An Esophageal Neoplasm Sans Lineage: Undifferentiated Carcinoma

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the "Surgical Pathology Cancer Case Summary (Checklist)" portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.This protocol applies to all invasive carcinomas of the perihilar bile ducts. Carcinomas of the distal extrahepatic bile ducts, intrahepatic bile ducts, and well-differentiated neuroendocrine neoplasms (carcinoid tumors) are not included. The seventh edition TNM staging system for perihilar bile ducts of the American Joint Committee on Cancer and the International Union Against Cancer is recommended.Perihilar Bile Ducts: Local or Segmental Resection, Hilar Resection With or Without Hepatic Resection (note A)Select a Single Response Unless Otherwise Indicated*Data elements with asterisks are not required. However, these elements may be clinically important but are not yet validated or regularly used in patient management.Specimen (select all that apply)Other Organs ReceivedProcedureTumor Site (select all that apply)Tumor SizeHistologic Type (note C)Histologic Grade (note D)Microscopic Tumor Extension (select all that apply)Margins (select all that apply) (note E)Segmental Resection SpecimenLymph-Vascular Invasion (note F)Perineural Invasion (note F)Pathologic Staging (pTNM) (note G)TNM Descriptors (required only if applicable) (select all that apply)Primary Tumor (pT)Regional Lymph Nodes (pN)Distant Metastasis (pM)*Additional Pathologic Findings (select all that apply) (note H)*Ancillary Studies*Clinical History (select all that apply)*Comment(s): ____________________________________* Data elements with asterisks are not required. However, these elements may be clinically important but are not yet validated or regularly used in patient management.Tumors arising in the biliary tree are classified into 3 groups: intrahepatic, perihilar, and distal (Figure 1). Perihilar tumors are defined as those involving the hepatic duct bifurcation or extrahepatic biliary tree proximal to the origin of the cystic duct1; distal tumors are defined as those arising between the junction of the cystic duct–bile duct and the ampulla of Vater.2 This protocol applies only to perihilar carcinomas. It does not include tumors of the extrahepatic bile ducts that arise distal to the cystic duct, low-grade neuroendocrine neoplasms (carcinoids), or tumors arising in the ampulla of Vater. Carcinomas arising in the cystic duct are grouped for staging purposes with carcinomas of the gallbladder. Tumors arising within the intrahepatic bile ducts are classified and staged as carcinomas of the intrahepatic bile ducts. Carcinomas arising in the middle portion of the extrahepatic bile duct are classified according to their treatment (combined hepatic and hilar resection for perihilar tumors, pancreaticoduodenectomy for distal bile duct tumors).Carcinomas may arise in choledochal cysts (congenital cystic dilatation or duplications) of the bile duct. Histologically, they are classified in the same way as those arising in the gallbladder or bile ducts. Stones may be found in these cysts. If dysplasia or carcinoma in situ is found on initial microscopic sections, then multiple additional sections should be examined to exclude invasive cancer in other areas of the cyst.For consistency in reporting, the histologic classification published by the World Health Organization (WHO), shown later, is recommended.3 However, this protocol does not preclude the use of other systems of classification or histologic types. According to WHO convention, the term cholangiocarcinoma is reserved for carcinomas arising in the intrahepatic bile ducts.Some histologic types of bile duct carcinoma are prognostically significant. Papillary carcinomas, which are often polypoid on macroscopic examination, have the best prognosis.4,5 High-grade tumors, such as signet-ring cell carcinomas, small cell carcinomas, and undifferentiated carcinomas, are associated with a poorer prognosis compared with adenocarcinoma. Many of the special subtypes, such as clear cell adenocarcinoma, are rarely encountered. The following classification is adapted from the WHO classification of carcinoma of the extrahepatic bile ducts.AdenocarcinomaPapillary adenocarcinoma*Adenocarcinoma, intestinal typeMucinous adenocarcinomaClear cell adenocarcinoma*Signet-ring cell carcinoma†Adenosquamous carcinomaSquamous cell carcinomaSmall cell carcinoma‡Large cell neuroendocrine carcinomaUndifferentiated carcinoma‡Biliary cystadenocarcinoma* These histologic types are not usually graded.† By convention, signet-ring cell carcinomas are assigned grade 3 (see later).‡ Small cell carcinomas and undifferentiated (histologic type) carcinomas are assigned grade 4 (see later).For adenocarcinomas, a quantitative grading system based on the proportion of gland formation within the tumor is suggested3 and shown in the following.Definitions corresponding to the previously listed histologic grades are as follows.For squamous cell carcinomas, a rare tumor type in the extrahepatic bile ducts, a suggested grading system follows. If there are variations in the differentiation within the tumor, the highest (least favorable) grade is recorded.Tumors with no differentiation or minimal differentiation that is discernible only in rare tiny foci (undifferentiated carcinomas by WHO classification) are categorized as grade 4.Locoregional recurrence, as opposed to distant metastases, is usually the first site of disease recurrence and occurs in up to 59% of patients with perihilar bile duct carcinomas.6 Tumor recurrence is often related to residual tumor located in the proximal or distal surgical margins of the bile duct or from tumor located along the dissected soft tissue margin in the portal area. Local recurrence (usually at the surgical margins) can be attributed in many cases to tumor spread longitudinally along the duct wall and to perineural and lymph-vascular invasion.7Complete surgical resection with microscopically negative surgical margins is an important predictor of outcome in multivariate analysis for both perihilar and distal bile duct carcinomas, with overall 5-year survival for perihilar tumor improved from 10% for all patients to 30% for those with negative resection margins.1Malignant tumors of the extrahepatic bile ducts are often multifocal.8 Therefore, microscopic foci of carcinoma or intraepithelial neoplasia may be found at the margin(s) even though the main tumor mass has been resected. In some cases it may be difficult to evaluate margins on frozen section preparations because of inflammation and reactive change of the surface epithelium or within the intramural mucous glands. If surgical margins are free of carcinoma, the distance between the closest margin and the tumor edge should be measured.Because 5% of patients with bile duct carcinoma have synchronous carcinomas of the gallbladder, examination of the entire surgical specimen, including the gallbladder, is advised.Perineural and lymphatic invasion are common in extrahepatic bile duct carcinomas, although they are found less often in early-stage cancers (11%).9 They should be specifically evaluated because they are associated with adverse outcome on univariate analysis.10 Although perineural invasion is sometimes useful for distinguishing carcinoma from nonneoplastic glands, caution should be used in interpretation of this finding in ducts affected by PSC, because perineural invasion by benign hyperplastic intramural glands has been reported in this setting11 and may be seen in adenomatous hyperplasia.Surgical resection is the most effective therapy for extrahepatic biliary tract carcinomas, and the best estimation of prognosis is related to the anatomic extent (stage) of disease at the time of resection. In particular, lymph node metastases are predictors of poorer outcome.1,12For malignant tumors of the perihilar bile ducts, the TNM staging system of the American Joint Committee on Cancer and the International Union Against Cancer is recommended.2 The staging system also applies to tumors arising in choledochal cysts.According to the American Joint Committee on Cancer/International Union Against Cancer convention, the designation "T" refers to a primary tumor that has not been previously treated. The symbol "p" refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.The "m" suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.The "y" prefix indicates those cases in which classification is performed during or after initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The "y" categorization is not an estimate of tumor before multimodality therapy (ie, before initiation of neoadjuvant therapy).The "r" prefix indicates a recurrent tumor when staged after a documented disease-free interval and is identified by the "r" prefix: rTNM.The "a" prefix designates the stage determined at autopsy: aTNM.T Category Considerations (Figures 2 and 3)pTisFor bile duct carcinomas, "carcinoma in situ" (pTis) as a staging term includes neoplastic cells cytologically indistinguishable from invasive carcinoma but confined within the glandular basement membrane.8 Separation of high-grade dysplasia from carcinoma in situ is subjective and, because morphologic criteria are ill defined, subject to interobserver variability. The term carcinoma in situ is not widely applied to glandular neoplastic lesions in the gastrointestinal tract but is retained for tumor registry reporting purposes as specified by law in many states. Noninvasive bile duct carcinomas with a papillary growth pattern are classified as pTis.pT2 and pT3Because the histology of the extrahepatic biliary tree varies along its length, with little smooth muscle in the wall of the proximal ducts compared with the distal bile duct, assessment of depth of tumor invasion may be difficult. In addition to the problem caused by lack of discrete tissue boundaries, inflammatory changes in the bile ducts and desmoplastic stromal response to tumor may cause distortion. To overcome these difficulties, it has been proposed that the pathologist should measure the depth of invasion of tumor from the basal lamina of normal epithelium to the point of deepest tumor invasion.13 However, this system has not yet been widely adopted for staging purposes.According to the American Joint Committee on Cancer/International Union Against Cancer convention, vessel invasion (lymphatic or venous) does not affect the T category indicating local extent of tumor unless specifically included in the definition of a T category.The regional nodes for perihilar bile duct carcinomas are hilar nodes along the cystic duct, common bile duct, hepatic artery, and portal vein (N1) and periaortic, pericaval, superior mesentery artery, and/or celiac artery lymph nodes (N2).Tumor involvement of other nodal groups is considered distant metastasis. Anatomic division of regional lymph nodes is not necessary, but separately submitted lymph nodes should be reported as submitted.Routine assessment of regional lymph nodes is limited to conventional pathologic techniques (gross assessment and histologic examination), and data are currently insufficient to recommend special measures to detect micrometastasis or isolated tumor cells. Thus, neither multiple levels of paraffin blocks nor the use of special/ancillary techniques, such as immunohistochemistry, are recommended for routine examination of regional lymph nodes.Stage GroupingsChronic inflammatory conditions affecting the bile ducts are associated with higher risk for biliary tract carcinomas. The most common risk factor for cholangiocarcinoma of the extrahepatic bile ducts in Western countries is PSC, characterized by multifocal strictures and inflammation of the extrahepatic and intrahepatic biliary tree. Patients with PSC are at risk for multifocal biliary carcinomas. In Japan and Southeast Asia, hepatolithiasis due to recurrent pyogenic cholangitis with biliary stones is a more common risk factor for biliary malignancy. Biliary parasites such as Clonorchis sinensis and Opisthorchis viverrini, prevalent in parts of Asia, are also associated with carcinomas of the extrahepatic bile ducts.The authors have no relevant financial interest in the products or companies described in this article.

Two hundred and eighty-six patients presenting with metastatic adenocarcinoma or undifferentiated carcinoma whose primary site was not identified by clinical history, physical examination and chest radiograph have been studied. Median survival from presentation was 22 weeks. Factors independently predicting improved survival were lymph node presentations, good performance status and body weight loss of less than 10 per cent. In 88 (31 per cent) patients the primary tumour site was subsequently identified, in 58 (20 per cent) during life. Lung cancer was the most frequently identified primary tumour, and in only 32 (11 per cent) of the patients was a 'treatable' primary tumour (i.e. germ cell, breast, ovarian, prostate, thyroid cancer or lymphoma) identified. Among the treatable primary tumours were those in eight out of 16 female patients presenting with axillary metastases who were subsequently shown to have primary breast cancer and four of 13 females presenting with ascites who were found to have primary ovarian cancer. Prostatic cancer was confirmed in five out of 13 men with raised serum acid phosphatase. Of 22 patients with elevated serum alphafoetoprotein (AFP) or beta-human chorionic gonadotrophin levels (beta HCG) 18 had some features of the 'atypical teratoma syndrome'. Of the total of 32 patients with treatable tumour types, 29 (90 per cent) were identified during life. Median survival for patients with treatable tumour types identified during life was 104 weeks, compared with 22 weeks for the group as a whole. Retrospective immunocytochemical staining of the original biopsy showed that prostatic specific antigen and antibodies to beta HCG and AFP were diagnostically useful, but a series of organ site non-specific markers of histogenesis or cellular differentiation (carcinoembryonic antigen, secretory component for IgA, peanut lectin binding, epithelial membrane antigen and keratin) showed no significant correlations with identified primary sites, responsiveness to empirical chemotherapy or survival. Metastatic undifferentiated carcinoma or adenocarcinoma from an unknown primary site represents 6.5 per cent of all referrals to the medical oncology unit, Royal Prince Alfred Hospital, Sydney. We offer guidelines for the rapid identification of the limited number of primary sites for which effective and specific forms of systemic treatment are available.

Undifferentiated gastric carcinoma is a rare histopathological type of cancer that does not show any differentiation toward adenocarcinoma or squamous cell carcinoma. It is thought to be highly malignant, and is associated with a poor prognosis. However, its clinical behavior has not yet been fully analyzed because of its rarity. We herein review the clinical characteristics and prognoses of patients with undifferentiated gastric carcinoma treated at our institutions. Among 2,651 gastric cancer patients, four (0.2 %) were histopathologically diagnosed to have undifferentiated carcinoma. These four patients included three males and one female. The median age of the patients was 60-year old (range 47-75). Three cases had distant metastases at diagnosis. One of these three cases was treated with chemotherapy alone, and the other two were treated with palliative gastrectomy and chemotherapy. The patient with no distant metastasis underwent curative gastrectomy and adjuvant chemotherapy. All patients died of cancer at a median of 5.4 (range 3.5-7.1) months after their diagnoses.

Undifferentiated carcinoma with osteoclast-like giant cells (UC−OGCs) of the pancreas is a rare neoplasm that accounts for less than 1% of all pancreatic malignancies. The aim of this study was to review the literature regarding UC−OGC, and to highlight its biological behavior, clinicopathologic characteristics, prognosis, and therapeutic options. A systematic review of the literature in PubMed/Medline and Scopus databases was performed (last search October 31st, 2023) for articles concerning pancreatic UC−OGC in the adult population. Fifty-seven studies met the inclusion criteria, involving 69 patients with a male-to-female ratio of 1.1:1 and a mean age of 62.96. Main symptoms included abdominal pain (33.3%), jaundice (14.5%), weight loss (8.7%), while fourteen patients (20.3%) were asymptomatic. Surgical resection was performed in 88.4% of cases. Survival rates at one, three, and five years were 58%, 44.7%, and 37.3% respectively. Sex, age, size (cut-off of 4 cm), location, and adjuvant treatment did not significantly affect patient survival. UC−OGC of the pancreas is a rare subtype of undifferentiated pancreatic carcinoma with a better prognosis than conventional pancreatic ductal adenocarcinoma or undifferentiated carcinoma without giant cells. The establishment of a dedicated patient registry is imperative to further delineate the optimal treatment for this uncommon clinical entity.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

Undifferentiated pancreatic carcinoma with osteoclast-like giant cells: Report of a case with osteochondroid differentiation

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.The protocol applies to all carcinomas arising in the colon and rectum.1The colon is divided into 4 parts: the right (ascending), the middle (transverse), the left (descending), and the sigmoid. The right colon is subdivided into the cecum (peritoneally located and measuring about 6 × 9 cm) and the ascending colon (located retroperitoneally and measuring 15 to 20 cm long). The descending colon, also located retroperitoneally, is 10 to 15 cm in length. The descending colon becomes the sigmoid colon at the origin of the mesosigmoid, and the sigmoid colon becomes the rectum at the termination of the mesosigmoid. The upper third of the rectosigmoid segment is covered by peritoneum on the front and both sides. The middle third is covered by peritoneum only on the anterior surface. The lower third (also known as the rectum or rectal ampulla) has no peritoneal covering.1Tumors located at the border between 2 subsites of the colon (eg, cecum and ascending colon) are registered as tumors of the subsite that is more involved. If 2 subsites are involved to the same extent, the tumor is classified as an "overlapping" lesion. The rectum is defined clinically as the distal large intestine, which commences opposite the sacral promontory and ends at the upper border of the anal canal. When measuring below with a rigid sigmoidoscope, it extends 16 cm from the anal verge. A tumor is classified as rectal if its inferior margin lies less than 16 cm from the anal verge or if any part of the tumor is located at least partly within the supply of the superior rectal artery.2 A tumor is classified as rectosigmoid when differentiation between rectum and sigmoid, according to these guidelines, is not possible.3For consistency in reporting, the histologic classification proposed by the World Health Organization is recommended.4 However, this protocol does not preclude the use of other systems of classification or histologic types.World Health Organization Classification of Colorectal CarcinomaAdenocarcinoma in situ/severe dysplasia*Adenocarcinoma[Medullary carcinoma]†Mucinous (colloid) adenocarcinoma (>50% mucinous)‡Signet-ring cell carcinoma (>50% signet-ring cells)§Squamous cell (epidermoid) carcinomaAdenosquamous carcinomaSmall cell (oat cell) carcinoma§Undifferentiated carcinoma§Other (specify)∥* To avoid confusion with the term carcinoma in situ as it applies to pTis in the TNM staging (see note F), the term intraepithelial carcinoma should be used to refer to histologically malignant epithelium that does not penetrate the basement membrane (ie, shows no evidence of stromal [lamina propria] invasion).5,6† Medullary carcinoma has been added to the revised World Health Organization histologic classification that will be published in 2000. Medullary carcinoma is a histologic type that is strongly associated with a high degree of microsatellite instability (MSI-H) indicative of loss of normal DNA repair gene function.6–8 With loss of function of any of the genes involved in the repair of mitosis-associated mistakes in DNA synthesis (ie, replication errors), mutations in daughter cells are rapidly accumulated. Ultimately, tumors with defective DNA repair acquire inactivating mutations of genes necessary for complex biological activities such as metastasis. For this reason, tumors with MSI-H, such as most (if not all) medullary carcinomas, have a favorable prognosis compared with microsatellite stable tumors or tumors with low levels of microsatellite instability. Medullary carcinoma may occur either sporadically7 or in association with the hereditary nonpolyposis colon cancer syndrome.8 This tumor type is characterized by uniform polygonal tumor cells that exhibit solid growth in nested, organoid, or trabecular patterns and that only focally produce small amounts of mucin. In addition, medullary carcinomas are typically infiltrated by lymphocytes (tumor-infiltrating lymphocytes) and have no immunohistochemical evidence of neuroendocrine differentiation.‡ In most previous studies on prognostic factors in colorectal cancer, the impact of genetic status (ie, loss of DNA repair gene function with microsatellite instability) on the relationship between histologic type and outcome has not been considered. This shortfall is particularly relevant to mucinous carcinoma, a histologic type that is common among tumors with MSI-H. Overall, most mucinous carcinomas are microsatellite stable. Thus, it is not surprising that the prognostic significance of mucinous carcinoma has proven controversial.6,9 A few studies, largely limited to univariate analyses, have indicated that mucinous adenocarcinoma may be an adverse prognostic factor. Alternatively, mucinous carcinoma has been linked with adverse outcome only when occurring in specific anatomic regions of the bowel (eg, the rectosigmoid) or in a specific subset of patients (ie, those younger than 45 years). In yet other studies, mucinous carcinoma has been linked to adverse outcome only when mucinous and signet-ring cell carcinomas have been grouped together and compared with typical adenocarcinoma. Data of this type may merely reflect the aggressive biological behavior of most signet-ring cell tumors. Only one multivariate analysis has shown mucinous carcinoma to be a stage-independent predictor of adverse outcome, but the study was limited to tumors presenting with large bowel obstruction, which itself is an adverse prognostic factor.9§ By convention, signet-ring cell carcinomas, small cell carcinomas, and undifferentiated (histologic type) carcinomas are high grade. The only histologic types of colorectal carcinoma that have been shown to have adverse prognostic significance independent of stage are signet-ring cell carcinoma and small cell carcinoma.9 Nevertheless, signet-ring cell carcinoma may occur in hereditary nonpolyposis colon cancer syndrome in association with MSI-H.10 Thus, in cases of MSI-H signet-ring cell carcinoma, the prognostic significance may be determined by the molecular pathogenesis and may be favorable.∥ The term carcinoma, NOS (not otherwise specified) is not part of the World Health Organization classification.A number of grading systems have been suggested in the literature, but a single widely accepted and uniformly used standard for grading is lacking. Among the suggested grading schemes, the number of grades and the criteria for distinguishing among different grades vary markedly. In some systems, grades are defined on the basis of a single microscopic feature, such as the degree of gland formation, and in other systems, a large number of features are included in the evaluation. Irrespective of the complexity of the criteria, however, most systems stratify tumors into 3 or 4 grades as follows:Grade 1 Well differentiatedGrade 2 Moderately differentiatedGrade 3 Poorly differentiatedGrade 4 UndifferentiatedAppearance of individual histologic features may vary widely enough to make implementation of even the simplest grading systems problematic and, ultimately, subjective. Thus, a significant degree of interobserver variability in the grading of colorectal cancer has been shown to exist.9,11 Nevertheless, despite this variability, histologic grade has repeatedly been shown by multivariate analysis to be a stage-independent prognostic factor.9,12,13 Specifically, it has been demonstrated that high tumor grade is an adverse prognostic factor. In most studies documenting the prognostic power of tumor grade,9 the number of grades has been collapsed to produce a 2-tiered stratification for data analysis as follows:Low grade Well differentiated and moderately differentiatedHigh grade Poorly differentiated and undifferentiatedIn general practice, a 2-tiered grading system would also be expected to greatly reduce interobserver variability, since the widest variations in grading concern the stratification of low-grade tumors into well- or moderately differentiated categories. Pathologic identification of poorly differentiated or undifferentiated tumors is more consistent, and interobserver variability in diagnosing high-grade carcinoma is relatively small. Therefore, in light of its proven prognostic value, relative simplicity, and reproducibility, a 2-tiered grading system for colorectal carcinoma (ie, low grade and high grade) is recommended.6 The grading should be based on gland formation alone as follows6:Low grade ≥50% gland formationHigh grade <50% gland formationColorectal adenomas containing invasive adenocarcinoma that extends through the muscularis mucosae into the submucosa have been defined as malignant polyps. These polyps constitute a form of early (ie, curable) colorectal carcinoma. The definition of malignant polyps excludes adenomas containing in situ carcinoma (also known as intraepithelial carcinoma) and carcinoma either limited to the lamina propria of the polyp mucosa or invading no deeper than the muscularis mucosae (intramucosal carcinoma), because these polyps possess no biological potential for metastasis. The term malignant polyp encompasses both polypoid carcinomas in which the entire polyp head is replaced by carcinoma and adenomas with focal malignancy.Malignant polyps removed by endoscopic polypectomy require evaluation of histologic parameters that have been determined to be significant prognostic factors related to the risk of adverse outcome (ie, lymph node metastasis or local recurrence from residual malignancy) following polypectomy.9,14–30 Pathologic features that have been shown to have independent prognostic significance and are crucial for evaluating risk and determining the possible need for further surgical treatment (ie, segmental colectomy) include the following: histologic grade of the carcinoma, extent (level) of invasion of the carcinoma within the polyp, status of the resection margin, and lymphatic/venous vessel involvement.Specifically, an increased risk of adverse outcome has been shown to be associated with high-grade (poorly differentiated) carcinoma, tumor at or less than 1 mm from the resection margin, and presence of lymphatic/venous vessel involvement.Configurations include exophytic (fungating), endophytic (ulcerative), and diffusely infiltrative (linitis plastica) or annular, but overlap among these types is common. Exophytic is divided into pedunculated and sessile. Overall, gross tumor configuration has no independent influence on prognosis.6,9 The uncommon linitis plastica type represents a possible exception. It has an unfavorable prognosis, but its association with adverse outcome is probably related to the underlying histologic type of tumor (signet-ring cell carcinoma) rather than the macroscopic configuration itself.Surgical resection remains the most effective therapy for colorectal carcinoma, and the best estimation of prognosis is related to the pathologic findings on the resection specimen. The anatomic extent of disease is by far the most important prognostic factor.12The protocol recommends the TNM staging system of the AJCC/UICC1,31 but does not preclude the use of other staging systems.Tumor (T)*TX Primary tumor cannot be assessedTO No evidence of primary tumorTis Carcinoma in situ, intraepithelial or invasion of the lamina propria or muscularis mucosae†T1 Tumor invades the submucosaT2 Tumor invades the muscularis propriaT3 Tumor invades through the muscularis propria into the subserosa or into the nonperitonealized pericolic or perirectal tissues‡pT3a Minimal invasion: <1 mm beyond the border of the muscularis propriapT3b Slight invasion: 1 to 5 mm beyond the border of the muscularis propriapT3c Moderate invasion: >5 to 15 mm beyond the border of the muscularis propriapT3d Extensive invasion: >15 mm beyond the border of the muscularis propriaT4 Tumor directly invades other organs or structures§ (T4a) or perforates the visceral peritoneum∥ (T4b)* The designation T refers to the first resection of a primary tumor. The symbol pT refers to the pathologic classification of the TNM as opposed to the clinical classification. Pathologic classification is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy sample adequate to evaluate the highest pT category; pN entails removal of nodes adequate to validate lymph node metastasis; and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually performed by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible and is typically based on information obtained by physical examination, serologic analyses, imaging studies, etc.1Tumor remaining in a patient after primary therapy (eg, surgical resection) is categorized by a system known as R classification.1,6,12 For example, this classification may be used by the surgeon to indicate the known or assumed status of the completeness of the surgical resection. For the pathologist, the R classification is relevant only to the margins of surgical resection specimens. That is, tumor involving the proximal, distal, or radial (circumferential) resection margin (see note K) on pathologic examination may be assumed to correspond to residual tumor in patient and classified as to whether the involvement is macroscopic or microscopic.6RX Presence of residual tumor cannot be assessedR0 No residual tumorR1 Microscopic residual tumorR2 Macroscopic residual tumorTumor remaining in a resection specimen following previous (neoadjuvant) treatment of any type (radiation therapy alone, chemotherapy therapy alone, or any combined modality treatment) is codified by the TNM using a prescript "y" to indicate the posttreatment status of the tumor (eg, ypT1).1,6 For many therapies, the classification of residual disease has been shown to be a strong predictor of postoperative outcome. In addition, the ypTNM classification provides a standardized framework for the collection of data needed to accurately evaluate new neoadjuvant therapies.Tumor that is locally recurrent after a documented disease-free interval following surgical resection is classified according to the TNM categories but modified with the prefix "r" (eg, rpT1). By convention, the recurrent tumor is topographically assigned to the proximal segment of the anastomosis unless that segment is small intestine.1,3† For colorectal carcinomas, carcinoma in situ (Tis) as a staging term includes cancer cells confined within the glandular basement membrane (intraepithelial carcinoma) or invasive into the mucosal lamina propria, up to but not through the muscularis mucosae (intramucosal carcinoma). This may be confusing because, in all other organ systems, the term carcinoma in situ is used to refer exclusively to malignant neoplasms that do not invade the underlying stroma. Therefore, for colorectal cancer, the terms intraepithelial carcinoma and intramucosal carcinoma are recommended as descriptive terms to subclassify pTis and to clarify the status of the tumor.5,6 Tumor extension through the muscularis mucosae into the submucosa is classified as T1. Some pathologists classify intraepithelial carcinoma as severe or high-grade dysplasia, especially in cases of inflammatory bowel disease.‡ The extent of perimuscular invasion has been reported to influence prognosis, regardless of whether regional lymph node metastasis is present. Thus, an optional expansion pT3 has been proposed.3 Extramural extension greater than 5 mm has been shown to be the critical subdivision associated with adverse outcome in most studies. Thus, a simpler subdivision, based on extension of 5 mm or less versus greater than 5 mm (ie, pT3a,b vs pT3c,d), may be justified.3 Extension of the tumor within lymphatics or veins does not count as local spread of tumor as defined by the T classification.3§ Direct invasion of other organs or structures includes invasion of other segments of colorectum by way of the serosa or mesocolon, for example, invasion of the sigmoid colon by carcinoma of the cecum. Intramural extension of tumor from one subsite (segment) of the large intestine into an adjacent subsite or into the ileum (eg, for a cecal carcinoma) or anal canal (eg, for a rectal carcinoma) does not affect the pT classification.3∥ Perforation of carcinoma through a peritonealized surface of the colon is classified as T4b.3 Subdivision of T4 into T4a and b is justified, because a number of large studies that have evaluated serosal penetration as an independent prognostic variable have demonstrated by multivariate analysis that it has a strong negative impact on prognosis.32–35 Specifically, it has been shown that the frequency of distant metastasis is higher in cases with perforation of the visceral peritoneum compared with cases with direct invasion of adjacent organs or structures without perforation of the visceral peritoneum (occurring in about 50% and 30% of cases, respectively).3 Furthermore, the median survival time following surgical resection for cure has been shown to be shorter for patients with pT4b tumors compared with those with pT4a tumors (with or without distant metastasis) as follows.3A study by Shepherd et al34 has suggested that the prognostic power of local peritoneal involvement in curative resections may supersede that of either local extent of tumor (T category) or regional lymph node status (N category). However, serosal penetration is often difficult to assess histopathologically and may be underdiagnosed. Documentation of peritoneal involvement by tumor demands meticulous pathologic analysis and may require extensive sampling and/or serial sectioning and can be missed on routine histopathologic examination. It has been shown that cytologic examination of serosal scrapings reveals malignant cells in as many as 26% of tumor specimens categorized as pT3 by histologic examination alone.34,36 In addition, the histopathologic findings associated with peritoneal penetration are heterogeneous, and standard guidelines for their diagnostic interpretation are lacking. Therefore, interobserver variability in the diagnosis of peritoneal penetration may be substantial, and since most pathologists tend to err on the side of conservative interpretation, underdiagnosis is likely for this reason as well.Shepherd et al34 analyzed the spectrum of microscopic features that may be seen with local peritoneal involvement by tumor and defined 3 types of local peritoneal involvement as follows:(1) A mesothelial inflammatory and/or hyperplastic reaction with tumor close to, but not at, the serosal surface(2) Tumor present at the serosal surface with inflammatory reaction, mesothelial hyperplasia, and/or erosion/ulceration(3) Free tumor cells on the serosal surface (in the peritoneum) with underlying of the visceral 3 types of local peritoneal involvement associated with tumor of the serosal no independent adverse on Therefore, the diagnosis of should these 3 types of serosal lymph nodes cannot be No regional lymph node in 1 to 3 lymph in 4 or more lymph The regional lymph nodes for the anatomic subsites of the large intestine are as right right middle right left inferior inferior superior rectal sigmoid left sigmoid inferior superior middle sigmoid inferior sacral superior middle inferior the sigmoid are pericolic and their involvement is classified as or according to the number lymph nodes include the sacral promontory middle rectal and inferior rectal in the or common nodes is classified as distant on of for Microscopic negative or lymph nodes are to be lymph nodes may be for microscopic of has been shown that negative lymph nodes for regional node Therefore, if than nodes are (ie, should be considered. If than nodes are after the use of this should be in the The should state the number of lymph nodes and the number involved by Data are to routine use of levels or microscopic examination of lymph nodes in large resection lymph nodes must be as regional versus according to the anatomic of the tumor. to lymph nodes is classified as distant metastasis and as by tumor greater than 3 mm in in the perirectal or without histologic evidence of residual lymph node in the is classified as regional node metastasis. However, a tumor less than or to 3 mm in is classified in the T as extension (ie, seen only in the should be as metastasis in a single lymph node for of regional lymph node metastasis is limited to the use of pathologic and histologic A of tumor in a single lymph node that is by routine histologic examination and mm or less may be defined as a The biological significance of disease single in a single within a single or involvement of as yet is studies, it is recommended that be classified as but reported with a note that the biological significance is The number of lymph nodes involved by should be biological significance of metastasis only by studies (eg, immunohistochemical or molecular is also at present. It is recommended that metastasis using studies alone also be reported with a note the significance of the findings in to histologically be classified as the data are to either the routine examination of levels of or the use of such as for and/or (eg, or reaction to tumor and Presence of distant metastasis cannot be No distant of organs is classified as studies, both invasion and invasion have been shown by multivariate analysis to be independent of The prognostic if of the anatomic of these structures is not Furthermore, it is not possible to from since both are Thus, the presence or of tumor invasion of should be reported in all cases and its anatomic within the invasion has been demonstrated by multivariate analysis to be an independent adverse prognostic of in has been shown to be an independent of unfavorable outcome and increased risk of of It has been shown that the of 5 or more of tumor the of invasion when it and to sampling significance of invasion is less because data specific to this are lacking. Nevertheless, it is recommended that the presence or of invasion and its anatomic should be reported in all reaction at the of invasive tumor and the presence of in the and or perirectal have both been shown in small studies to be independent favorable prognostic are associated with microsatellite instability and medullary and should be from Only and lymphocytes 4 or more should be of is If should be made between and growth of the tumor at the has been shown to have prognostic significance independent of stage and may Specifically, an of growth at the tumor border as opposed to a border is an adverse prognostic have been defined as of growth at the tumor has also been to as focal and tumor and defined as microscopic of undifferentiated cancer cells of the invasive front of the may be to the to the tumor with by should be in the macroscopic include the proximal, distal, and radial The radial margin represents the margin to the penetration of tumor. For all segments of the large intestine that are either colon, descending colon, sigmoid colon, upper or not by the radial margin is by of the or at radial margin has been demonstrated to be of in to risk of local recurrence after surgical resection of the rectal analysis has suggested that tumor involvement of the radial margin is the most critical in local recurrence in rectal For this reason, routine of the radial margin is suggested in all colorectal and of the from the tumor to the radial margin, the surgical the tumor is For segments of the colon that are by a peritonealized surface (eg, the only radial margin is the resection margin, and it is relevant when the of penetration of the tumor is on the of the colon and extends to this margin, with or without the serosal surface. For those tumors limited to an peritonealized of the the radial margin is not of its association with local involvement of the radial margin has for the primary tumor is serosal or (with serosal resection is only if all surgical margins are the radial That is, whether or not the tumor a serosal resection is if the resection margins distal, and do not tumor. If a radial margin is involved by therapy (eg, local may be to evaluate the proximal and distal resection margins can be obtained in 2 to the margin or to the on the of the tumor to the margin, the that best the status of the The from the tumor to the resection should be In cases of carcinoma arising in a of inflammatory bowel proximal and distal resection margins should be evaluated for and

Pancreatic cancer is an intractable malignancy associated with a dismal prognosis. Undifferentiated carcinoma, a rare subtype, poses a clinical challenge owing to a limited understanding of its molecular characteristics. In this study, we conducted genomic analysis specifically on a caseof undifferentiated carcinoma of the pancreas exhibiting squamous differentiation. An 80-year-old male, previously treated for colorectal cancer, presented with a mass with central cystic degeneration in the pancreatic tail. The mass was diagnosed pathologically as undifferentiated carcinoma of the pancreas with squamous differentiation.Despite surgical resection and chemotherapy, the patient faced early postoperative recurrence, emphasizing the aggressive nature of this malignancy. Genomic analysis of distinct histologic components revealed some common mutations between undifferentiated and squamous components, including Kirsten rat sarcoma virus (KRAS) and TP53. Notably, the squamous component harbored some specific mutations in SMARCA4 and SMARCB1 genes that code for members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. The common mutations in the undifferentiated and squamous cell carcinoma components from this analysis suggest that they originate from a common origin. The discussion also underscores the scarcity of genomic analyses on undifferentiated carcinoma of the pancreas, with existing literature pointing to SWI/SNF complex-related gene mutations. However, our case introduces chromatin remodeling factor mutations as relevant in squamous differentiation. In conclusion, this study provides valuable insights into the genomic landscape of undifferentiated pancreatic carcinoma with squamous differentiation. These findings suggest the importance of further research and targeted therapies to improve the management of undifferentiated carcinoma of the pancreas and enhance patient outcomes.

Making use of a new histologic classification developed by the World Health Organization, we reviewed 177 US and 30 foreign cases of nasopharyngeal carcinoma (NPC). Tumors of US whites included undifferentiated, squamous cell, and non-keratinizing carcinomas, while US blacks had undifferentiated carcinomas only. There were no significant histological differences between the tumors from US- and foreign-born patients. White male subjects from the United States had a braod age distribution, with a peak in the 60- to 69-year range. Black subjects from the United States, on the other hand, had a prominent incidence peak in the 10- to 19-year age range. These pathologic and age-related differences may provide clues as to those factors involved in the cause and pathogenesis of NPC.

Current classifications of lung cancer are based upon the morphologic patterns and cytologic features of the tumors, and the degree of cell differentiation can in addition be used in histologic grading. The four main categories recognized in most classifications, including the recent (1977) revision [1] of the 1967 World Health Organization nomenclature [2], are squamous carcinoma, adenocarcinoma, undifferentiated large cell carcinoma and undifferentiated small cell carcinoma. The better differentiated squamous and adenocarcinomas can be recognized by the pathologist with little difficulty when acceptable material for light microscopy is available. In contrast, poorly differentiated and undifferentiated tumors are open to the subjective impression of the examiner and may be designated by a variety of makeshift terms such as unclassified malignant neoplasm and anaplastic carcinoma reflecting frustration with neoplasms that do not demonstrate distinct cyto-morphologic features. The degree of distortion that is often present in small biopsies is undoubtedly a major contributing factor to this lack of specificity in the labelling of lung tumors, but criteria for identifying the poorly differentiated and undifferentiated carcinomas are not well defined, and it is hardly surprising that problems constantly arise in the evaluation of small, distorted biopsies. Imprecise designations appear in pathology reports of lung neoplasms with a degree of frequency that significantly impairs the accuracy of clinico-pathologic studies, yet the pathologist who honestly attempts to append a more specific label to as many tumors as possible is likely to find that colleagues reviewing the cases will produce varying interpretations.

Undifferentiated carcinoma of the gallbladder is a rare cancer type with a poor prognosis. The present study described a case of undifferentiated gallbladder carcinoma of the spindle- and giant-cell type, according to the 2010 World Health Organization classification. Hematoxylin and eosin staining revealed that the tumor consisted of dense interlacing bundles of spindle-shaped cells. No evidence of cartilaginous, osseous or rhabdomyosarcomatous differentiation was observed. Immunohistochemical staining revealed that spindle- and polygonal-shaped cells of the undifferentiated carcinoma were positive for cytokeratin AE1/3, vimentin and vascular endothelial growth factor. Furthermore, numerous spindle-shaped cells were positive for cluster of differentiation (CD)34 and CD31, and certain spindle-shaped cells were positive for Factor VIII. These results suggested classification of the present case as 'undifferentiated gallbladder carcinoma with endothelial differentiation'.

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow these authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol owing to the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.Evaluation of adequacy should be based on correlation with clinical history, quality and quantity of material aspirated, and quality of smears. Most malignant tumors, other than follicular carcinomas, can be recognized on fine-needle aspirate if adequately sampled. Guidelines for fine-needle aspiration of the thyroid have been published.1The World Health Organization Histologic Classification of Carcinoma of the Thyroid is recommended by the protocol and is as follows.23The diagnosis of follicular carcinoma or H;auurthle cell carcinoma depends on the identification of capsular and/or blood vessel invasion. Blood vessels should be of venous caliber and be located outside the tumor, within or immediately outside the capsule. Encapsulated follicular tumors with vascular invasion have potential for metastasis.4 Tumor cells should be attached to the vessel wall and protrude into the lumen. Encapsulated follicular tumors with invasion of the capsule may have potential for metastasis, although this is still controversial.“Minimally invasive” follicular carcinoma refers to lesions with no vascular invasion. “Angioaggressive” follicular carcinoma refers to those tumors in which vascular invasion is identified. “Widely invasive” follicular and H;auurthle cell carcinomas are those tumors with grossly apparent invasion of thyroid and/or soft tissue.According to the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), staging of thyroid cancer depends primarily on the histologic type.5 Thus, there are specific TNM stage groupings for papillary and follicular carcinomas that are stratified by age, and there are separate stage groupings not stratified by age for medullary carcinomas and undifferentiated carcinomas. H;auurthle cell tumors are staged the same as follicular carcinomas. Undifferentiated or anaplastic carcinomas are always assigned stage IV. Age is not a prognostically important consideration for medullary or undifferentiated carcinomas. Tumor size and lymph node status are also considered in the TNM classification. With multifocal tumors, the largest one is used for classification. The lymph nodes must be specifically identified to classify regional node involvement.* By AJCC/UICC convention, the designation “T” of the TNM classification refers exclusively to the first resection of a primary tumor. The prefix symbol “p” refers to the pathologic classification of the TNM (pTNM), as opposed to the clinical classification. Pathologic classification is based on gross and microscopic examination. Therefore, pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category; pN entails removal of nodes adequate to validate lymph node metastasis; and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.The absence or presence of residual tumor following preoperative nonsurgical therapy (eg, chemotherapy or radiation treatment) may be described by the symbol “R” and is classified as follows:If residual tumor is present, its extent may be documented by the TNM classification preceded by the symbol “y” (eg, ypT1). Local recurrence following a previous resection should be classified with the prefix “r” (eg, rpT1).For medullary carcinomas, the stage of disease and postsurgical serum calcitonin levels are the most useful prognostic factors.3Contributors: the College of American Pathologists Cancer Committee; Virginia A. Livolsi, MD; Michael Cibull, MD; Edward Paloyan, MD; and Henry Travers, MD.

By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD). Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients. All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward. Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.

We report a Chinese patient who presented with metastatic undifferentiated carcinoma in the cervical lymph node of unknown primary origin. Despite a raised IgA titre against Epstein-Barr virus capsid antigen, examination and biopsy of the nasopharynx were negative. Radiotherapy was given to the head and neck region with the orbit shielded. There was complete resolution of the metastatic lymph nodes. She developed proptosis of her left eye one year afterward when a large tumour was found in the lacrimal sac region. Review of the initial computerized tomography revealed a small soft tissue mass in the same region. The tumour was composed of undifferentiated carcinoma cells associated with dense lymphoid infiltrate. In situ hybridization for Epstein-Barr virus EBER RNA showed strong positive signals in the malignant cells. This is the first reported case of an Epstein-Barr virus positive undifferentiated carcinoma with lymphoid stroma in the lacrimal sac. In addition to the nasopharynx, salivary glands, nasal cavity and paranasal sinuses, the lacrimal sac should be considered as a potential primary site for Epstein-Barr virus positive metastatic undifferentiated carcinoma in the cervical lymph nodes.

Dedifferentiated endometrial carcinomas (DDECs)/undifferentiated endometrial carcinomas (UDECs) frequently harbour genomic activation of switch/sucrose non-fermentable (SWI/SNF)-complex proteins, and can show histological overlap with neuroendocrine carcinoma (NEC). The aim of this study was to compare the extent of the expression of neuroendocrine markers, SWI/SNF proteins and mismatch repair (MMR) proteins in DDEC/UDEC and NEC. The extent of expression of synaptophysin, chromogranin, CD56, ARID1A, ARID1B, SMARCA4, SMARCB1 and MMR proteins was evaluated by immunohistochemistry on 44 SWI/SNF-deficient DDECs/UDECs and 15 NECs. Thirty-three of 44 (75%) DDECs/UDECs showed expression of at least one neuroendocrine marker, with 18 of 44 (41%) expressing two or more neuroendocrine markers, whereas all 15 NECs showed expression of at least one neuroendocrine marker, with 14 of 15 (93%) expressing two or more neuroendocrine markers. Neuroendocrine marker expression in DDECs/UDECs was typically focal when present, with average extents of 17%, 4% and 8% for synaptophysin, chromogranin and CD56 in the positive cases, respectively, in contrast to 73%, 40% and 62% in the positive NEC cases, respectively. All 15 NECs showed intact expression of SWI/SNF-complex proteins, except for one that showed isolated loss of ARID1A. Thirty-eight of 44 DDECs/UDECs were MMR-abnormal (34 with loss of MLH1 and PMS2, and four with loss of PMS2 alone), whereas all NECs retained MMR protein expression. Our study demonstrates frequent but typically focal neuroendocrine marker expression in SWI/SNF-deficient DDECs/UDECs, whereas NECs typically express two or more neuroendocrine markers, with diffuse expression of at least one marker. ARID1B, SMARCA4 and SMARCB1 immunohistochemistry can be used to aid in the differentiation between DDEC/UDEC and NEC.