（１）膵嚢胞性疾患（ここではIPMN）
膵嚢胞は腹部超音波検査などの 精査で１割の人に指摘され、その約半数がIPMN とされる。本当によく見る病態なだけにフォローアップに苦慮する。症例の多くは「臨床的には」発癌しない。その中の一部が年単位で大きくなったり、併存腫瘍が出現したりする。
小生の外来にも8年目で大きくなり始めたり、一方で10年診るけど不変で観察のみという膵腫瘍はいる。IPMNはそんな病態だが、一方GNAS変異が消化管で注目されるきっかけになった病気でもある。
そのIPMNからの膵癌発がんには3タイプあるという報告が旭川医大から出ている。来月のGastroenterologyに掲載予定だとか。下図でBranched Typeというのが新規概念である。3つのタイプとGNASの関連についてはややわかりにくくなってきた。詳説が必要であろう。
（２）虫垂癌
以前のノートには粘液性虫垂腫瘍と書いたが、虫垂癌の一部にGNAS変異を持つものがあり、この一群の予後が一般の虫垂癌より良いという報告がJournal of Clinical Oncologyの姉妹誌、JCO Precision Oncologyに出たのは2018年の8月である。
Genomic Landscape of Appendiceal Neoplasms
Celina S.-P. Ang, John Paul Shen, Camille J. Hardy-Abeloos, Justin K. Huang, Jeffrey S. Ross, Vincent A. Miller, Miriam T. Jacobs, Ingrid L. Chen, David Xu, Siraj M. Ali, Joel Baumgartner, Andrew Lowy, Paul Fanta, Trey Ideker, Sherri Z. Millis, and Olivier Harismendy Celina S.-P. Ang, Camille J. Hardy-Abeloos, Jeffrey S. Ross, Paul Fanta, and Trey Ideker, Mount Sinai Hospital, New York, NY; John Paul Shen, Justin K. Huang, Miriam T. Jacobs, Ingrid L. Chen, David Xu, Joel Baumgartner, Andrew Lowy, Paul Fanta, Trey Ideker, and Olivier Harismendy, University of California, San Diego, La Jolla, CA; Jeffrey S. Ross, Albany Medical College, Albany, NY; Vincent A. Miller, Siraj M. Ali, and Sherri Z. Millis, Foundation Medicine, Cambridge, MA.
Appendiceal neoplasms are heterogeneous and are often treated with chemotherapy similarly to colorectal cancer (CRC). Genomic profiling was performed on 703 appendiceal cancer specimens to compare the mutation profiles of appendiceal subtypes to CRC and other cancers, with the ultimate aim to identify potential biomarkers and novel therapeutic targets.
Tumor specimens were submitted to a Clinical Laboratory Improvement Amendments–certified laboratory (Foundation Medicine, Cambridge, MA) for hybrid-capture–based sequencing of 3,769 exons from 315 cancer-related genes and 47 introns of 28 genes commonly rearranged in cancer. Interactions between genotype, histologic subtype, treatment, and overall survival (OS) were analyzed in a clinically annotated subset of 76 cases.
There were five major histopathologic subtypes: mucinous adenocarcinomas (46%), adenocarcinomas (30%), goblet cell carcinoids (12%), pseudomyxoma peritonei (7.7%), and signet ring cell carcinomas (5.2%). KRAS (35% to 81%) and GNAS (8% to 72%) were the most frequent alterations in epithelial cancers; APC and TP53 mutations were significantly less frequent in appendiceal cancers relative to CRC. Low-grade and high-grade tumors were enriched for GNAS and TP53 mutations, respectively (both χ2 P < .001). GNAS and TP53 were mutually exclusive (Bonferroni corrected P < .001). Tumor grade and TP53mutation status independently predicted OS. The mutation status of GNAS and TP53strongly predicted OS (median, 37.1 months for TP53 mutant v 75.8 GNAS-TP53 wild type v 115.5 GNAS mutant; log-rank P = .0031) and performed as well as grade in risk stratifying patients.
Epithelial appendiceal cancers and goblet cell carcinoids show differences in KRAS and GNAS mutation frequencies and have mutation profiles distinct from CRC. This study highlights the benefit of performing molecular profiling on rare tumors to identify prognostic and predictive biomarkers and new therapeutic targets.
以前はGNAS変異が報告された胆嚢腺腫であるが、2018年の順天堂病理の報告によるとGNAS変異は認められないようである。
Pyloric Gland Adenoma (PGA) of the Gallbladder: A Unique and Distinct Tumor from PGAs of the Stomach, Duodenum, and Pancreas
The American Journal of Surgical Pathology: September 2018 - Volume 42 - Issue 9 - p 1237–1245
abstract
Twenty-four surgically resected, gallbladder pyloric gland adenomas (GB-PGAs) were examined and their features were compared with the reported features of stomach, duodenum, and pancreatic PGAs to better understand GB-PGAs. Clinical information on background gallbladder lesions and histologic data, including tumor grade, existence of squamoid morules, intratumoral cholesterosis, and intracytoplasmic mucins were collected. Immunohistochemical staining for MUC2, MUC5AC, MUC6, CDX2, pepsinogen I, p53, and MIB-1/nuclear β-catenin were evaluated. Targeted mutational analyses of KRAS exon2, GNAS exon 7, and CTNNB1 exon 3 were conducted. We found that 29.2% of the GB-PGAs were histologically high-grade dysplasias/carcinomas; 70.8% were low grade; and 20.8% and 33.3% contained squamoid morules and intratumoral cholesterosis, respectively. In addition, 45.8% and 54.2% of GB-PGAs were mucin-rich and mucin-poor types, respectively. Immunohistochemically, MUC6 was diffusely positive in all GB-PGAs; MUC2, MUC5AC, and CDX2 were only focally positive, and no pepsinogen-I positive cells were observed. Nuclear β-catenin accumulation was observed in all cases; however, the ratio varied among cases. Mucin-poor types were significantly associated with high histologic grade dysplasias/carcinomas and high nuclear β-catenin labeling indices. Mutational analyses identified CTNNB1 mutations in 100% of GB-PGAs (21/21), KRAS in 4.2% (1/23), and GNAS in 0% (0/22). The present study clarified the unique histologic features, phenotypic differentiation, and molecular statuses frequently associated with GB-PGAs. Altogether, our data suggest that tumorigenesis of GB-PGA is distinct from that of stomach, duodenum, and pancreatic PGAs.
