Pub Date : 2023-12-18DOI: 10.1097/pas.0000000000002166
David P Cyr, Cherry Pun, Sameer Shivji, Bojana Mitrovic, Kai Duan, Rossi Tomin, Aysegul Sari, Amanpreet Brar, Siham Zerhouni, Mantaj S Brar, Erin D Kennedy, Carol J Swallow, Richard Kirsch, James R Conner
Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785 mm2) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival (P<0.0001). Examining both 0.95 and 0.785 mm2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95 mm2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785 mm2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P=0.0007) downgraded when a true 0.785 mm2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95 mm2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.
{"title":"Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited.","authors":"David P Cyr, Cherry Pun, Sameer Shivji, Bojana Mitrovic, Kai Duan, Rossi Tomin, Aysegul Sari, Amanpreet Brar, Siham Zerhouni, Mantaj S Brar, Erin D Kennedy, Carol J Swallow, Richard Kirsch, James R Conner","doi":"10.1097/pas.0000000000002166","DOIUrl":"https://doi.org/10.1097/pas.0000000000002166","url":null,"abstract":"Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785 mm2) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival (P<0.0001). Examining both 0.95 and 0.785 mm2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95 mm2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785 mm2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P=0.0007) downgraded when a true 0.785 mm2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95 mm2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138740002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-12DOI: 10.1097/pas.0000000000002167
David Suster, A Craig Mackinnon, Natali Ronen, Haider A Mejbel, Shuko Harada, Saul Suster
Seven cases of primary lung tumors characterized histologically by clear cell morphology and a distinctive FGFR3::TACC3 gene rearrangement are described. The tumors arose in 4 women and 3 men, aged 47 to 81 years (mean=68). They occurred in peripheral locations, predominantly subpleural, and ranged in size from 1.4 to 6.5 cm (mean=4.1 cm). All tumors showed a solid growth pattern with abundant central areas of necrosis and marked nuclear pleomorphism. The tumors demonstrated clear cell histology, with large cohesive tumor cells displaying atypical nuclei and abundant clear cytoplasm. Immunohistochemical stains identified a squamous phenotype in 5 cases and an adenocarcinoma phenotype in 2 cases. One case was a squamous cell carcinoma with focal glandular component, and one of the squamous cell carcinomas showed focal sarcomatoid changes. Next generation sequencing identified FGFR3::TACC3 gene rearrangements in all 7 cases. One case demonstrated a concurrent activating FGFR3 mutation and a second case demonstrated concurrent FGFR3 amplification. Two cases harbored a concurrent KRAS G12D mutation. One case harbored both KRAS and EGFR mutations, and 1 case had a concurrent TP53 mutation. Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.
{"title":"Non-Small Cell Lung Carcinoma with Clear Cell Features and FGFR3::TACC3 Gene Rearrangement: Clinicopathologic and Next Generation Sequencing Study of 7 Cases.","authors":"David Suster, A Craig Mackinnon, Natali Ronen, Haider A Mejbel, Shuko Harada, Saul Suster","doi":"10.1097/pas.0000000000002167","DOIUrl":"https://doi.org/10.1097/pas.0000000000002167","url":null,"abstract":"Seven cases of primary lung tumors characterized histologically by clear cell morphology and a distinctive FGFR3::TACC3 gene rearrangement are described. The tumors arose in 4 women and 3 men, aged 47 to 81 years (mean=68). They occurred in peripheral locations, predominantly subpleural, and ranged in size from 1.4 to 6.5 cm (mean=4.1 cm). All tumors showed a solid growth pattern with abundant central areas of necrosis and marked nuclear pleomorphism. The tumors demonstrated clear cell histology, with large cohesive tumor cells displaying atypical nuclei and abundant clear cytoplasm. Immunohistochemical stains identified a squamous phenotype in 5 cases and an adenocarcinoma phenotype in 2 cases. One case was a squamous cell carcinoma with focal glandular component, and one of the squamous cell carcinomas showed focal sarcomatoid changes. Next generation sequencing identified FGFR3::TACC3 gene rearrangements in all 7 cases. One case demonstrated a concurrent activating FGFR3 mutation and a second case demonstrated concurrent FGFR3 amplification. Two cases harbored a concurrent KRAS G12D mutation. One case harbored both KRAS and EGFR mutations, and 1 case had a concurrent TP53 mutation. Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138635030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-12DOI: 10.1097/pas.0000000000002169
Justin A Bishop, Masato Nakaguro, Makoto Urano, Yoshinari Yamamoto, Yoshitaka Utsumi, Rong Li, Ilan Weinreb, Yoji Nagashima, Chiraag Gangahar, Katsushige Yamashiro, Kimio Hashimoto, Lisa M Rooper, Brian Carlile, Richard C Wang, Jeffrey Gagan, Toshitaka Nagao
Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2-rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2. Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age ran
{"title":"Keratocystoma: A Distinctive Salivary Gland Neoplasm Characterized by RUNX2 Rearrangements.","authors":"Justin A Bishop, Masato Nakaguro, Makoto Urano, Yoshinari Yamamoto, Yoshitaka Utsumi, Rong Li, Ilan Weinreb, Yoji Nagashima, Chiraag Gangahar, Katsushige Yamashiro, Kimio Hashimoto, Lisa M Rooper, Brian Carlile, Richard C Wang, Jeffrey Gagan, Toshitaka Nagao","doi":"10.1097/pas.0000000000002169","DOIUrl":"https://doi.org/10.1097/pas.0000000000002169","url":null,"abstract":"Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2-rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2. Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age ran","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138634925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1097/pas.0000000000002163
Tangchen Yin, Mengyuan Shao, Meng Sun, Lu Zhao, I Weng Lao, Lin Yu, Jian Wang
Occurrence of extraskeletal Ewing sarcoma (ES) in the gastrointestinal (GI) tract is extremely rare. Here, we report 25 cases of ES arising primarily in the GI tract with a focus on the clinicopathological and molecular features, differential diagnosis, and biological behavior. Thirteen patients (52%) were male, and 12 (48%) were female with age ranging from 9 to 59 years (mean: 36.2 years; median: 38 years). Twenty-one tumors (84%) occurred in the small intestine, 3 (12%) in the stomach, and 1 (4%) in the anal canal. At operation, 8/18 (44.4%) patients presented with abdominopelvic disseminated disease. Tumor size measured from 2 to 25 cm (mean: 8.2 cm; median: 6 cm) in maximum size. Microscopically, the tumors were composed of infiltrative small round, ovoid, or short spindle cells arranged mostly in lobular and solid sheet-like patterns with a rich capillary vasculature. Focal formation of Homer Wright-type rosettes and pseudoalveolar architecture was noted each in 2 (8%) cases and 3 (12%) cases. Besides CD99 (25/25; 100%), Fli-1 (15/15, 100%), and NKX2.2 (14/16; 87.5%), the tumor cells also showed variable staining of CD117 (14/17; 82.4%). Of 25 cases, 23 (92%) demonstrated EWSR1 rearrangement by fluorescence in situ hybridization analysis. The 2 cases with negative fluorescence in situ hybridization results were found to harbor EWSR1::ERG and EWSR1::FLI1 fusion by further RNA sequencing, respectively, with a median follow-up of 12 months (range: 1 to 42 months), 5/19 (26.3%) patients developed visceral metastasis and 12/19 (63.2%) patients died of the disease (range:1 to 33 months; median: 9 months). This study showed that GI ES had a predilection for the small intestine, although other sites of the GI tract could also be involved. GI ES had a poor prognosis with a high rate of mortality, particularly in patients with abdominopelvic disseminated disease. In light of appropriate therapeutic strategies and prognostic considerations, it is essential not to misdiagnose GI ES as gastrointestinal stromal tumor owing to the expression of aberrant CD117.
胃肠道骨外尤文肉瘤（ES）极为罕见。在此，我们报告了25例主要发生在消化道的ES病例，重点介绍了临床病理和分子特征、鉴别诊断和生物学行为。13例患者（52%）为男性，12例（48%）为女性，年龄从9岁到59岁不等（平均：36.2岁；中位：38岁）。21例肿瘤（84%）发生在小肠，3例（12%）发生在胃，1例（4%）发生在肛管。手术时，8/18（44.4%）名患者出现腹盆腔播散性疾病。肿瘤最大尺寸为2至25厘米（平均：8.2厘米；中位数：6厘米）。显微镜下，肿瘤由浸润性小圆形、卵圆形或短纺锤形细胞组成，大多呈分叶状和实片状排列，并伴有丰富的毛细血管。有 2 例（8%）和 3 例（12%）肿瘤病灶形成 Homer Wright 型花环和假肺泡结构。除了CD99（25/25；100%）、Fli-1（15/15，100%）和NKX2.2（14/16；87.5%）外，肿瘤细胞还显示出不同程度的CD117染色（14/17；82.4%）。在 25 个病例中，23 例（92%）通过荧光原位杂交分析显示出 EWSR1 重排。中位随访时间为12个月（1至42个月），5/19（26.3%）例患者出现内脏转移，12/19（63.2%）例患者死于该病（1至33个月；中位：9个月）。这项研究表明，消化道 ES 偏爱小肠，但也可能累及消化道的其他部位。消化道癌的预后较差，死亡率较高，尤其是腹盆腔播散性疾病患者。考虑到适当的治疗策略和预后因素，切勿因 CD117 表达异常而将 GI ES 误诊为胃肠道间质瘤。
{"title":"Gastrointestinal Ewing Sarcoma: A Clinicopathological and Molecular Genetic Analysis of 25 Cases.","authors":"Tangchen Yin, Mengyuan Shao, Meng Sun, Lu Zhao, I Weng Lao, Lin Yu, Jian Wang","doi":"10.1097/pas.0000000000002163","DOIUrl":"https://doi.org/10.1097/pas.0000000000002163","url":null,"abstract":"Occurrence of extraskeletal Ewing sarcoma (ES) in the gastrointestinal (GI) tract is extremely rare. Here, we report 25 cases of ES arising primarily in the GI tract with a focus on the clinicopathological and molecular features, differential diagnosis, and biological behavior. Thirteen patients (52%) were male, and 12 (48%) were female with age ranging from 9 to 59 years (mean: 36.2 years; median: 38 years). Twenty-one tumors (84%) occurred in the small intestine, 3 (12%) in the stomach, and 1 (4%) in the anal canal. At operation, 8/18 (44.4%) patients presented with abdominopelvic disseminated disease. Tumor size measured from 2 to 25 cm (mean: 8.2 cm; median: 6 cm) in maximum size. Microscopically, the tumors were composed of infiltrative small round, ovoid, or short spindle cells arranged mostly in lobular and solid sheet-like patterns with a rich capillary vasculature. Focal formation of Homer Wright-type rosettes and pseudoalveolar architecture was noted each in 2 (8%) cases and 3 (12%) cases. Besides CD99 (25/25; 100%), Fli-1 (15/15, 100%), and NKX2.2 (14/16; 87.5%), the tumor cells also showed variable staining of CD117 (14/17; 82.4%). Of 25 cases, 23 (92%) demonstrated EWSR1 rearrangement by fluorescence in situ hybridization analysis. The 2 cases with negative fluorescence in situ hybridization results were found to harbor EWSR1::ERG and EWSR1::FLI1 fusion by further RNA sequencing, respectively, with a median follow-up of 12 months (range: 1 to 42 months), 5/19 (26.3%) patients developed visceral metastasis and 12/19 (63.2%) patients died of the disease (range:1 to 33 months; median: 9 months). This study showed that GI ES had a predilection for the small intestine, although other sites of the GI tract could also be involved. GI ES had a poor prognosis with a high rate of mortality, particularly in patients with abdominopelvic disseminated disease. In light of appropriate therapeutic strategies and prognostic considerations, it is essential not to misdiagnose GI ES as gastrointestinal stromal tumor owing to the expression of aberrant CD117.","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138550864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1097/pas.0000000000002165
Kianoosh Keyhanian, Lucy Han, Brooke E Howitt, Teri Longacre
Identification of ultramutated/POLE-mutated endometrial carcinomas (POLEM ECs) has important implications given its association with better prognosis. However, POLE mutation testing is not widely available. Our objective was to evaluate POLEM ECs versus POLE wild-type (POLEWT) ECs, within a cohort of consultation cases with features suggestive of an ultramutated phenotype. Consultation cases of EC that had undergone POLE hotspot mutation testing over a 3.5-year period were included. Tumor morphology and immunohistochemistry were reviewed for both groups. Chi-square test and t test were used for statistical analysis. Of 25 consultation cases, 12 harbored a POLE mutation (48%) and 13 were wild-type (52%). Patients with POLEM ECs were younger (59 vs. 71.3 y; P=0.01). Ambiguous histomorphology (5/12 vs. 1/13; P=0.04) and the presence of more than rare bizarre nuclei (8/12 vs. 2/12; P=0.01) differed significantly between POLEM and POLEWT ECs, respectively. In the POLEM group, one case (1/12) demonstrated PMS2 loss, and one (1/12) showed subclonal MLH1/PMS2 loss. Among POLEWT ECs, 3/13 (23%) showed MLH1/PMS2 loss. p53 was subclonally overexpressed in 4/10 POLEM and 1/13 POLEWT cases (P=0.06). Mutant p53 patterns were seen in 1/10 POLEM versus 6/13 of POLEWT ECs, respectively (P=0.06). Within our cohort, the specificity of ambiguous histomorphology, bizarre nuclei, subclonal biomarker expression, and marked tumor-infiltrating lymphocytes for POLEM EC was 83%, 80%, 80%, and 71%, respectively. Where universal POLE testing is not available, these data suggest that morphologic screening (particularly ambiguous histomorphology and the presence of more than rare bizarre nuclei) can be useful for selective enrichment of ECs for POLE testing.
{"title":"Specific Pathology Features Enrich Selection of Endometrial Carcinomas for POLE Testing.","authors":"Kianoosh Keyhanian, Lucy Han, Brooke E Howitt, Teri Longacre","doi":"10.1097/pas.0000000000002165","DOIUrl":"https://doi.org/10.1097/pas.0000000000002165","url":null,"abstract":"Identification of ultramutated/POLE-mutated endometrial carcinomas (POLEM ECs) has important implications given its association with better prognosis. However, POLE mutation testing is not widely available. Our objective was to evaluate POLEM ECs versus POLE wild-type (POLEWT) ECs, within a cohort of consultation cases with features suggestive of an ultramutated phenotype. Consultation cases of EC that had undergone POLE hotspot mutation testing over a 3.5-year period were included. Tumor morphology and immunohistochemistry were reviewed for both groups. Chi-square test and t test were used for statistical analysis. Of 25 consultation cases, 12 harbored a POLE mutation (48%) and 13 were wild-type (52%). Patients with POLEM ECs were younger (59 vs. 71.3 y; P=0.01). Ambiguous histomorphology (5/12 vs. 1/13; P=0.04) and the presence of more than rare bizarre nuclei (8/12 vs. 2/12; P=0.01) differed significantly between POLEM and POLEWT ECs, respectively. In the POLEM group, one case (1/12) demonstrated PMS2 loss, and one (1/12) showed subclonal MLH1/PMS2 loss. Among POLEWT ECs, 3/13 (23%) showed MLH1/PMS2 loss. p53 was subclonally overexpressed in 4/10 POLEM and 1/13 POLEWT cases (P=0.06). Mutant p53 patterns were seen in 1/10 POLEM versus 6/13 of POLEWT ECs, respectively (P=0.06). Within our cohort, the specificity of ambiguous histomorphology, bizarre nuclei, subclonal biomarker expression, and marked tumor-infiltrating lymphocytes for POLEM EC was 83%, 80%, 80%, and 71%, respectively. Where universal POLE testing is not available, these data suggest that morphologic screening (particularly ambiguous histomorphology and the presence of more than rare bizarre nuclei) can be useful for selective enrichment of ECs for POLE testing.","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138550865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.
{"title":"Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma.","authors":"Aitoshi Hoshimoto, Atsushi Tatsuguchi, Takeshi Yamada, Sho Kuriyama, Ryohei Hamakubo, Takayoshi Nishimoto, Jun Omori, Naohiko Akimoto, Katya Gudis, Keigo Mitsui, Shu Tanaka, Shunji Fujimori, Tsutomu Hatori, Akira Shimizu, Katsuhiko Iwakiri","doi":"10.1097/pas.0000000000002161","DOIUrl":"https://doi.org/10.1097/pas.0000000000002161","url":null,"abstract":"Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.","PeriodicalId":501610,"journal":{"name":"The American Journal of Surgical Pathology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138550866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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