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2. |
- Ameline, Baptiste, et al.
(författare)
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Methylation and copy number profiling : emerging tools to differentiate osteoblastoma from malignant mimics?
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 35:9, s. 1204-1211
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Tidskriftsartikel (refereegranskat)abstract
- Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.
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3. |
- Asa, Sylvia L., et al.
(författare)
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Pituitary neuroendocrine tumors : a model for neuroendocrine tumor classification
- 2021
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Ingår i: Modern Pathology. - : Springer Nature. - 0893-3952 .- 1530-0285. ; 34:9, s. 1634-1650
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Forskningsöversikt (refereegranskat)abstract
- The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.
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5. |
- Bokhorst, J. M., et al.
(författare)
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Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning
- 2020
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Ingår i: Modern Pathology. - : NATURE PUBLISHING GROUP. - 0893-3952 .- 1530-0285. ; 33:5, s. 825-833
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Tidskriftsartikel (refereegranskat)abstract
- Tumor budding is a promising and cost-effective biomarker with strong prognostic value in colorectal cancer. However, challenges related to interobserver variability persist. Such variability may be reduced by immunohistochemistry and computer-aided tumor bud selection. Development of computer algorithms for this purpose requires unequivocal examples of individual tumor buds. As such, we undertook a large-scale, international, and digital observer study on individual tumor bud assessment. From a pool of 46 colorectal cancer cases with tumor budding, 3000 tumor bud candidates were selected, largely based on digital image analysis algorithms. For each candidate bud, an image patch (size 256 x 256 mu m) was extracted from a pan cytokeratin-stained whole-slide image. Members of an International Tumor Budding Consortium (n = 7) were asked to categorize each candidate as either (1) tumor bud, (2) poorly differentiated cluster, or (3) neither, based on current definitions. Agreement was assessed with Cohens and Fleiss Kappa statistics. Fleiss Kappa showed moderate overall agreement between observers (0.42 and 0.51), while Cohens Kappas ranged from 0.25 to 0.63. Complete agreement by all seven observers was present for only 34% of the 3000 tumor bud candidates, while 59% of the candidates were agreed on by at least five of the seven observers. Despite reports of moderate-to-substantial agreement with respect to tumor budding grade, agreement with respect to individual pan cytokeratin-stained tumor buds is moderate at most. A machine learning approach may prove especially useful for a more robust assessment of individual tumor buds.
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7. |
- Bokhorst, John-Melle, et al.
(författare)
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Fully Automated Tumor Bud Assessment in Hematoxylin and Eosin-Stained Whole Slide Images of Colorectal Cancer
- 2023
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Ingår i: Modern Pathology. - : ELSEVIER SCIENCE INC. - 0893-3952 .- 1530-0285. ; 36:9
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Tidskriftsartikel (refereegranskat)abstract
- Tumor budding (TB), the presence of single cells or small clusters of up to 4 tumor cells at the invasive front of colorectal cancer (CRC), is a proven risk factor for adverse outcomes. International definitions are necessary to reduce interobserver variability. According to the current international guidelines, hotspots at the invasive front should be counted in hematoxylin and eosin (H & E)-stained slides. This is time-consuming and prone to interobserver variability; therefore, there is a need for computer-aided diagnosis solutions. In this study, we report an artificial intelligence-based method for detecting TB in H & E-stained whole slide images. We propose a fully automated pipeline to identify the tumor border, detect tumor buds, characterize them based on the number of tumor cells, and produce a TB density map to identify the TB hotspot. The method outputs the TB count in the hotspot as a computational biomarker. We show that the proposed automated TB detection workflow performs on par with a panel of 5 pathologists at detecting tumor buds and that the hotspot-based TB count is an independent prognosticator in both the univariate and the multivariate analysis, validated on a cohort of n 1/4 981 patients with CRC. Computer-aided detection of tumor buds based on deep learning can perform on par with expert pathologists for the detection and quantification of tumor buds in H & E-stained CRC histopathology slides, strongly facilitating the introduction of budding as an independent prognosticator in clinical routine and clinical trials. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
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8. |
- Bulten, Wouter, et al.
(författare)
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Artificial intelligence assistance significantly improves Gleason grading of prostate biopsies by pathologists
- 2021
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Ingår i: Modern Pathology. - : NATURE PUBLISHING GROUP. - 0893-3952 .- 1530-0285. ; 34, s. 660-671
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Tidskriftsartikel (refereegranskat)abstract
- The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohens kappa, 0.799 vs. 0.872;p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohens kappa, 0.733 vs. 0.786;p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.
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9. |
- Cloutier, Jeffrey M., et al.
(författare)
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“Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor” : a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor”
- 2021
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 34:4, s. 758-769
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory leiomyosarcoma (ILMS), defined as “a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization”, is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of “histiocyte-rich rhabdomyoblastic tumor” (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as “inflammatory rhabdomyoblastic tumor”, a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.
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11. |
- Ferreyra Vega, Sandra, et al.
(författare)
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Spatial heterogeneity in DNA methylation and chromosomal alterations in diffuse gliomas and meningiomas
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 35:11, s. 1551-1561
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Tidskriftsartikel (refereegranskat)abstract
- Adult-type diffuse gliomas and meningiomas are the most common primary intracranial tumors of the central nervous system. DNA methylation profiling is a novel diagnostic technique increasingly used also in the clinic. Although molecular heterogeneity is well described in these tumors, DNA methylation heterogeneity is less studied. We therefore investigated the intratumor genetic and epigenetic heterogeneity in diffuse gliomas and meningiomas, with focus on potential clinical implications. We further investigated tumor purity as a source for heterogeneity in the tumors. We analyzed genome-wide DNA methylation profiles generated from 126 spatially separated tumor biopsies from 39 diffuse gliomas and meningiomas. Moreover, we evaluated five methods for measurement of tumor purity and investigated intratumor heterogeneity by assessing DNA methylation-based classification, chromosomal copy number alterations and molecular markers. Our results demonstrated homogeneous methylation-based classification of IDH-mutant gliomas and further corroborates subtype heterogeneity in glioblastoma IDH-wildtype and high-grade meningioma patients after excluding samples with low tumor purity. We detected a large number of differentially methylated CpG sites within diffuse gliomas and meningiomas, particularly in tumors of higher grades. The presence of CDKN2A/B homozygous deletion differed in one out of two patients with IDH-mutant astrocytomas, CNS WHO grade 4. We conclude that diffuse gliomas and high-grade meningiomas are characterized by intratumor heterogeneity, which should be considered in clinical diagnostics and in the assessment of methylation-based and molecular markers.
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13. |
- Hofvander, Jakob, et al.
(författare)
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PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells
- 2020
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 33:7, s. 1331-1340
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Tidskriftsartikel (refereegranskat)abstract
- Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor frequently displaying gene fusions, most of which affect the PHF1 gene. PHF1 encodes plant homeodomain finger protein 1, which is involved in various processes regulating gene transcription, including those orchestrated by the polycomb repressor complex 2. Here, a series of 37 OFMTs, including 18 typical, 9 atypical, and 10 malignant variants, was analyzed with regard to transcriptomic features, gene fusion and copy number status, and/or single-nucleotide variants. The effects on gene expression and chromatin accessibility of three detected fusions (EP400–PHF1, MEAF6–PHF1, and PHF1–TFE3) were further evaluated in fibroblasts. Genomic imbalances showed a progression-related pattern, with more extensive copy number changes among atypical/malignant lesions than among typical OFMTs; loss of the RB1 gene was restricted to atypical/malignant OFMTs, occurring in one-third of the cases. RNA sequencing identified fusion transcripts in >80% of the cases analyzed, including a novel CSMD1–MEAF6. The gene-expression profile of OFMT was distinct from that of other soft tissue tumors, with extensive transcriptional upregulation of genes in OFMT. These findings were largely recapitulated in gene fusion-expressing fibroblast lines, suggesting that genes involved in, e.g., Wnt signaling and/or being regulated through trimethylation of lysine 27 in histone 3 (H3K27me3) are pivotal for OFMT development. The genes showing differentially higher expression in fusion-expressing cells paralleled increased chromatin accessibility, as revealed by ATAC sequencing. Thus, the present study suggests that OFMT develops through gene fusions that have extensive epigenetic consequences.
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14. |
- Kang, E. Y., et al.
(författare)
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Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses
- 2021
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 34:1, s. 194-206
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (INC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
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15. |
- Kao, Yu Chien, et al.
(författare)
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Identification of COL1A1/2 Mutations and Fusions With Noncoding RNA Genes in Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion)
- 2023
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Ingår i: Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. - : Elsevier BV. - 1530-0285. ; 36:2
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Tidskriftsartikel (refereegranskat)abstract
- Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.
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16. |
- Kindler, Csaba, et al.
(författare)
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A Deep Neural Network-Based Decision Support Tool for the Detection of Lymph Node Metastases in Colorectal Cancer Specimens
- 2023
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Ingår i: Modern Pathology. - : Elsevier. - 0893-3952 .- 1530-0285. ; 36:2
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Tidskriftsartikel (refereegranskat)abstract
- The identification of lymph node metastases in colorectal cancer (CRC) specimens is crucial for the planning of postoperative treatment and can be a time-consuming task for pathologists. In this study, we developed a deep neural network (DNN) algorithm for the detection of metastatic CRC in digitized histologic sections of lymph nodes and evaluated its performance as a diagnostic support tool. First, the DNN algorithm was trained using pixel-level annotations of cancerous areas on 758 whole slide images (360 with cancerous areas). The algorithm's performance was evaluated on 74 whole slide images (43 with cancerous areas). Second, the algorithm was evaluated as a decision support tool on 288 whole slide images covering 1517 lymph node sections, randomized in 16 batches. Two senior pathologists (C.K. and C.O.) assessed each batch with and without the help of the algorithm in a 2 x 2 crossover design, with a washout period of 1 month in between. The time needed for the evaluation of each node section was recorded. The DNN algorithm achieved a median pixel-level accuracy of 0.952 on slides with cancerous areas and 0.996 on slides with benign samples. N+ disease (metastases, micrometastases, or tumor deposits) was present in 103 of the 1517 sections. The algorithm highlighted cancerous areas in 102 of these sections, with a sensitivity of 0.990. Assisted by the algorithm, the median time needed for evaluation was significantly shortened for both pathologists (median time for pathologist 1, 26 vs 14 seconds; P < .001; 95% CI, 11.0-12.0; median time for pathologist 2, 25 vs 23 seconds; P < .001; 95% CI, 2.0-4.0). Our DNN showed high accuracy for detecting metastatic CRC in digitized histologic sections of lymph nodes. This decision support tool has the potential to improve the diagnostic workflow by shortening the time needed for the evaluation of lymph nodes in CRC specimens without impairing diagnostic accuracy.
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18. |
- Nguyen, Huu-Giao, et al.
(författare)
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Image-based assessment of extracellular mucin-to-tumor area predicts consensus molecular subtypes (CMS) in colorectal cancer
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 35, s. 240-248
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Tidskriftsartikel (refereegranskat)abstract
- The backbone of all colorectal cancer classifications including the consensus molecular subtypes (CMS) highlights microsatellite instability (MSI) as a key molecular pathway. Although mucinous histology (generally defined as >50% extracellular mucin-to-tumor area) is a “typical” feature of MSI, it is not limited to this subgroup. Here, we investigate the association of CMS classification and mucin-to-tumor area quantified using a deep learning algorithm, and the expression of specific mucins in predicting CMS groups and clinical outcome. A weakly supervised segmentation method was developed to quantify extracellular mucin-to-tumor area in H&E images. Performance was compared to two pathologists’ scores, then applied to two cohorts: (1) TCGA (n = 871 slides/412 patients) used for mucin-CMS group correlation and (2) Bern (n = 775 slides/517 patients) for histopathological correlations and next-generation Tissue Microarray construction. TCGA and CPTAC (n = 85 patients) were used to further validate mucin detection and CMS classification by gene and protein expression analysis for MUC2, MUC4, MUC5AC and MUC5B. An excellent inter-observer agreement between pathologists’ scores and the algorithm was obtained (ICC = 0.92). In TCGA, mucinous tumors were predominantly CMS1 (25.7%), CMS3 (24.6%) and CMS4 (16.2%). Average mucin in CMS2 was 1.8%, indicating negligible amounts. RNA and protein expression of MUC2, MUC4, MUC5AC and MUC5B were low-to-absent in CMS2. MUC5AC protein expression correlated with aggressive tumor features (e.g., distant metastases (p = 0.0334), BRAF mutation (p < 0.0001), mismatch repair-deficiency (p < 0.0001), and unfavorable 5-year overall survival (44% versus 65% for positive/negative staining). MUC2 expression showed the opposite trend, correlating with less lymphatic (p = 0.0096) and venous vessel invasion (p = 0.0023), no impact on survival.The absence of mucin-expressing tumors in CMS2 provides an important phenotype-genotype correlation. Together with MSI, mucinous histology may help predict CMS classification using only histopathology and should be considered in future image classifiers of molecular subtypes.
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19. |
- Oggiano, Florian, et al.
(författare)
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Overlapping morphological, immunohistochemical and genetic features of superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor.
- 2022
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Ingår i: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. - : Elsevier BV. - 1530-0285. ; 35:6, s. 767-776
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Tidskriftsartikel (refereegranskat)abstract
- Superficial CD34-positive fibroblastic tumor (SCD34FT) is a recently recognized soft tissue tumor that is considered to be of borderline malignancy. The pathogenesis of this tumor remains incompletely understood, but it has been suggested that SCD34FT overlaps with tumors showing fusions involving the PRDM10 gene. Previous analyses of PRDM10-rearranged tumors have demonstrated that they have a distinct gene expression profile, resulting in high expression of CADM3 (also known as SynCam3), which can be detected immunohistochemically. Here, we investigated a series (n=43) of SCD34FT or PRDM10-rearranged tumors and potential mimics (n=226) with regard to morphological, genetic, and immunohistochemical features. The results show that SCD34FT and PRDM10-rearranged tumor are morphologically indistinguishable; 41 of 43 tumors of both entities are CADM3-positive. Hence, we suggest that they constitute a single entity, preferably referred to as SCD34FT. Expression of CADM3 was only rarely seen in other soft tissue tumors, except in tumors with Schwann cell differentiation. Thus, IHC for CADM3, in combination with the characteristic morphological features, is a valuable adjunct in the diagnosis of SCD34FT.
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22. |
- Ricci, Costantino, et al.
(författare)
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HPV Status and World Health Organization 2016 Classification of Penile Squamous Cell Carcinoma and Penile Intraepithelial Neoplasia : 206 Cases from a Single, Contemporary, Western Cohort of Patients with Emphasis on the "Discordant Cases"
- 2020
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Ingår i: Modern Pathology. - : Nature Publishing Group. - 0893-3952 .- 1530-0285. ; 33:Suppl 2, s. 960-961
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Penile squamous cel carcinoma (pSCC) cancer has been considered a rare tumour in the western world. Although some conflicting results, the most recent meta-analyses report an increase in its incidence and in the percentage of HPV(+) cases in numerous western countries. This scenario mirrors what observed for HPV(+) oropharynx cancer and could be explained by changes in sexual practice and in exposure of men to HPV. In this study, we analyzed pathological features and HPV-DNA prevalence in a contemporary, western pSCC cohort.Design: This study enrolled 206 patients with pSCC from Örebro University. DNA was extracted from paraffin-embedded tumor tissue samples, and HPV-DNA genotyping were performed using PCR method Anyplex II HPV28. In a subset of cases, HPV-DNA was also assessed in penile intraepithelial neoplasia (PeIN), lymph node metastasis (LnM) or both (51%, 11.6% and 18.9%). All the cases have been histologically re-classified according to the WHO 2016 classification of pSCC.Results: HPV -DNA was detected in 92/206 (44.7%) pSCC, 78/141 (55.3%) PeIN and 28/61 LnM (45.9%), respectively. HPV16 was the predominant type, representing 78.3% for pSCC, 79.5% for PeIN and 96.4% for LnM. In 7.8% of the cases, more than a HPV genotype has been detected in the same specimen or in different specimens of the same patients. Curiously, we found 8.5% of cases (14/164) with discordance of HPV-DNA detection in different specimens from the same patient (pSCC, PeIN and/or /LnM). In HPV(+) pSCC the predominant histologic subtype was “warty” (41.3%); in HPV(-) pSCC it was “usual” (65.8%). For PeIN, “warty” was the predominant subtype in HPV(+) PeIN (39.7%) and “differentiated” in HPV(-) PeIN (79.4%). For pSCC, we observed disagreement between histology and HPV status in 23.8% of cases: 13.1% HPV(+)/Non-HPV -related histology and 10.7% HPV(-)/HPV-related histology.Conclusions: HPV -DNA was observed in a relevant portion of pSCC and PeIN in our case series, confirming an increasing role of HPV in the pathogenesis of this disease. These results are particularly relevant, as they reflect the current epidemiological trend in the western world. Future studies are needed to clarify the exact role of HPV in cases with discordance between histology and HPV status and in cases with disagreement of HPV detection in different specimens from the same patient (pSCC, PeIN and/or LnM).
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23. |
- Siesing, Christina, et al.
(författare)
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Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 35:7, s. 979-988
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Tidskriftsartikel (refereegranskat)abstract
- In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.
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