Pub Date : 2019-09-12DOI: 10.1097/PAS.0000000000001371
C. Voskuilen, H. Oo, V. Genitsch, L. Smit, Á. Vidal, M. Meneses, A. Necchi, M. Colecchia, E. Xylinas, J. Fontugne, M. Sibony, M. Rouprêt, L. Lenfant, J. Côté, Lorenz Buser, K. Saba, M. Furrer, M. S. van der Heijden, M. Daugaard, P. Black, B. V. van Rhijn, K. Hendricksen, C. Poyet, R. Seiler
Supplemental Digital Content is available in the text. Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.
{"title":"Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma","authors":"C. Voskuilen, H. Oo, V. Genitsch, L. Smit, Á. Vidal, M. Meneses, A. Necchi, M. Colecchia, E. Xylinas, J. Fontugne, M. Sibony, M. Rouprêt, L. Lenfant, J. Côté, Lorenz Buser, K. Saba, M. Furrer, M. S. van der Heijden, M. Daugaard, P. Black, B. V. van Rhijn, K. Hendricksen, C. Poyet, R. Seiler","doi":"10.1097/PAS.0000000000001371","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001371","url":null,"abstract":"Supplemental Digital Content is available in the text. Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123554627","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 : 2019-09-09DOI: 10.1097/PAS.0000000000001370
Maryam Shabihkhani, J. Simpson, Marissa J. White, A. Cimino-Mathews, P. Argani
Needle tract displacement is a recognized mimicker of invasive ductal carcinoma (IDC). Artifactual displacement of ductal carcinoma in situ (ADDCIS) unassociated with needle tracts may occur secondary to mechanical compression of breast specimens but has not been systematically studied. We identified 16 cases of ADDCIS unassociated with needle tract changes; the majority (75%) were internal referrals to the breast pathology service to rule out IDC, 19% were received as external diagnostic consultations to rule out IDC, and 6% were routine second review cases originally diagnosed as IDC at an outside hospital. The majority (62.5%) of ADDCIS occurred in lumpectomies, whereas 25% occurred in mastectomies and 12.5% in core biopsies. ADDCIS foci ranged from <1 to 5 mm; however, all ADDCIS spanning >4 mm demonstrated a linear pattern of displacement. In all cases, ADDCIS involved mammary stroma in a nonlobular distribution; in half, ADDCIS extended between benign lobules. Immunohistochemistry revealed no myoepithelial cells around the ADDCIS (n=7), adding to the concern for IDC. However, in contrast to most IDC, ADDCIS lacked stromal reaction and showed degenerative, smudged chromatin. None of the 9 patients with significant follow-up (mean, 7 y) developed metastasis. All received further local therapy for DCIS (5 radiation, 4 completion mastectomy); 1 received adjuvant systemic therapy (hormone therapy for contralateral IDC). In conclusion, ADDCIS mimics IDC, particularly given its permeative pattern and absence of myoepithelial cells. ADDCIS is most common in lumpectomies but can occur in mastectomies or core biopsies. Diagnostic clues include smudged nuclear chromatin, lack of stromal response, and linear pattern of displacement in larger lesions. The benign follow-up without systemic therapy supports our view that ADDCIS does not represent true IDC.
{"title":"Artifactual Displacement of Ductal Carcinoma In Situ (ADDCIS) (Toothpaste Effect)","authors":"Maryam Shabihkhani, J. Simpson, Marissa J. White, A. Cimino-Mathews, P. Argani","doi":"10.1097/PAS.0000000000001370","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001370","url":null,"abstract":"Needle tract displacement is a recognized mimicker of invasive ductal carcinoma (IDC). Artifactual displacement of ductal carcinoma in situ (ADDCIS) unassociated with needle tracts may occur secondary to mechanical compression of breast specimens but has not been systematically studied. We identified 16 cases of ADDCIS unassociated with needle tract changes; the majority (75%) were internal referrals to the breast pathology service to rule out IDC, 19% were received as external diagnostic consultations to rule out IDC, and 6% were routine second review cases originally diagnosed as IDC at an outside hospital. The majority (62.5%) of ADDCIS occurred in lumpectomies, whereas 25% occurred in mastectomies and 12.5% in core biopsies. ADDCIS foci ranged from <1 to 5 mm; however, all ADDCIS spanning >4 mm demonstrated a linear pattern of displacement. In all cases, ADDCIS involved mammary stroma in a nonlobular distribution; in half, ADDCIS extended between benign lobules. Immunohistochemistry revealed no myoepithelial cells around the ADDCIS (n=7), adding to the concern for IDC. However, in contrast to most IDC, ADDCIS lacked stromal reaction and showed degenerative, smudged chromatin. None of the 9 patients with significant follow-up (mean, 7 y) developed metastasis. All received further local therapy for DCIS (5 radiation, 4 completion mastectomy); 1 received adjuvant systemic therapy (hormone therapy for contralateral IDC). In conclusion, ADDCIS mimics IDC, particularly given its permeative pattern and absence of myoepithelial cells. ADDCIS is most common in lumpectomies but can occur in mastectomies or core biopsies. Diagnostic clues include smudged nuclear chromatin, lack of stromal response, and linear pattern of displacement in larger lesions. The benign follow-up without systemic therapy supports our view that ADDCIS does not represent true IDC.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127591174","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001369
N. Patel, Monika Vyas, R. Celli, D. Jain, Xuchen Zhang
Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.
肿瘤分化、淋巴血管侵袭、边缘状态、息肉形状和大小是恶性息肉(pT1)的重要参数，提示可能的淋巴结转移，这是手术的理由。然而，在非带蒂恶性息肉的碎片性息肉切除术中，其大小、边缘和淋巴血管的浸润通常是未知的或难以评估的。该研究的目的是确定与淋巴结转移风险增加相关的非带蒂恶性息肉的不良组织学特征，这可能需要进行结肠切除术。本文回顾了2005年至2018年共24例淋巴结阳性和18例淋巴结阴性的无带蒂恶性息肉及其相应的后续切除术标本。淋巴结转移患者高级别肿瘤出芽阳性率更高(70.8% vs. 16.7%;P=0.0005)，低分化集群(54.2% vs. 22.2%;P=0.0369)，高级别肿瘤出芽和低分化簇(45.8% vs. 11.1%;P=0.0160)与无淋巴结转移的对照组比较。高级别肿瘤出芽、低分化簇以及高级别肿瘤出芽和低分化簇合并增加了淋巴结转移的风险，比值比分别为12.1、4.1和14.3。此外，即使完全切除的恶性息肉具有不良的组织学特征，在随后的结肠切除术标本中也可以看到淋巴结转移。我们的研究结果表明，高级别肿瘤出芽和低分化簇是预测淋巴结转移潜力的重要不良组织学风险特征。这些组织学特征应报告，当它们出现时可能需要结肠切除术。
{"title":"Adverse Histologic Features in Colorectal Nonpedunculated Malignant Polyps With Nodal Metastasis","authors":"N. Patel, Monika Vyas, R. Celli, D. Jain, Xuchen Zhang","doi":"10.1097/PAS.0000000000001369","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001369","url":null,"abstract":"Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115501331","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001366
B. Harrison, Elizabeth Fowler, G. Krings, Yunni-Yi Chen, G. Bean, A. Vincent-Salomon, L. Fuhrmann, S. Barnick, Beiyun Chen, Elizabeth M. Hosfield, J. Hornick, S. Schnitt
Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in <5% of tumor cells and 1 (0.5%) showed focal membranous staining. All histologic mimics were negative. In conclusion, diffuse and/or at least focally strong nuclear pan-TRK staining is a sensitive and specific marker for secretory carcinoma of the breast.
{"title":"Pan-TRK Immunohistochemistry","authors":"B. Harrison, Elizabeth Fowler, G. Krings, Yunni-Yi Chen, G. Bean, A. Vincent-Salomon, L. Fuhrmann, S. Barnick, Beiyun Chen, Elizabeth M. Hosfield, J. Hornick, S. Schnitt","doi":"10.1097/PAS.0000000000001366","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001366","url":null,"abstract":"Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in <5% of tumor cells and 1 (0.5%) showed focal membranous staining. All histologic mimics were negative. In conclusion, diffuse and/or at least focally strong nuclear pan-TRK staining is a sensitive and specific marker for secretory carcinoma of the breast.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"242 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133065998","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001362
S. Newman, A. Pappo, S. Raimondi, Jinghui Zhang, R. Barnhill, A. Bahrami
Spitz melanoma is a rare variant of melanoma defined by distinct clinical, histologic, and genetic features and affecting patients of all ages. Half of these tumors are driven by fusion of kinase genes including ALK, NTRK1/3, ROS1, RET, MET, or BRAF. We recently reported recurrent fusion or truncation of the potentially targetable serine-threonine kinase gene MAP3K8 in 33% of Spitz melanomas. Here we describe the histologic features of these MAP3K8-rearranged tumors (16 pediatric Spitz melanomas; 1 atypical Spitz tumor), using hematoxylin-eosin slides, p16 immunohistochemistry, and CDKN2A fluorescence in situ hybridization. The lesions consisted of a compound melanocytic proliferation, ranging in thickness from 1.5 to 13.4 mm (median, 3.1 mm), with 8 having a predominant dermal and 3 having a predominant junctional component. The predominant cell type was epithelioid (94%). The epithelioid melanocytes were generally monomorphic and amelanotic, arranged in expansile epithelial aggregates, confluent hypercellular nests, or enlarged syncytial nodules in the dermis. Ulceration was present in 9 of 17 tumors (53%) and deep mitotic figures were seen in 15 of 17 tumors (88%). Complete loss of p16 expression and homozygous CDKN2A deletion were observed in 82% and 70% of tumors, respectively. Recognition of MAP3K8-altered Spitz melanoma may thus be facilitated by these morphologic features, most notably presence of cohesive cellular nodules in the dermis and an epithelioid-cell phenotype.
{"title":"Pathologic Characteristics of Spitz Melanoma With MAP3K8 Fusion or Truncation in a Pediatric Cohort","authors":"S. Newman, A. Pappo, S. Raimondi, Jinghui Zhang, R. Barnhill, A. Bahrami","doi":"10.1097/PAS.0000000000001362","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001362","url":null,"abstract":"Spitz melanoma is a rare variant of melanoma defined by distinct clinical, histologic, and genetic features and affecting patients of all ages. Half of these tumors are driven by fusion of kinase genes including ALK, NTRK1/3, ROS1, RET, MET, or BRAF. We recently reported recurrent fusion or truncation of the potentially targetable serine-threonine kinase gene MAP3K8 in 33% of Spitz melanomas. Here we describe the histologic features of these MAP3K8-rearranged tumors (16 pediatric Spitz melanomas; 1 atypical Spitz tumor), using hematoxylin-eosin slides, p16 immunohistochemistry, and CDKN2A fluorescence in situ hybridization. The lesions consisted of a compound melanocytic proliferation, ranging in thickness from 1.5 to 13.4 mm (median, 3.1 mm), with 8 having a predominant dermal and 3 having a predominant junctional component. The predominant cell type was epithelioid (94%). The epithelioid melanocytes were generally monomorphic and amelanotic, arranged in expansile epithelial aggregates, confluent hypercellular nests, or enlarged syncytial nodules in the dermis. Ulceration was present in 9 of 17 tumors (53%) and deep mitotic figures were seen in 15 of 17 tumors (88%). Complete loss of p16 expression and homozygous CDKN2A deletion were observed in 82% and 70% of tumors, respectively. Recognition of MAP3K8-altered Spitz melanoma may thus be facilitated by these morphologic features, most notably presence of cohesive cellular nodules in the dermis and an epithelioid-cell phenotype.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"37 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114654886","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001365
S. Leskela, I. Romero, E. Cristóbal, B. Pérez-Mies, J. M. Rosa-Rosa, A. Gutiérrez-Pecharromán, A. Santón, B. O. González, Raquel López-Reig, D. Hardisson, F. Vera-Sempere, C. Illueca, B. Vieites, J. López-Guerrero, J. Palacios, A. Poveda
Supplemental Digital Content is available in the text. The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, β-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.
{"title":"The Frequency and Prognostic Significance of the Histologic Type in Early-stage Ovarian Carcinoma","authors":"S. Leskela, I. Romero, E. Cristóbal, B. Pérez-Mies, J. M. Rosa-Rosa, A. Gutiérrez-Pecharromán, A. Santón, B. O. González, Raquel López-Reig, D. Hardisson, F. Vera-Sempere, C. Illueca, B. Vieites, J. López-Guerrero, J. Palacios, A. Poveda","doi":"10.1097/PAS.0000000000001365","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001365","url":null,"abstract":"Supplemental Digital Content is available in the text. The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, β-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"74 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115947980","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001364
A. Goyal, L. Ellenson, E. Pirog
With increasing use of p16 immunohistochemistry (IHC) in diagnosis of premalignant lesions of cervix, we occasionally encounter p16 positivity in squamous metaplasia that lacks morphologic characteristics of “atypical squamous metaplasia” or of squamous intraepithelial lesion (SIL). Our study aims to investigate if transcriptionally active human papilloma virus (HPV) can be identified in such foci and if they have any relationship with squamo-columnar junction (SCJ) cells. Twenty-two cases of cervical specimens with at least a focus of p16 positive bland squamous metaplasia, were selected. HPV E6/E7 mRNA in situ hybridization followed by IHC for CK7 (SCJ biomarker), Ki67, and HPV16 E2, were performed. Follow-up information was obtained. Four cases were excluded due to insufficient tissue. Of the final 18 cases, HPV E6/E7 mRNA in situ hybridization was positive in all. Nine cases showed positivity in >50% cells and the epithelial thickness involved was ≥lower two-thirds in 13 cases. Of the further evaluable 15 cases, CK7 was positive in 14, Ki67 was positive in 10, and HPV16 E2 was negative in all. Concomitant high-grade squamous intraepithelial lesion was identified in 10 cases. On follow-up (duration: 1 to 19 mo), 6 patients showed histologic high-grade squamous intraepithelial lesion. Our study demonstrates that p16 positivity in squamous metaplasia of cervix is associated with the presence of transcriptionally active high-risk HPV even when there are no clear morphologic features of dysplasia. Our results suggest that these lesions are early SILs or SILs that are not yet morphologically evident, most of which arise from SCJ and should be closely followed.
{"title":"p16 Positive Histologically Bland Squamous Metaplasia of the Cervix","authors":"A. Goyal, L. Ellenson, E. Pirog","doi":"10.1097/PAS.0000000000001364","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001364","url":null,"abstract":"With increasing use of p16 immunohistochemistry (IHC) in diagnosis of premalignant lesions of cervix, we occasionally encounter p16 positivity in squamous metaplasia that lacks morphologic characteristics of “atypical squamous metaplasia” or of squamous intraepithelial lesion (SIL). Our study aims to investigate if transcriptionally active human papilloma virus (HPV) can be identified in such foci and if they have any relationship with squamo-columnar junction (SCJ) cells. Twenty-two cases of cervical specimens with at least a focus of p16 positive bland squamous metaplasia, were selected. HPV E6/E7 mRNA in situ hybridization followed by IHC for CK7 (SCJ biomarker), Ki67, and HPV16 E2, were performed. Follow-up information was obtained. Four cases were excluded due to insufficient tissue. Of the final 18 cases, HPV E6/E7 mRNA in situ hybridization was positive in all. Nine cases showed positivity in >50% cells and the epithelial thickness involved was ≥lower two-thirds in 13 cases. Of the further evaluable 15 cases, CK7 was positive in 14, Ki67 was positive in 10, and HPV16 E2 was negative in all. Concomitant high-grade squamous intraepithelial lesion was identified in 10 cases. On follow-up (duration: 1 to 19 mo), 6 patients showed histologic high-grade squamous intraepithelial lesion. Our study demonstrates that p16 positivity in squamous metaplasia of cervix is associated with the presence of transcriptionally active high-risk HPV even when there are no clear morphologic features of dysplasia. Our results suggest that these lesions are early SILs or SILs that are not yet morphologically evident, most of which arise from SCJ and should be closely followed.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"67 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127574546","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001361
M. Collins, E. Dellon, D. Katzka, I. Hirano, James R. Williams, Lan Lan
Supplemental Digital Content is available in the text. Budesonide oral suspension (BOS) is a novel topical corticosteroid, which has been shown to improve symptoms and endoscopic appearance, and reduce peak eosinophil counts in patients with eosinophilic esophagitis (EoE). This trial evaluated the effect of BOS or placebo on the severity (grade) and extent (stage) of 8 histopathologic features observed in EoE, using the validated eosinophilic esophagitis histologic scoring system (EoE HSS). Patients with EoE aged 11 to 40 years with dysphagia were randomized to receive either BOS (2.0 mg twice daily) or placebo for 12 weeks. Mean (SD) EoE HSS grade and stage total scores at baseline for placebo and BOS groups were: grade, 0.42 (0.16) and 0.49 (0.14), respectively; stage: 0.38 (0.14) and 0.46 (0.11), respectively. These scores significantly decreased (improved) from baseline for patients receiving BOS versus placebo (grade: least squares mean change [SE]: placebo vs. BOS, −0.04 [0.03] vs. −0.24 [0.02]; P<0.0001; stage: −0.01 [0.02] vs. −0.19 [0.02]; P<0.0001). EoE HSS total scores improved for 6 of the 8 and 5 of the 8 histopathologic features for grade and stage, respectively, versus placebo. Change in EoE HSS total scores correlated moderately but significantly with change in endoscopic severity (endoscopic reference score; grade: R=0.5349; stage: R=0.5416; both P<0.0001). Change in EoE HSS stage total score correlated weakly with change in Dysphagia Symptom Questionnaire scores (grade: R=0.1925; P=0.0740; stage: R=0.2135; P=0.0471). These data demonstrate that the EoE HSS is a valuable endpoint of treatment response in randomized clinical trials and should be considered for future trials for EoE.
{"title":"Budesonide Oral Suspension Significantly Improves Eosinophilic Esophagitis Histology Scoring System Results","authors":"M. Collins, E. Dellon, D. Katzka, I. Hirano, James R. Williams, Lan Lan","doi":"10.1097/PAS.0000000000001361","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001361","url":null,"abstract":"Supplemental Digital Content is available in the text. Budesonide oral suspension (BOS) is a novel topical corticosteroid, which has been shown to improve symptoms and endoscopic appearance, and reduce peak eosinophil counts in patients with eosinophilic esophagitis (EoE). This trial evaluated the effect of BOS or placebo on the severity (grade) and extent (stage) of 8 histopathologic features observed in EoE, using the validated eosinophilic esophagitis histologic scoring system (EoE HSS). Patients with EoE aged 11 to 40 years with dysphagia were randomized to receive either BOS (2.0 mg twice daily) or placebo for 12 weeks. Mean (SD) EoE HSS grade and stage total scores at baseline for placebo and BOS groups were: grade, 0.42 (0.16) and 0.49 (0.14), respectively; stage: 0.38 (0.14) and 0.46 (0.11), respectively. These scores significantly decreased (improved) from baseline for patients receiving BOS versus placebo (grade: least squares mean change [SE]: placebo vs. BOS, −0.04 [0.03] vs. −0.24 [0.02]; P<0.0001; stage: −0.01 [0.02] vs. −0.19 [0.02]; P<0.0001). EoE HSS total scores improved for 6 of the 8 and 5 of the 8 histopathologic features for grade and stage, respectively, versus placebo. Change in EoE HSS total scores correlated moderately but significantly with change in endoscopic severity (endoscopic reference score; grade: R=0.5349; stage: R=0.5416; both P<0.0001). Change in EoE HSS stage total score correlated weakly with change in Dysphagia Symptom Questionnaire scores (grade: R=0.1925; P=0.0740; stage: R=0.2135; P=0.0471). These data demonstrate that the EoE HSS is a valuable endpoint of treatment response in randomized clinical trials and should be considered for future trials for EoE.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133691585","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 : 2019-09-06DOI: 10.1097/PAS.0000000000001367
Christine Arnesen, Marie‐Lisa Eich, M. R. Pena, J. Cappel, L. Schwartz, S. Rais-Bahrami, S. Faraj, C. P. Prieto Granada, J. Gordetsky
Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.
{"title":"NKX3.1 and Prostein Expression in Testicular Tissue and Sex Cord-stromal Tumors","authors":"Christine Arnesen, Marie‐Lisa Eich, M. R. Pena, J. Cappel, L. Schwartz, S. Rais-Bahrami, S. Faraj, C. P. Prieto Granada, J. Gordetsky","doi":"10.1097/PAS.0000000000001367","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001367","url":null,"abstract":"Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"34 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117333089","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 : 2019-09-04DOI: 10.1097/PAS.0000000000001356
K. Slik, Riku Turkki, O. Carpén, S. Kurki, E. Korkeila, J. Sundström, T. Pellinen
Current risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been shown to associate with poor clinical outcome and predict benefit for adjuvant chemotherapy in stage II and III colorectal carcinoma. The prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to clinical risk factors, such as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. In this study, we evaluated the protein expression of CDX2 in tumor center and front areas in a tissue microarrays material of stage II colorectal carcinoma patients (n=232). CDX2 expression showed a partial or total loss in respective areas in 8.6% and 10.9% of patient cases. Patients with loss of CDX2 had shorter disease-specific survival when scored independently either in tumor center or tumor front areas (log rank P=0.012; P=0.012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding (hazard ratio=5.96, 95% confidence interval=1.55-22.95; hazard ratio=3.70, 95% confidence interval=1.30-10.56). Importantly, CDX2 loss predicted inferior survival only in patients with microsatellite stable, but not with MSI-high phenotype. Interestingly, CDX2 loss associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The work demonstrates that loss of CDX2 is an independent risk factor of poor disease-specific survival in stage II colorectal carcinoma. Furthermore, the study suggests that CDX2 loss is linked with epithelial-to-mesenchymal transition independently of tumor budding.
{"title":"CDX2 Loss With Microsatellite Stable Phenotype Predicts Poor Clinical Outcome in Stage II Colorectal Carcinoma","authors":"K. Slik, Riku Turkki, O. Carpén, S. Kurki, E. Korkeila, J. Sundström, T. Pellinen","doi":"10.1097/PAS.0000000000001356","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001356","url":null,"abstract":"Current risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been shown to associate with poor clinical outcome and predict benefit for adjuvant chemotherapy in stage II and III colorectal carcinoma. The prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to clinical risk factors, such as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. In this study, we evaluated the protein expression of CDX2 in tumor center and front areas in a tissue microarrays material of stage II colorectal carcinoma patients (n=232). CDX2 expression showed a partial or total loss in respective areas in 8.6% and 10.9% of patient cases. Patients with loss of CDX2 had shorter disease-specific survival when scored independently either in tumor center or tumor front areas (log rank P=0.012; P=0.012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding (hazard ratio=5.96, 95% confidence interval=1.55-22.95; hazard ratio=3.70, 95% confidence interval=1.30-10.56). Importantly, CDX2 loss predicted inferior survival only in patients with microsatellite stable, but not with MSI-high phenotype. Interestingly, CDX2 loss associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The work demonstrates that loss of CDX2 is an independent risk factor of poor disease-specific survival in stage II colorectal carcinoma. Furthermore, the study suggests that CDX2 loss is linked with epithelial-to-mesenchymal transition independently of tumor budding.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"13 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127742192","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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