Mixed Carcinoma Research Articles

Digital mammography and digital breast tomosynthesis for detecting invasive lobular and ductal carcinoma.

Invasive lobular carcinoma (ILC) is a distinct histological subtype of breast cancer that can make early detection with mammography challenging. We compared imaging performance of digital breast tomosynthesis (DBT) to digital mammography (DM) for diagnoses of ILC, invasive ductal carcinoma (IDC), and invasive mixed carcinoma (IMC) in a screening population. We included screening exams (DM; n = 1,715,249 or DBT; n = 414,793) from 2011 to 2018 among 839,801 women in the Breast Cancer Surveillance Consortium. Examinations were followed for one year to ascertain incident ILC, IDC, or IMC. We measured cancer detection rate (CDR) and interval invasive cancer rate/1000 screening examinations for each histological subtype and stratified by breast density and modality. We calculated relative risk (RR) for DM vs. DBT using log-binomial models to adjust for the propensity of receiving DBT vs. DM. Unadjusted CDR per 1000 mammograms of ILC overall was 0.33 (95%CI: 0.30-0.36) for DM; 0.45 (95%CI: 0.39-0.52) for DBT, and for women with dense breasts- 0.33 (95%CI: 0.29-0.37) for DM and 0.54 (95%CI: 0.43-0.66) for DBT. Similar results were noted for IDC and IMC. Adjusted models showed a significantly increased RR for cancer detection with DBT compared to DM among women with dense breasts for all three histologies (RR; 95%CI: ILC 1.53; 1.09-2.14, IDC 1.21; 1.02-1.44, IMC 1.76; 1.30-2.38), but no significant increase among women with non-dense breasts. DBT was associated with higher CDR for ILC, IDC, and IMC for women with dense breasts. Early detection of ILC with DBT may improve outcomes for this distinct clinical entity.

Neuroendocrine prostate tumors: histologic features and therapy

Neuroendocrine (NE) tumors of the prostate are rare tumors, that can arise de novo but much more commonly occur after androgen deprivation therapy for prostate adenocarcinoma. NE tumors of the prostate are classified into: adenocarcinoma with NE differentiation, well-differentiated NE tumor/carcinoid, small-cell NE carcinoma, large cell NE carcinoma, adenocarcinoma with Paneth cell NE differentiation and mixed NE carcinoma—acinar adenocarcinoma. IHC plays a vital role and should be approached at two levels. For the issue of confirming NE differentiation, markers for NE differentiation include synaptophysin, chromogranin, and CD56. If there is any uncertainty about the histogenesis, that is, whether a tumor is primary to the prostate, markers for prostatic lineage—PSA, PSAP, PSMA, prostein (p501s), NKX3.1, ERG (by IHC or FISH)—may be used. Actually, platinum-based chemotherapy is commonly administered to patients with pure small cell carcinoma based on small cell lung cancer (SCLC) data and the accumulating data for aggressive variants of castration-resistant prostate cancer (AVPC). This may consist of a combination of carboplatin (or sometimes cisplatin) plus either etoposide (based on SCLC) or a taxane (especially if mixed histology or AVPC features). A combination regimen of cisplatin, etoposide, and doxorubicin has been also investigated but the benefit-risk ratio of the three-drug combination was considered unfavorable. Unfortunately, platinum-based chemotherapy often presents high toxicity and a short overall survival. Results of currently ongoing preclinical and clinical studies are expected to enhance our understanding of these tumors’ underlying biology and guide our efforts toward the development of personalized medicine through targeted diagnostic and therapeutic approaches.

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

Clinicopathologic features and prognostic significance of mixed (Low and high-grade) papillary urothelial carcinoma comparison with low and high-grade papillary urothelial carcinoma.

The World Health Organization/International Society of Urological Pathology (2022 WHO/ISUP) classification categorizes noninvasive carcinomas based on the highest grade observed in a pathology sample. According to this classification, a lesion is classified as mixed-grade (MG) if the highest-grade component comprises less than 5% high-grade (HG) carcinoma [14]. This study included 160 cases of low-grade papillary urothelial carcinoma (LGUC) and 160 cases of HG papillary urothelial carcinoma (HGUC), selected randomly. In addition, 160 consecutive and unselected cases of MG papillary urothelial carcinoma (MGUC) were obtained from all bladder transurethral resection specimens diagnosed with papillary urothelial carcinoma between January 2007 and January 2021. The results of the multivariate analysis showed that histologic grade, invasion of the lamina propria, and the presence of carcinoma in situ at presentation were independent prognostic parameters regarding recurrence-free survival (p = 0.002; hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.059-1.956, p = 0.02; and HR = 1.76, 95% CI = 1.159-2.684, p = 0.008, respectively). Histologic grade was the only independent prognostic parameter of disease-specific survival (DSS) (p < 0.001). Comparisons between non-muscle invasive (NMI) MGUC and NMI LGUC, as well as between NMI MGUC and NMI HGUC, revealed statistically significant differences in terms of DSS (HR = 0.07, 95% CI = 0.024-0.252,p< 0.001 and HR = 1.59, 95% CI = 1.023-2.460, p = 0.039, respectively). Our study findings demonstrate statistically significant differences regarding DSS between NMI MGUC and NMI HGUC, as well as between NMI MGUC and NMI LGUC. Therefore, we suggested that considering the presence of less than 5% MGUC as a separate category may be appropriate. However, it is important to validate our results in larger cohorts with longer follow-up periods to establish the clinical significance of MGUC and provide guidance for patient management.

Mixed clear cell/endometrioid and clear cell/serous carcinoma of the uterus are clinicopathologically similar to pure clear cell carcinoma: An NRG Oncology/Gynecologic Oncology Group (GOG-210) study of 311 women

ObjectivesClear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. MethodsThe term “mixed” was applied to tumors with multiple identifiable components, and “indeterminate” was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. ResultsOne hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. ConclusionIn clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

High expression of insulinoma-associated protein 1 (INSM1) distinguishes colorectal mixed and pure neuroendocrine carcinomas from conventional adenocarcinomas with diffuse expression of synaptophysin.

Complementary to synaptophysin and chromogranin A, insulinoma-associated protein 1 (INSM1) has emerged as a sensitive marker for the diagnosis of neuroendocrine neoplasms. Since there are no comparative data regarding INSM1 expression in conventional colorectal adenocarcinomas (CRCs) and colorectal mixed adenoneuroendocrine carcinomas/neuroendocrine carcinomas (MANECs/NECs), we examined INSM1 in a large cohort of conventional CRCs and MANECs/NECs. In conventional CRC, we put a special focus on conventional CRC with diffuse expression of synaptophysin, which carry the risk of being misinterpreted as a MANEC or a NEC. We investigated INSM1 according to the immunoreactive score in our main cohort of 1,033 conventional CRCs and 21 MANECs/NECs in comparison to the expression of synaptophysin and chromogranin A and correlated the results with clinicopathological parameters and patient survival. All MANECs/NECs expressed INSM1, usually showing high or moderate expression (57% high, 34% moderate, and 9% low), which distinguished them from conventional CRCs, which were usually INSM1 negative or low, even if they diffusely expressed synaptophysin. High expression of INSM1 was not observed in conventional CRCs. Chromogranin A was negative/low in most conventional CRCs (99%), but also in most MANECs/NECs (66%). Comparable results were observed in our independent validation cohorts of conventional CRC (n = 274) and MANEC/NEC (n = 19). Similar to synaptophysin, INSM1 expression had no prognostic relevance in conventional CRCs, while true MANEC/NEC showed a highly impaired survival in univariate and multivariate analyses (e.g. disease-specific survival: p < 0.001). MANECs/NECs are a highly aggressive variant of colorectal cancer, which must be reliably identified. High expression of INSM1 distinguishes MANEC/NEC from conventional CRCs with diffuse expression of the standard neuroendocrine marker synaptophysin, which do not share the same dismal prognosis. Therefore, high INSM1 expression is a highly specific/sensitive marker that is supportive for the diagnosis of true colorectal MANEC/NEC.

Clinical significance of the pathological type of tumor in common forms of ovarian cancer: A retrospective study

Background. Epithelial forms of ovarian cancer account for up to 90% of all ovarian malignancies. Epithelial forms of ovarian cancer are classified according to the WHO criteria of 2014 into several types: the most common are serous carcinomas (70%), mucinous carcinomas (3%), endometrioid tumors (10%), light cell cancer, transitional cell cancer, mixed and undifferentiated carcinomas are rare.&#x0D; Aim. To study the overall survival and progression-free survival depending on the stage of the disease, the pathological type of tumor and the degree of differentiation of tumor cells.&#x0D; Materials and methods. A retrospective analysis of the treatment of 467 patients with stage IIICIVB ovarian cancer in the Primorsky Regional Oncological Dispensary for the period from 2003 to 2021 was carried out. The obtained parameters were processed using standard statistical analysis methods using the IBM SPSS Statistics 26 program.&#x0D; Results. The overall results showed that the most favorable course of stage IIICIVB ovarian cancer has a serous type of ovarian cancer, probably due to its sensitivity to chemotherapy and aggressive surgical tactics. Patients with a mutation in the BRCA1/2 genes have a better prognosis in overall survival rates. BRCA1/2 mutations are associated with an improved response to chemotherapy with platinum-based drugs.&#x0D; Conclusion. The analysis made it possible to determine the most favorable prognostic factors for advanced stages of ovarian cancer, when comparing the groups of high-grade and low-grade IIIIV stage serous carcinoma, it was noted that the median overall survival, depending on the histological type, is better in the group of patients with low-grade IIIIV stage serous carcinoma. When comparing, depending on the timing of the operation performed, it can be noted that the median overall survival and median progression-free survival rates are better in the group of patients who received primary cytoreductive surgery.

Cytomorphologic, immunophenotypical and molecular features of pancreatic acinar cell carcinoma.

As a rare tumor in pancreas, pancreatic acinar cell carcinoma (PACC) possesses a distinct molecular feature from pancreatic ductal carcinoma (PDAC). Though the diagnosis of PACC is often established based on cytology specimens, its cytologic diagnosis can be challenging. Furthermore, the correlation between PACC cytomorphology and its unique different molecular alterations have not been fully explored. Cytology features were analyzed in 8 histologically proven PACC and cytohistological correlation was performed. Immunocytochemistry for trypsin, chymotrypsin, BCL10, synaptophysin, chromogranin A, INSM1, β-catenin, and Ki-67 was assessed. Comprehensive molecular profiling and additional targetable treatment biomarker assessment were also performed. The cohort included 4 mixed acinar-neuroendocrine carcinomas, 3 pure PACCs, and 1 mixed acinar-ductal carcinoma. Immunophenotypical features are consistent with diagnoses of PACC or PACC with neuroendocrine features. Identified genetic alterations included somatic mutations of CTNNB1, TP53, MAP2K1, PTEN, RAC1, germline mutations of NBN and BRAC2, and gene fusion of CCDC6-RET. The current study is the first attempt to explore the correlation between the cytomorphology characteristics and molecular features of PACC and a few intriguing findings were observed. Further validation in larger cohorts is warranted.

Mixed acinar-neuroendocrine carcinoma of the pancreas with positive for microsatellite instability: a case report and review of the literature

BackgroundMixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas is a rare tumor. We report a case of successful surgical resection of expansively growing MANEC of the pancreas with microsatellite instability (MSI)-high.Case presentationThe patient was an asymptomatic 65-year-old male. A computed tomography (CT) scan for a follow-up after treatment of pneumonia incidentally revealed a hypoenhancing 12-cm expansively growing tumor in the pancreatic body. An endoscopic ultrasound-guided fine-needle aspiration of the tumor suggested the diagnosis of MANEC. We performed distal pancreatectomy with combined resection of the spleen, left adrenal gland, transverse colon, small bowel, and stomach. The intraoperative findings showed that the tumor was capsular and was in contact with the SMA, SMV, and CA; however, obvious infiltration of these vessels was not observed..Pathological findings indicated MANEC with MSI-high. Among mismatch repair (MMR) gene proteins, PMS2 was lost and MLH1, MSH2, and MSH6 were retained. The tumor recurred 5 months after surgery. The patient was treated with gemcitabine plus nab-paclitaxel followed by pembrolizumab, which did not show objective response.DiscussionThis is the first report investigating MSI and MMR in MANEC. Standard chemotherapy has not been established for MANEC. Detection of MSI-high is essential since PD-1 monoclonal antibodies for MSI-high cases might be one of the good treatment options. Herein, we discuss the various cytomorphologic and clinical features of MANEC and present a brief review of the literatures.ConclusionsThe accumulation of data from additional cases is necessary to further evaluate this type of carcinoma and provide a standardized optimal therapy for MANEC.

A special esophageal carcinoma: both dual neoplasms and concurrent 3-type mixed esophageal carcinoma diagnosed by endoscopic submucosal dissection

A special esophageal carcinoma: both dual neoplasms and concurrent 3-type mixed esophageal carcinoma diagnosed by endoscopic submucosal dissection

Mixed medullary-follicular carcinoma: A national analysis and the demographic features.

e18090 Background: Mixed medullary-follicular carcinoma (MMFC) is a rare malignant type of cancer that affects the thyroid. Unlike other thyroid cancers, MMFC is distinct by its solid-nonfollicular pattern which includes both follicular and C-cell elements. Nearly 70% of patients present with distant metastasis to the lungs, bone, brain and/or liver with a median survival time of 75 months, plus or minus 51 months. Because MMFC is a rare cancer, analyzing the trend in diagnoses can provide important information about its epidemiology. The National Cancer Database (NCDB) was analyzed to determine how patient demographic characteristics affected diagnosis of MMFC. Methods: A retrospective cohort study from 2004 to 2020 was conducted using the NCDB. 153 patients were found with a histologically confirmed diagnosis of MMFC (ICD-8346-3). Gender, race, Hispanic origin, level of education, insurance coverage, type of treatment facility, and distance from facility were analyzed via descriptive statistics and trends in incidence were interpreted using regression analysis. Results: The frequency of patients diagnosed with MMFC has remained consistent since 2004 (R2 = 0.1) with over 10 diagnoses per year. Of the 153 patients found, the average age of diagnosis was 59.05 years (SD = 14.36, range = 18 – 90 years). Approximately two-thirds of patients were female (62.7%) and the remainder were male (37.3%). Most of the patients were Non-Hispanic White (86.3%) compared to 7.2% of the patients which were of Spanish-hispanic origin. More patients were in the top income quartile (37.3%) than those in the second (18.3%), third (21.6%), or fourth (11.1%) quartiles. The other 11.8% were of unknown income status. The majority of patients were privately insured (52.9%), followed by coverage under Medicare/Medicaid (43.1%). More patients lived in metropolitan counties with a population of 250,000 or more (88.2%) compared to urban or rural areas (11.8%). A large percentage of patients were treated at an academic or comprehensive community cancer program (72.6%) compared to non-academic programs (27.4%). Patients traveled an average of 33.9 miles (SD = 93.90, Range = 0.5 – 806.8) to get to the treatment facility. Conclusions: MMFC remains a rare diagnosis. This study explores a significant gap in existing knowledge on patient characteristics that might present with MMFC. The majority of patients were White, non-Hispanic, insured by private insurance, lived in metropolitan areas, and in the top quartile of income earners. This novel study of socioeconomic factors in MMFC patients suggest that patients diagnosed with this uncommon cancer might have better access to diagnosis. Previous literature on MMFC suggested a predilection for males, but our findings serve as contrary evidence for such preference. As such, additional research to comprehend the role that sex and socioeconomic status might have on MMFC would be valuable.

The differences in biological behavior and gene expression characteristics between pure and mixed early gastric signet ring cell carcinomas.

The biological behavior of signet ring cell carcinoma (SRCC) in early gastric cancer (EGC) is not well understood. We aimed to investigate the clinicopathologic and prognostic differences, and explore differences in the gene expression characteristics between pure early SRCC and mixed early SRCC. We retrospectively analyzed 1707 EGC patients. We also conducted a meta-analysis to compare biological behavior in pure SRCC and mixed SRCC. We explored gene expression levels of N6-methyadenosine (m6A) regulators in pure SRCC and mixed SRCC. Compared with pure SRCC, mixed SRCC was associated with an increased risk of submucosal invasion, perineural invasion, LVI and LNM. LNM was more common in mixed SRCC than with pure SRCC who met the indications for endoscopic submucosal dissection (ESD) (16.67%vs 2.78%). There was no difference in the overall survival between pure SRCC and mixed SRCC in EGCs (P=0.10). Expression of m6A regulators WTAP, FTO and VIRMA was significantly higher in mixed SRCC than that in pure SRCC (P<0.05). Mixed SRCC displayed more aggressive biological behavior than pure SRCC in EGC. WTAP, FTO and VIRMA were expressed at significantly different levels in the two types of EGC, and may have important roles in the observed differences in biological behavior.

Cover Image

The cover image is based on the Original Article Comparison of clinicopathological characteristics, gene expression profiles, mutational analysis, and clinical outcomes of pure and mixed small-cell carcinoma of the bladder by Vamsi Parimi et al., https://doi.org/10.1111/his.14883.

Mixed papillary-medullary thyroid carcinoma and cystic adrenal mass

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An unusual association between Burkitt's lymphoma and a Carcinoid tumor in a Syrian boy: a rare case report.

The authors report a case of a 15-year-old Syrian adolescent who was admitted to our hospital due to a persistent, severe generalized abdomen pain accompanied by nausea, vomiting, loss of appetite, and inability to pass stool or gas. An abdominal radiograph revealed dilated intestinal loops with air-fluid levels. The patient underwent emergency surgery through which a retroperitoneal mass was removed as well as part of the ileum and the appendix. The final diagnosis was consistent with intestinal BL associated with an appendiceal carcinoid tumor. The correlation between gastrointestinal carcinoids and other types of tumors was frequently reported. However, there have been few reports of carcinoid tumors being associated with lymphoreticular system cancers. BLs were classified into three variants: endemic, sporadic, and acquired immunodeficiency-associated BL while appendiceal neuroendocrine tumors were classified as the following: well-differentiated neuroendocrine tumors with benign or uncertain malignant potential; well-differentiated neuroendocrine carcinoma with low malignant potential; and mixed exocrine-neuroendocrine carcinoma. Our article demonstrates an unusual association between BL and an appendiceal carcinoid tumor that highlights the significant role of histological and immunohistochemical staining in confirming the diagnosis, as well as the role of surgery in treating the complications of intestinal BLs.

Abstract #1402263: A Malignant Duo: Mixed Medullary and Follicular Variant Papillary Thyroid Cancer

Medullary thyroid cancer (MTC) is rare and only constitutes 5-10% of all thyroid malignancies. Mixed MTC and papillary thyroid cancer (PTC) are even more rare and are only found in less than 1% of MTC cases. These malignancies arise from different cell origins, follicular cells of endoderm and parafollicular C cell of neural crest. It is not clear if the coexistence of these tumors in the same patient is a coincidence or if there is a common genetic culprit. We present a case of a lady with metastatic mixed MTC and PTC. A 61-year-old woman with history of Hashimoto disease was found to have bilateral thyroid nodules, the largest (1.7cm) was in the right lobe. This nodule met fine needle aspiration (FNA) biopsy criteria and was found to have a follicular neoplasm of undetermined significance. The patient elected to pursue total thyroidectomy instead of lobectomy given presence of bilateral nodules. Postoperative pathology showed mixed medullary carcinoma (pT3b) and follicular variant papillary thyroid microcarcinoma (pT1a) involving the right lobe with positive anterior and posterior margins and lymphovascular invasion. Preoperative calcitonin was not checked. However, post-thyroidectomy calcitonin was 1599 pg/mL. She underwent central and right lateral neck dissection which showed 27 out of 35 lymph nodes were positive for malignancy. Postoperative calcitonin dropped to 38.7 pg/mL. She then established care in our endocrine clinic. Screening for pheochromocytoma and primary hyperparathyroidism was normal. She underwent external beam radiation of the neck. A year after her initial surgery, her neck ultrasound and computed tomography (CT) studies show no signs of local or distant anatomic recurrence. Her thyroglobulin level remains undetectable, CEA within normal range, and calcitonin stable at about 20 pg/mL. She is on levothyroxine 100mcg daily with TSH at suppression goal of < 0.1 mIU/L. Mixed PTC and MTC is poorly studied due to its rarity. The origin of these mixed tumors is unclear, but some suggest that they arise from neoplastic changes of remnant multipotent cells in the thyroid. While patients with PTC often have a favorable prognosis following surgical therapy, MTC has a more aggressive course. A retrospective study of 183 patients suggests that this entity is more common in patients older than 45 years and is associated with a better survival than MTC alone. We suggest monitoring patients like ours for both MTC and PTC, as if present in isolation. Our case will highlight the clinical aspects of this condition and our current knowledge of its pathophysiology.

Mismatch repair protein status of non-neoplastic uterine and intestinal mucosa in patients with Lynch syndrome and double somatic mismatch repair protein mutations

Mismatch repair (MMR) protein-deficient non-neoplastic colonic crypts and endometrial glands (dMMR crypts and glands) have been reported as a unique marker of underlying Lynch syndrome (LS). However, no large studies have directly compared the frequency of detection in cases with double somatic (DS) MMRmutations. We retrospectively analyzed 42 colonic resection specimens (24 LS and 18 DS) and 20 endometrial specimens (9 LS and 11 DS), including 19 hysterectomies and 1 biopsy for dMMR crypts and glands. All specimens were from patients with known primary cancers, including colonic adenocarcinomas and endometrial endometrioid carcinomas (including 2 mixed carcinomas). Four blocks of normal mucosa away from the tumor were selected from most cases, as available. MMR immunohistochemistryspecific to the primary tumor mutations was analyzed. dMMR crypts were found in 65% of LS and 0% of DS MMR-mutated colonic adenocarcinomas (P<.001). Most dMMR crypts were detected in the colon (12 of 15) compared to the ileum (3 of 15). dMMR crypts showed single and grouped losses of MMR immunohistochemical expression. dMMR glands were found in 67% of LS and 9% (1 of 11) of DS endometrial cases (P=.017). Most dMMR glands were found in the uterine wall, with 1LS and 1 DS case exhibiting dMMR glands in the lower uterine segment. Most cases exhibited multifocal and grouped dMMR glands. No morphologic atypia was identified in dMMR crypts or glands. Overall, we demonstrate that dMMR crypts and glands are highly associated with underlying LS, while being rarer in those with DS MMR mutations.

Extrauterine Mesonephric-like Carcinoma: A Comprehensive Single Institution Study of 33 Cases.

Extrauterine mesonephric-like carcinoma (ExUMLC) shares histologic, immunohistochemical (IHC), and molecular (MOL) features with endometrial mesonephric-like carcinoma (EnMLC). Its rarity and histologic overlap with Mullerian carcinomas contribute to underrecognition of ExUMLC. Aggressive behavior of EnMLC is well-documented; behavior of ExUMLC is yet to be characterized. This study presents the clinicopathologic, IHC, and MOL features of 33 ExUMLC identified over a 20-year time period (2002-2022) and compares the behavior of this cohort to more common upper gynecologic Mullerian carcinomas (low-grade endometrioid, LGEC; clear cell, CCC; high-grade serous, HGSC) and EnMLC diagnosed over the same time period. ExUMLC patients ranged from 37 to 74 years old (median=59y); 13 presented with advanced stage (FIGO III/IV) disease. Most ExUMLC had the characteristic mixture of architectural patterns and cytologic features, as previously described. Two ExUMLC had sarcomatous differentiation, 1 with heterologous rhabdomyosarcoma. Twenty-one ExUMLC (63%) had associated endometriosis, and 7 (21%) arose in a borderline tumor. In 14 (42%) cases, ExUMLC was part of a mixed carcinoma representing >50% of the tumor in 12. Twenty-six cases (79%) were incorrectly classified as follows: LGEC or HGEC (12); adenocarcinoma, not otherwise specified (3); HGSC (3); LGSC (2); mixed carcinoma (1); carcinosarcoma, Mullerian type (2); seromucinous carcinoma (1); transitional pattern of HGSC (1); and female adnexal tumor of probable Wolffian origin (1). Three patients had occult synchronous endometrial LGEC. IHC facilitated diagnosis in all cases with an expression of GATA-3 and/or TTF-1 in conjunction with decreased hormone receptor expression in most tumors. MOL testing (n=20) identified a variety of mutations, most frequently: KRAS (15); TP53 (4); SPOP (4); and PIK3CA (4). ExUMLC and CCC were more likely to be associated with endometriosis ( P <0.0001). ExUMLC and HGSC had more recurrences compared with CCC and LGEC ( P <0.0001). Histologic subtype was associated with longer disease-free survival for LGEC and CCC versus HGSC and ExUMLC ( P <0.001). ExUMLC trended towards a similar poor overall survival as HGSC compared with LGEC and CCC, and EnMLC trended to shorter survival compared with ExUMLC. Neither finding reached significance. No differences were seen between EnMLC and ExUMLC with respect to presenting stage or recurrence. Staging, histotype, and endometriosis were associated with disease-free survival, but on multivariate analysis, only stage remained as an independent predictor of outcome. The tendency of ExUMLC to present at an advanced stage and have distant recurrence points to more aggressive behavior compared with LGEC with which it is most frequently confused, underscoring the importance of an accurate diagnosis.

Abstract 4212: Comparison of thirty-year population-based incidence rates of invasive lobular vs ductal vs mixed breast carcinoma in Ontario, Canada

Abstract Purpose: We calculated crude, age-adjusted and age-specific incidence rates for invasive lobular, ductal and mixed ductal-lobular breast carcinoma from 1990 to 2020 in the province of Ontario, Canada. We further examined incidence relationships between clinical stage, age at diagnosis and time. Methods: We used population-based administrative healthcare datasets from the Institute of Clinical Evaluative Sciences (ICES Ontario), including the Ontario Cancer Registry, to identify all women diagnosed with breast cancer between 1990 and 2020. We calculated crude, age-adjusted and age-specific incidence rates for invasive lobular (ILC), ductal (IDC) and mixed ductal-lobular (IDC-ILC) breast carcinoma. Incidence rates were adjusted to the 2011 Canadian female standard population. We further examined the incidence relationships between clinical stage and age at diagnosis over time. Results: From 1990 to 2020, the 5-year crude incidence rates of ILC increased from 53.1 to 73.4 per 100,000 (+38%), while IDC increased from 501 to 746.5 per 100,000 (+49%). The crude incidence of mixed IDC-ILC peaked at 45 per 100,000 between 2005 and 2009 and is currently 29 per 100,000. The age-adjusted 5-year incidence rate of ILC has slightly increased from 64 to 70 per 100,000 (+9%) while that of IDC has increased from 598 to 726 per 100,000 (+21%). The age-adjusted 5-year incidence of mixed IDC-ILC peaked at 47 per 100.000 between 2005 and 2009 and has declined to 29 per 100,000. Age-specific 5-year incidence rates for ILC has decreased over time in women &amp;lt; 40 years of age and increased in women over the age of 65. In contrast, age-specific 5-year incidence rates for IDC have remained stable in women over 75. For mixed IDC-ILC, age-specific 5-year incidence rates have increased over time in all age categories. Among women with ILC, there is a greater proportion of women under the age of 50 diagnosed with stage III disease (30%) compared with women diagnosed over the age of 50 (16%). Women between the ages of 50 and 74 have higher rates of being diagnosed at stage I (43%) compared with 35% and 31% for women diagnosed between the ages of 40-49 and over 75, respectively. Conclusions: The incidence of invasive lobular breast carcinoma in increasing, particularly in women over the age 65. Consequently, the burden of lobular breast carcinoma is expected to increase, as the proportion of women over the age of 65 is expected to rise exponentially in the foreseeable future, highlighting a need for further study of this not uncommon breast cancer subtype. While representing a smaller proportion of breast cancer diagnoses, the incidence of mixed invasive ductal-lobular subtype is increasing in all age groups. Citation Format: David Wai Lim, Vasily Giannakeas, Steven Narod, Kelly A. Metcalfe. Comparison of thirty-year population-based incidence rates of invasive lobular vs ductal vs mixed breast carcinoma in Ontario, Canada. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4212.

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.