Distinguishing Gastric/Esophageal Adenocarcinoma from Pancreatic Adenocarcinoma Using Methylation-Based Droplet Digital PCR.

The goal of this study was to develop a methylation-based droplet digital PCR to separate 2 cancer classes that do not have sensitive and specific immunohistochemical stains: gastric/esophageal and pancreatic adenocarcinomas. The assay used methylation-independent primers and methylation-dependent probes to assess a single differentially methylated CpG site; analyses of array data from The Cancer Genome Atlas network showed that high methylation at the cg06118999 probe supports the presence of cells originating from the stomach or esophagus (eg, as in gastric metastasis), whereas low methylation suggests that these cells are rare to absent (eg, pancreatic metastasis). On validation using formalin-fixed paraffin-embedded primary and metastatic samples from our institution, methylation-based droplet digital PCR targeting the corresponding CpG dinucleotide generated evaluable data for 60 of the 62 samples (97%) and correctly classified 50 of the 60 evaluable cases (83.3%), mostly adenocarcinomas from the stomach or pancreas. This ddPCR was created to be easy-to-interpret, rapid, inexpensive, and compatible with existing platforms at many clinical laboratories. We suggest that similarly accessible PCRs could be developed for other differentials in pathology that do not have sensitive and specific immunohistochemical stains.

SWI/SNF-deficient cancers of the Gastroenteropancreatic tract: an in-depth review of the literature and pathology.

The SWItch Sucrose non-fermentable (SWI/SNF) complex is a large, multi-subunit ATP-dependent nucleosome remodeling complex that acts as a tumor suppressor by modulating transcription. Mutations of SWI/SNF subunits have been described in relation to developmental disorders, hereditary SWI/SNF deficiency syndromes, as well as malignancies. In this review we summarize the current literature in regards to SWI/SNF-deficient tumors of the luminal gastrointestinal tract (GIT) and pancreas. As a group they range from moderately to undifferentiated tumors composed of monotonous anaplastic cells, prominent macronucleoli and a variable rhabdoid cell component. Deficiency of a SWI/SNF subunit is typified by complete loss of nuclear staining by immunohistochemistry for respective subunit.

Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome.

INTRODUCTION: Transcriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC. DESIGN: We first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes. RESULTS: We identified four morphological patterns that segregated into two components ('gland forming' and 'non-gland forming') based on the presence/absence of well-formed glands. A morphological cut-off (≥40% 'non-gland forming') was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as 'classical' using RNA-Seq. CONCLUSION: Our study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

Challenges with colorectal cancer staging: results of an international study.

Challenges exist with standardized colorectal cancer reporting despite adoption of the American Joint Committee on Cancer-Staging Manual 8th edition. We performed this study to gauge current practice patterns among a diverse group of surgical pathologists. A web-based questionnaire depicting problematic issues and images related to colorectal carcinoma staging was circulated among 118 surgical pathologists and their responses were correlated with their geographic location (North America vs. Europe vs. others), nature of practice (academic vs. community), the sign-out model (gastrointestinal subspecialty vs. general surgical pathology), and years of professional experience. We found that a substantial number of practicing pathologists ignore recommended-staging criteria in specific settings, particularly with respect to assessment of advanced T stage. Tumors that communicated with the serosa through inflammatory foci were staged as pT3 (49%) or pT4a (51%) by nearly equal numbers of pathologists regardless of level of experience, the sign-out model, or geographic location. Only 65% assigned T stage and margin status based on extent of viable tumor in the neoadjuvant setting. One-third of pathologists, particularly those in Europe (p = 0.015), classified acellular mucin deposits as N1 disease when detected in treatment-naive cases. Nearly 50% of pathologists classified isolated tumor cells (i.e., deposits <0.2 mm) in lymph nodes as metastatic disease (i.e., pN1, p = 0.02). Our results suggest that pathologists ignore recommendations that are based on insufficient data and apply individualized criteria when faced with situations that are not addressed in the American Joint Committee on Cancer Staging Manual 8th edition. These variations in practice limit the ability to compare outcome data across different institutions and draw attention to areas that require further study.

Minimalist approaches to cancer tissue-of-origin classification by DNA methylation.

Classification of cancers by tissue-of-origin is fundamental to diagnostic pathology. While the combination of clinical data, tissue histology, and immunohistochemistry is usually sufficient, there remains a small but not insignificant proportion of difficult-to-classify cases. These challenging cases provide justification for ancillary molecular testing, including high-throughput DNA methylation array profiling, which promises cell-of-origin information and compatibility with formalin-fixed specimens. While diagnostically powerful, methylation profiling platforms are costly and technically challenging to implement, particularly for less well-resourced laboratories. To address this, we simulated the performance of "minimalist" methylation-based tests for cancer classification using publicly-available and internal institutional profiling data. These analyses showed that small and focused sets of the most informative CpG biomarkers from the arrays are sufficient for accurate diagnoses. As an illustrative example, one classifier, using information from just 53 out of about 450,000 available CpG probes, achieved an accuracy of 94.5% on 2575 fresh primary validation cases across 28 cancer types from The Cancer Genome Atlas Network. By training minimalist classifiers on formalin-fixed primary and metastatic cases, generally high accuracies were also achieved on additional datasets. These results support the potential of minimalist methylation testing, possibly via quantitative PCR and targeted next-generation sequencing platforms, in cancer classification.

A reappraisal of sclerosing nodular and/or polypoid lesions of the gastrointestinal tract rich in IgG4-positive plasma cells.

AIMS: To describe additional cases of nodular and polypoid sclerosing lesions of the gastrointestinal tract (GIT) that are associated with numerous IgG4-positive plasma cells, review the pertinent literature to ascertain the relationship with systemic IgG4-related disease, and provide a reporting framework for such lesions. METHODS AND RESULTS: Five new cases of sclerosing polyps or nodules were collected over a 10-year period, occurring in four females and one male ranging in age from 32 years to 56 years (mean, 41.6 years). Patients were asymptomatic or had epigastric pain, and one had rectal bleeding. None had autoimmune or other obvious IgG4-related disease, and serum IgG4 levels were normal. All were solitary nodules in the stomach (two cases), ileum, caecum, and rectum. Four lesions were submucosal and one was subserosal; all were well circumscribed, composed of hyalinised, keloidal fibrous tissue with lymphoplasmacytic inflammation. Obliterative phlebitis was not seen. Lineage-specific immunomarkers were negative. In excess of 10 IgG4-positive plasma cells per high-power field were seen, and the IgG4/IgG ratios were >0.4. CONCLUSIONS: Very few IgG4-related lesions in the tubular GIT are associated with disease at other sites and/or elevated serum IgG4 levels. The majority may represent a lesion in the spectrum of IgG4-related disease. The use of the term 'IgG4-positive nodule or polyp with probable histological features of IgG4-related disease' is advocated for nodular and/or polypoid lesions in the GIT with ≥10 IgG4-positive plasma cells in a high-power field and an IgG/IgG4 ratio of >0.4.

Unexpected histopathological findings after sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) represents one of the most commonly performed bariatric procedures and, in contrast to the Roux-en-Y gastric bypass, produces a specimen for pathologic examination. This study aims to describe unexpected histopathological findings in order to better define preoperative management of patients undergoing LSG. METHODS: All LSG cases performed at an academic center in Toronto, Ontario between 2010 and 2017 were reviewed. All specimens underwent histopathological assessment, while those with findings suspicious for neoplasia or the presence of Helicobacter pylori underwent additional immunohistochemical stainings. Baseline patient characteristics and surgical outcomes were obtained from our internal database. RESULTS: A total of 222 patients underwent LSG during the study period and had their specimens examined histologically. Among them, 22.5% underwent preoperative endoscopy. The most common histopathological diagnosis was no abnormal findings (50.9%) followed by gastritis (25.7%). Abnormal findings warranting a change in postoperative management or follow-up were discovered in 8.6% of specimens and included H. pylori infection, intestinal metaplasia, malignancy, and atrophic gastritis. Only 4.7% of all patients had not undergone preoperative endoscopy and had truly unexpected findings. No significant association was found between abnormal findings and age, sex, or baseline body mass index (BMI). CONCLUSIONS: Although a majority of patients had a gastric specimen within normal limits, 8.6% had findings requiring a change in postoperative management. This rate dropped to 4.7% when patients whose diagnoses were known preoperatively were excluded. Our findings suggest that further research is needed to better define the role of preoperative endoscopy to potentially reduce the number of unexpected findings following LSG.

E-cadherin can limit the transforming properties of activating ß-catenin mutations.

Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in ß-catenin (CTNNB1). We have compared the dynamics and the potency of ß-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ß-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of ß-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ß-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:ß-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ß-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ß-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ß-catenin.

Colorectal large-cell neuroendocrine carcinoma with lymphoid stroma: further evidence confirming a unique subtype associated with MLH1/PMS2 loss, BRAF mutation, Epstein-Barr virus negativity, and the possibility of a better prognosis.

AIMS: Pure large-cell neuroendocrine carcinoma (LCNEC) is an uncommon but well-recognised primary tumour of the colorectum. It is characterised by large cells organised in a discernible neuroendocrine pattern with >20 mitoses per 10 high-power fields (HPFs), and/or a Ki67 index of >20%, and coagulative tumour necrosis is invariably present. These features are supplemented by positivity for neuroendocrine immunohistochemical markers. The aim of this study was to highlight three primary LCNECs of the colorectum. METHODS AND RESULTS: All three patients were elderly females, aged 79, 85 and 89 years, who presented with ascending colon (two) tumours and a rectal tumour. All three tumours were large, ulcerated, polypoid masses (85, 76 and 55 mm; average size 72 mm) and were pT3N2. Histologically, the tumours were composed of packets and nests of cells with rosettes; other areas were in sheets composed of large cells. The mitotic counts were 23/10 HPFs, 27/10 HPFs and 24/10 HPFs, respectively. There was no mucosal dysplasia, precursor adenoma or associated adenocarcinoma component. All cases contained mainly peritumoral lymphoid aggregates, with smaller numbers of intratumoral lymphocytes. Synaptophysin, chromogranin (less intensely) and epithelial markers were expressed in all cases in the majority of the tumour cells. The Ki67 proliferative indices were 95%, 100%, and 80%, respectively. Two patients survived for 48 and 72 months, whereas the third is alive after 12 months without evidence of recurrence. CONCLUSIONS: These unusual primary colorectal LCNECs with an accompanying lymphoid component are characterised by loss of MLH1/PMS2, BRAF mutation, microsatellite instability, and Epstein-Barr virus negativity. The patients also have better overall survival than those with LCNECs lacking an accompanying lymphoid component.

Predicting Underlying Neoplasms in Appendiceal Mucoceles at CT: Focal Versus Diffuse Luminal Dilatation.

OBJECTIVE. The purpose of this study was to determine whether a novel morphologic characteristic of appendiceal mucoceles at CT-focal distal appendiceal dilatation with a segment of morphologically normal appendix proximally-could predict an underlying neoplastic pathologic abnormality before surgery and histopathologic assessment. MATERIALS AND METHODS. A retrospective study was performed that assessed CT cases from 2012 through 2014. Cases showing morphologic features of a mucocele were identified and categorized into two subgroups: focal distal dilatation with a segment of normal appendix proximally and generalized appendiceal dilatation. The underlying histopathologic diagnosis for each case was assessed and categorized as neoplastic or nonneoplastic. Several additional morphologic findings were also assessed. RESULTS. Forty-nine cases with confirmed histopathologic diagnoses were identified. Of those, 20 of 23 (87.0%) cases with the finding of focal distal dilatation had an underlying neoplastic cause, whereas 14 of 26 (53.8%) cases with generalized dilatation had an underlying neoplastic cause (p = 0.012). The findings of periappendiceal fat stranding (p = 0.004), mural calcification (p = 0.006), and degree of luminal dilatation (p = 0.002) also reached statistical significance. When seen in combination with focal distal dilatation, the positive predictive value for underlying neoplasm approached or reached 100%. CONCLUSION. Our study shows that isolated focal distal appendiceal dilatation with a segment of morphologically normal appendix proximally is significantly associated with an underlying neoplastic histopathologic cause. When seen in combination with mural calcification, a diameter of more than 2 cm, and absence of periappendiceal stranding, an underlying neoplastic cause is strongly suggested.

Mucin-rich variant of traditional serrated adenoma: a distinct morphological variant.

AIMS: Traditional serrated adenomas (TSAs) account for 5% of serrated polyps, and have a villiform architecture, eosinophilic cells with a brush border, and indented, flat-topped luminal serrations. However, some are composed of mucin-filled goblet cells (GCs): mucin-rich TSA (MrTSA). The aim of this study was to determine whether this variant has unique features as compared with classic TSA (cTSA). METHODS AND RESULTS: One hundred and fifty-six TSAs were retrieved from the period 2010-2016. Patient demographics, site of polyps and 16 microscopic variables were evaluated. TSAs containing ≥50% GCs were classified as MrTSAs. Ectopic crypt foci (ECFs) were quantified as low (1-10) or high (>10), counted at ×200 magnification, and the average was taken for 10 fields. Twenty-four fulfilled the criteria for MrTSA. In males, MrTSAs (65%) were more prevalent than cTSAs (55%). There was no age difference, and both variants had a predilection for the left colon, although, in the right colon, MrTSAs were more frequent (39%) than cTSAs (10%) (P = 0.012). Adenomatous dysplasia was present in four of 24 MrTSAs (low grade, 3; high grade, 1). The most distinctive features of MrTSAs were: a variable growth pattern [endophytic (9%), mixed (30%), or villiform/exophytic (61%)], and a lower frequency of ECFs (P = 0.001) and more intraepithelial lymphocytes (P < 0.05) than in cTSAs. MrTSAs retain characteristic luminal serrations, at least focally. Inflamed MrTSAs can mimic inflammatory polyps and hamartomatous polyps (when there are >95% GCs). CONCLUSIONS: MrTSA is characterized by >50% GCs, and fewer ECFs than cTSA, but with preservation of archetypal luminal serrations. Awareness of this variant will prevent misdiagnosis, given the association of TSA with the accelerated pathway to colorectal cancer.

Wnt disruption in colorectal polyps - the traditional serrated adenoma enters the fray.

The adenoma-carcinoma sequence describes the development of colorectal carcinoma (CRC) from benign colorectal precursor lesions. Molecular classification of established CRC has demonstrated considerable disease heterogeneity; however, as an emerging cancer frequently outgrows and destroys the initial precursor lesion, CRC molecular taxonomy can only be partially reconciled with histologically classified polyps. Thus, the molecular pathogenesis of some colorectal polyp types, including the traditional serrated adenoma (TSA), is still unclear. Now, candidate driver gene analysis of a cohort of different polyps reveals characteristic, but highly variable, mutations disrupting the Wnt signalling pathway across different histological polyp subtypes. How and when different precursor lesions acquire Wnt disruption reflects important distinctions in polyp biology, dependent on a combination of the dominant molecular pathway and the cell of origin of individual lesions. TSAs preferentially acquire ligand-dependent Wnt activating mutations, which means that the cancers that arise from these aggressive polyps may be sensitive to targeted Wnt inhibition. This paper demonstrates that applying next-generation sequencing technology to improve our understanding of colorectal precursor lesion molecular pathogenesis could also give important and translationally relevant insights into colorectal cancer biology. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Colonic mucosubmucosal elongated polyp: report of a series of 14 cases and review of the literature.

AIMS: Most colorectal polyps can be reliably assigned to one of the known polyp categories, but a subset of polyps named colonic mucosubmucosal elongated polyps (CMSEPs) do not fall into any of these categories. First described in the Japanese literature, CMSEPs seem to be under-recognized in the Western literature. The aims of this study were to describe the clinicopathological features of 14 CMSEPs, discuss potential pathogenetic mechanisms, and increase awareness of this entity among pathologists. METHODS AND RESULTS: Fourteen pedunculated colorectal polyps that met the histopathological criteria for CMSEP (as described by Matake et al. and Alizart et al.) were assessed (12 males and two females; mean age 59.7 years). Five polyps were located in the sigmoid colon, four in the rectum, two in the descending colon, and three in the colon not otherwise specified. Nine of 14 polyps were discovered incidentally: two of nine on routine screening colonoscopy, two of nine on surveillance colonoscopy for inflammatory bowel disease (IBD), and five of nine upon surgical intervention for carcinoma or IBD. None coexisted with diverticular disease. The polyps were long and slender, varied from 5 to 30 mm in length (mean 15.9 mm), and showed a normal-looking colonic mucosal layer and underlying loose submucosa with thick-walled and congested blood vessels and lymphatics. CONCLUSIONS: CMSEPs show subtle but distinctive pathological features, and occur in normal and diseased colons. Pathologists need to be aware of this entity, to avoid confusion with other more commonly encountered colorectal polyps. With increasing colon cancer screening programmes and surveillance colonoscopy, it is likely that CMSEPs will be encountered more often.

Intraductal tubular neoplasms of the pancreas: an overview.

Intraductal lesions of the pancreas are an uncommon but increasingly recognized group of entities mainly because of advances in imaging technology. In the past, precise categorization and understanding of true pancreatic intraduct neoplasms were hampered not only by their relative rarity but also because of the plethora of terminology and criteria used in nomenclature and diagnosis. Although significant progress has been made in the characterization of some of these lesions, as exemplified by intraductal papillary mucinous neoplasms, understanding of the rare intraductal tubular adenoma (ITA) and intraduct tubular carcinoma (ITC) continues to evolve. By definition, these are a group of intraductal, radiologically detectable neoplasms that can progress to or be associated with invasive adenocarcinoma and, as such, are precursor lesions to pancreatic ductal adenocarcinoma. Their often shared clinical and radiological features make precise histological diagnosis essential for appropriate management and optimal outcome. We provide an overview of these neoplasms and highlight recent developments in the understanding of ITA and ITC which have led to ITA being considered a variant of gastric-type intraductal papillary mucinous neoplasms and ITC being encompassed within the intraductal tubulopapillary neoplasm category. We also emphasize the distinguishing histological features to aid diagnosis of these rare lesions.

Histological overlap between colorectal villous/tubulovillous and traditional serrated adenomas.

AIMS: To ascertain the degree of histological overlap between conventional villous/tubulovillous (VA/TVAs) and traditional serrated adenomas (TSA). METHODS AND RESULTS: A total of 180 polyps from the left colon/rectum diagnosed as VA/TVAs were retrieved randomly and reviewed by five pathologists looking specifically at luminal serration, cytoplasmic eosinophilia and the presence of ectopic crypt foci (ECF). For comparative purposes, 100 tubular adenomas and 80 TSAs were also examined. Twenty VA/TVAs were reclassified as TSA. Luminal serration as noted in TSA was not seen in any of the remaining 160 polyps, ECFs were noted in 55 of the 160 VA/TVAs (34%), while cytoplasmic eosinophilia (constituting <50% of the adenoma) was noted in only 10 of 160 cases (6.2%). CONCLUSIONS: Ectopic crypt foci and cytoplasmic eosinophilia are encountered in sporadic VA/TVAs but not to the same extent and degree as in TSA. ECFs were found in one-third of cases, but cytoplasmic eosinophilia is rare. The pattern of luminal serration in TSA is very characteristic and not recapitulated in VA/TVA. The occurrence of all three histological features together occurs only in TSA. ECFs are not a sine qua non for TSA and are encountered commonly in VA/TVAs. VA/TVAs often contain occasional glands typical of TSA.

Spectrum of histopathological changes encountered in stented colorectal carcinomas.

AIMS: Self-expanding metallic stents (SEMS) are increasingly being used in obstructing colorectal cancer (CRC) as a 'bridge to surgery', allowing conversion of potentially high-risk emergency resections to elective procedures. Stenting may cause a wide array of histological changes. We present the largest series to date of stented CRC, performed and reported at a single institution. METHODS AND RESULTS: Stented CRC specimens received in January 2006 to December 2011 were identified from our pathology database. Slides for each case were independently reviewed by two pathologists, and a consensus was reached. A total of 72 CRCs were identified, 15 at or proximal to the splenic flexure, and 57 left-sided. Thirty-six were stage pT3 and 36 were stage pT4. Perforation was observed in 14 cases. The effects of stenting on the tumour included tumour necrosis (100%) and flat ulceration (77.8%). The spectrum of changes in the background bowel included mimics of inflammatory bowel disease, tumour regression post-neoadjuvant therapy, and ischaemia. CONCLUSIONS: Given the inclusion of stenting of CRC as a bridge to surgery in the current NICE guidelines, we expect to see increasing numbers of such cases. In our study, a range of changes were encountered that mimic other bowel diseases, from simple fissuring to chronic inflammatory bowel disease and neoadjuvant regression change.

Republished: mucinous tumours of appendix and ovary: an overview and evaluation of current practice.

Mucinous lesions of the appendix and ovary are commonly encountered in routine practice. There are several published classification schemes for appendiceal mucinous neoplasms with resultant inconsistent use of terms and clinical doubt. While nomenclature is more settled with regards to ovarian mucinous neoplasms, the difficulty here lies with distinguishing primary from secondary mucinous tumours. This review highlights the terminology and nomenclature for appendiceal mucinous tumours, the relationship with ovarian mucinous neoplasms and pseudomyxoma peritonei, and the features that assist in separating primary from secondary ovarian mucinous tumours.

Predictive and prognostic biomarkers in gastrointestinal tract tumours.

Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.

Macroscopic examination of pathology specimens: a critical reappraisal.

Meticulous macroscopic examination of specimens and tissue sampling are crucial for accurate histopathology reporting. However, macroscopy has generally received less attention than microscopy and may be delegated to relatively inexperienced practitioners with limited guidance and supervision. This introductory paper in the minisymposium, Macroscopy Under the Microscope, focuses on issues regarding macroscopic examination and tissue sampling that have been insufficiently addressed in the published literature. It highlights the importance of specimen examination and sampling, discusses some general principles, outlines challenges and suggests potential solutions. It is critical to get macroscopy right the first time as it may not be possible to rectify errors even with expert histological assessment or to retrospectively collect missing data after the specimen retention period. Dissectors must, therefore, receive adequate guidance and supervision until they are proficient in macroscopic specimen examination. We emphasise the importance of the clinical context, optimal specimen fixation, succinct and clinically relevant macroscopic descriptions, macrophotography and judicious tissue sampling. We note that current recommendations based on the number of blocks to be submitted per maximum tumour dimension are ambiguous as the amount of tissue submitted in a cassette is not standardised and it is unclear whether 'block' refers to a tissue block or a paraffin block. Concerns around potential oversampling of 'therapeutic' specimens that could result in overdiagnosis due to detection of incidentalomas are also discussed. We hope that the issues discussed in this paper will engender debate on this clinically critical aspect of pathology practice.