinal metaplasia by the advancing carcinoma. All cases of intraepithelial neoplasia and T1a Stolte m1 carcinomas had intestinal metaplasia (42/42). The average density of columnar-lined mucosa showing goblet cells was significantly less in shorter segments compared to those ≥3 cm (0.31 vs 0.51, P=0.0304). Cases where segments measured less than 1 cm were seen in a higher proportion of females and also tended to lack intestinal metaplasia. We conclude that early Barrett neoplasia is always associated with intestinal metaplasia; absence of intestinal metaplasia is attributable to sampling error or obliteration of residual intestinal metaplasia by neoplasia and those with segments less than 1 cm show atypical features for Barrett-related disease (absent intestinal metaplasia and female gender), supporting that gastroesophageal junction adenocarcinomas are heterogeneous.

What Therapeutic Biomarkers in Gastro-Esophageal Junction and Gastric Cancer Should a Pathologist Know About?

Malignancies of upper gastrointestinal tract are aggressive, and most locally advanced unresectable and metastatic cancers are managed by a combination of surgery and neoadjuvant/adjuvant chemotherapy and radiotherapy. Current therapeutic recommendations include targeted therapies based on biomarker expression of an individual tumor. All G/gastro-esophageal junction (GEJ) cancers should be tested for HER2 status as a reflex test at the time of diagnosis. Currently, testing for PDL 1 and mismatch repair protein status is optional. HER2 testing is restricted to adenocarcinomas only and endoscopic biopsies, resections, or cellblocks. Facilities should be available for performing validated immunohistochemical stains and in-situ hybridization techniques, and importantly, pathologists should be experienced with preanalytical and analytical issues and scoring criteria. Genomic profiling via next-generation sequencing (NGS) is another strategy that assess numerous mutations and other molecular events simultaneously, including HER2 amplification, MSS status, tumor mutation burden, and neurotrophic tropomyosin-receptor kinases gene fusions.

Case report: Haemoperitoneum secondary to acute rupture of primary hepatic angiosarcoma.

INTRODUCTION AND IMPORTANCE: Primary hepatic angiosarcoma (PHA) is a rare and aggressive liver malignancy of endothelial cell origin and is associated with poor outcome. Pre-operative confirmation of the diagnosis is challenging, as clinical and radiological findings are generally non-specific. Very rarely, spontaneous haemoperitoneum may occur due to the spontaneous rupture of previously undiagnosed PHA. CASE PRESENTATION: We describe a case of a 28-year-old male with haemoperitoneum due to the rupture of previously undiagnosed PHA. After failing to respond to the non-operative measures, the patient underwent emergency partial liver resection and recovered without any post-operative complications. Histopathological examination of the specimen confirmed the diagnosis of PHA. Two months after the operation, the patient represented with advanced metastatic disease and disseminated intravascular coagulation (DIC). The patient died one month after discharge. CLINICAL DISCUSSION: A patient with PHA presents a diagnostic challenge due to its rare incidence and non-specific clinical findings. Spontaneous intra-abdominal haemorrhage can occur due to PHA rupture and carries a dismal prognosis. In addition to emergency haemorrhage control, complete surgical resection with clear margins is the definitive treatment to date, however, most cases of PHA are unresectable at diagnosis and recurrence is common even after complete resection. CONCLUSION: PHA is associated with very poor outcomes, due to its rapid progression, early recurrence, and metastatic nature. The median survival is approximately 5 months. Haemoperitoneum secondary to rupture of previously undiagnosed PHA is uncommon and is a poor prognostic indicator. Complete surgical resection of the disease is challenging and there is no established treatment.

The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: An international multi-institutional analysis.

PURPOSE: Increasing evidence is accumulating for an alarming rising incidence of oral tongue SCC in a younger cohort, particularly in developed countries. The aim of this study is to analyse the change in incidence of OSCC in patients under the age of 45 in developed nations in the Asia-Pacific region. PATIENTS AND METHODS: Population data was extracted from the Australian Cancer Incidence and Mortality 2017 database and National Registry of Diseases Office, Singapore to allow calculation of the incidence in the Australian and Singaporean populations. This was compared to multi-institutional data from four tertiary Australian institutions. The inclusion criteria were as follows: a) diagnosis of primary SCC of the mobile tongue; b) treatment with curative intent; c) complete histopathologic data; d) complete adjuvant treatment data; e) follow up data. RESULTS: Analysis of ACIM data demonstrated that there was a significant increase in the incidence of tongue SCC in those under the age of 45 in the Australian and Singaporean populations (p < 0.001). When analysed for gender, the incidence of tongue SCC increased at a significantly higher rate in females than males (p < 0.001). Similarly, in the multi-institutional analysis including 1814 patients, the number of females under the age of 45 with tongue SCC significantly increased over time (p < 0.001), with the proportion of smokers in this cohort decreasing over time. CONCLUSION: The incidence of tongue SCC is rising in young females in developed nations in the Asia Pacific region, in keeping with observed epidemiological trends worldwide.

Patterns of p53 immunoreactivity in non-neoplastic and neoplastic Barrett's mucosa of the oesophagus: in-depth evaluation in endoscopic mucosal resections.

There is increasing interest in p53 immunohistochemistry as an adjunct to haematoxylin and eosin (H&E) assessment for dysplasia in oesophageal Barrett's mucosa; however, published information on the patterns of staining remains scant. Here, we present descriptions of normal and aberrant p53 staining in non-neoplastic and dysplastic Barrett's mucosa in endoscopic mucosal resections. A retrospective series of archival endoscopic mucosal resections for biopsy proven dysplasia at our institution were retrieved for this study, comprising 28 sections from 23 patients. p53 immunohistochemistry was performed using an in-house optimised protocol and the staining pattern assessed in H&E confirmed non-neoplastic, dysplastic and neoplastic areas of Barrett's mucosa with regard to individual cell intensity and location of positive cells with respect to gland microanatomy. In non-neoplastic epithelium, normal p53 staining was weak, heterogenous and localised to the crypts. In dysplastic epithelium, p53 over-expression was seen which was of moderate to strong intensity in either a crypt predominant location or diffuse involving crypt and surface epithelium. The crypt predominant pattern was observed more commonly in low grade dysplasia while the diffuse pattern was more commonly seen in high grade dysplasia. In a minority of cases, there was complete loss of p53 staining in dysplastic epithelium and contiguous neoplasia (null phenotype). p53 immuno-expression in non-neoplastic and dysplastic Barrett's mucosa is distinctive when interpreted with regard to cell intensity and gland microanatomy. We propose that these staining patterns may assist in the interpretation of dysplasia in endoscopic biopsies of Barrett's mucosa.

Laboratory validation studies in Ki-67 digital image analysis of breast carcinoma: a pathway to routine quality assurance.

Ki-67 proliferative index (PI) has prognostic and predictive value in invasive breast carcinoma (IBC), but clinical uptake has been hampered by suboptimal accuracy, reproducibility and standardisation. Published guidelines have addressed pre-analytical and analytical factors to improve Ki-67 PI utility; however, practicalities of ongoing monitoring of Ki-67 PI quality in IBC reporting have not been established. We aimed to evaluate the internal and external quality of our established digital Ki-67 PI IBC reporting practice at a tertiary institution. In the 5 years since initial validation work, we've completed a series of internal and external quality assurance (QA) projects: (1) an interobserver agreement study, (2) a two site interlaboratory agreement study, (3) determination of the error of our Ki-67 results, (4) an audit of the year-to-year Ki-67 values, (5) an audit of Ki-67 in neoadjuvant chemotherapy (NAC) treated cases, and (6) comparison of our Ki-67 datasets with similar published datasets. There was excellent concordance (intra-class correlation = 0.98) and good agreement [kappa (κ) = 0.76-0.96] between pathologists, excellent concordance [Pearson correlation (R) = 0.94] and very good agreement (κ = 0.80) between laboratories and excellent concordance (R = 0.92-0.95) and good agreement (κ = 0.67-1.0) over time for our Ki-67 results. No significant difference was observed in Ki-67 data from year-to-year. Expected associations with clinico-pathological prognosticators, pathological complete response following NAC and mitotic index were evident. The median Ki-67 values from the overall and NAC treated datasets were within the range reported in other studies, and our data could be separated into similarly proportioned 'high' and 'low' Ki-67 PI groups when dichotomised as per protocols in other studies. Collectively, our work provides evidence of adequate internal and external quality control for our digital Ki-67 PI IBC reporting protocols. Given the paucity of formal Ki-67 QA programs, our approach could be emulated, and results compared between laboratories as a framework for internal and external Ki-67 QA.

Prevalence and Cellular Distribution of Novel Immune Checkpoint Targets Across Longitudinal Specimens in Treatment-naïve Melanoma Patients: Implications for Clinical Trials.

PURPOSE: Immunotherapies targeting costimulating and coinhibitory checkpoint receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known about the relative abundance, coexpression, and immune cells enriched for each specific drug target, limiting understanding of the biological basis of potential treatment outcomes and development of predictive biomarkers for personalized immunotherapy. We sought to assess the abundance of checkpoint receptors during melanoma disease progression and identify immune cells enriched for them.Experimental Design: Multiplex immunofluorescence staining for immune checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, VISTA) was performed on 96 melanoma biopsies from 41 treatment-naïve patients, including patient-matched primary tumors, nodal metastases, and distant metastases. Mass cytometry was conducted on tumor dissociates from 18 treatment-naïve melanoma metastases to explore immune subsets enriched for checkpoint receptors. RESULTS: A small subset of tumor-infiltrating leukocytes expressed checkpoint receptors at any stage of melanoma disease. GITR and OX40 were the least abundant checkpoint receptors, with <1% of intratumoral T cells expressing either marker. ICOS, PD-1, TIM-3, and VISTA were most abundant, with TIM-3 and VISTA mostly expressed on non-T cells, and TIM-3 enriched on dendritic cells. Tumor-resident T cells (CD69+/CD103+/CD8+) were enriched for TIGIT (>70%) and other coinhibitory but not costimulatory receptors. The proportion of GITR+ T cells decreased from primary melanoma (>5%) to lymph node (<1%, P = 0.04) and distant metastases (<1%, P = 0.0005). CONCLUSIONS: This study provides the first comprehensive assessment of immune checkpoint receptor expression in any cancer and provides important data for rational selection of targets for trials and predictive biomarker development.

Macroscopic Assessment and Cut Up of Endoscopic Resection Specimens for Early Esophageal Glandular Malignancies.

Pathological assessment of tissue is the gold standard for diagnosis and staging of neoplasia and provides key prognostic information for clinical management. Proper macroscopic assessment and cut-up technique is essential to ensure that the overall assessment is correct and reproducible. Endoscopic mucosal resection is a technique used for removing early neoplastic glandular lesions of the esophagus at the level of submucosa. Here, we describe the macroscopic assessment and dissection techniques used for the routine handling of endoscopic mucosal resection specimens in the clinical laboratory.

Processing of Surgical Specimen (Esophagogastrectomy) for Esophageal Adenocarcinoma.

An esophagogastrectomy is a surgical procedure that is performed for treatment of confirmed localized esophageal and esophagogastric junction adenocarcinoma. Proper macroscopic assessment and cut-up technique is essential to ensure that the overall assessment is correct and reproducible. Here, we describe a standard for macroscopic assessment and dissection to be used for routine handling of esophagogastrectomy specimens in the clinical laboratory.

Squamous Cell Carcinoma of the External Auditory Canal and Temporal Bone: An Update.

Squamous cell carcinoma (SCC) is the most common primary malignancy to affect the temporal bone, including primary cutaneous SCC of the pinna, external auditory canal, middle and inner ear. This anatomically complex region generates complicated three-dimensional specimens that can be a challenge for macroscopic and microscopic pathologic assessment. A universally accepted staging classification for these malignancies is still to be established. A brief summary of the regional anatomy, etiology and epidemiology, presentation and diagnosis, radiologic assessment and treatment follows with a review of the pathologic assessment of the different types of specimens generated and an update on staging for SCC of the temporal bone.

Oral malignant gastrointestinal neuroectodermal tumour with junctional component mimicking mucosal melanoma.

Malignant gastrointestinal neuroectodermal tumour (GNET) is a recently characterised rare and aggressive tumour that typically arises in association with the small intestine of adults. We present a novel case of this entity and expand the spectrum of its reported morphological features. The patient was a 5-year-old female, the youngest reported patient affected by the condition, and presented with extra-abdominal disease. The histopathological features included the presence of a junctional component of the palatal tumour, which mimicked mucosal melanoma, a feature that has not been previously reported in GNET. Whole genome and RNA sequencing was performed that demonstrated the EWSR1-ATF1 translocation characteristic of GNET. Knowledge of this entity and its features, together with careful morphological assessment supplemented by judicious immunohistochemical and molecular studies should enable the correct diagnosis to be established.