gastric adenocarcinoma

Images

 M 14y/o gastric adenocarcinoma with bone metastasis

• https://twitter.com/Sandro_CZ/status/778725943980417024

Digital cases

 JRC:10442 : cutaneous metastasis of a gastric adenocarcinoma.

Etiology

Gastric cancer is thought to result from a combination of environmental factors and the accumulation of specific genetic alterations due to increasing genetic instability, and consequently affects mainly older patients.

Microscopical subtypes

Histologically, gastric carcinoma demonstrates marked heterogeneity at both architectural and cytologic level, often with co-existence of several histologic elements.

Over the past half century the histologic classification of gastric carcinoma has been largely based on Lauren’s criteria, in which intestinal type and diffuse type adenocarcinoma are the two major histologic subtypes, plus indeterminate type as uncommon variant.

The relative frequencies are approximately:
 54% for intestinal type,
 32% for the diffuse type,
 15% for the indeterminate type.

There are indications that the diffuse type gastric carcinoma is more often seen in female and young individuals, while the intestinal type adenocarcinoma is more often associated with intestinal metaplasia and Helicobacter pylori infection.

The 2010 WHO classification recognizes four major histologic patterns of gastric cancers:
 tubular,
 papillary,
 mucinous
 poorly cohesive (including signet ring cell carcinoma),
 uncommon histologic variants.

The classification is based on the predominant histologic pattern of the carcinoma which often co-exists with less dominant elements of other histologic patterns.

In addition to the above four major histologic subtypes, WHO classification also endorses other uncommon histologic variants, such as:
 adenosquamous carcinoma ,
 squamous carcinoma ,
 hepatoid adenocarcinoma ,
 carcinoma with lymphoid stroma ,
 choriocarcinoma ,
 parietal cell carcinoma ,
 malignant rhabdoid tumor ,
 mucoepidermoid carcinoma ,
 paneth cell carcinoma ,
 undifferentiated carcinoma ,
 mixed adeno-neuroendocrine carcinoma ,
 endodermal sinus tumor ,
 embryonal carcinoma ,
 pure gastric yolk sac tumor
 oncocytic adenocarcinoma .

Early onset gastric carcinomas

Less than 10% of patients present with the disease before 45 years of age (early onset gastric carcinoma) and these patients are believed to develop gastric carcinomas with a molecular genetic profile differing from that of sporadic carcinomas occurring at a later age. In young patients, the role of genetics is presumably greater than in older patients, with less of an impact from environmental carcinogens.

As a result, hereditary gastric cancers and early onset gastric cancers can provide vital information about molecular genetic pathways in sporadic cancers and may aid in the unraveling of gastric carcinogenesis.

Variants

 gastric adenocarcinoma of fundic gland type (20410811)
 gastric oncocytic adenocarcinoma

Molecular subtypes

 HER2-amplified gastric carcinoma
 MET-amplified gastric carcinoma (26404902)

Predisposition

 Helicobacter infection

Genetic predisposition

10% of familial clustering

 E-cadherin gene (CDH1) mutations
 mismatch repair genes mutations

• MSH2
• MLH1

 germline P53 mutations (Li-Fraumeni syndrome)

Joined CNA-gene expression profiling study

 tumor suppressors or deleted in various tumors

• GATA binding protein 4 (GATA4)
• monoamine oxidase A (MAOA)
• cyclin C (CCNC)

 oncogenes

• malignant fibrous histiocytoma amplified sequence 1 (MFHAS1/MASL1)
• high mobility group AT-hook 2 (HMGA2)
• PPAR binding protein (PPARBP)
• growth factor receptor-bound protein 7 (GRB7)
• TBC1 (tre-2, BUB2, cdc16) domain family member 1 (TBC1D1)

 A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers and FAT4 genomic deletions in 4% of gastric tumors. (22484628)

 Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) occurred in 47% of the gastric cancers. (22484628)

• A study detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. (22484628)
• Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.(22484628)

CNVs - CGH (15623941)

 gains

• 1q gain
  • 1q21 gain
  • 1q32.3 gain

• 8p23.1-p23.3 gain
• 8q24.2 gain
• 8q24.1 gain

• 7p11.2 gain
• 10p gain
• 20q gain (20q11 gain, 20q13)
• 20q13.12 gain
• 20q13.2 gain

 losses

• 1p loss
• 5p loss
• 5q14.1 loss
• 9p21.3-p24.3 loss
• 13q31.1 loss
• 16q22.1 loss
• 17p13.1-p13.3 loss
• 18q22.1 loss
• 19p13.12-p13.3 loss
• 21q21.3 loss

 regional amplifications

• 7q21-q22 amplification
• 12q14.1-q21.1 amplification

Targeted therapy

 in 2016, trastuzumab , ramucirumab , and apatinib effectively treat gastric cancer.

 crizotinib in

• MET-overexpressed gastric carcinoma
• MET-amplified gastric carcinoma

Videos

 Endoscopy of a gastric carcinoma (stomach cancer)

• http://www.youtube.com/v/C_cxDOK7SGo

 Endoscopy of a small gastric carcinoma (stomach cancer)

• http://www.youtube.com/v/G-4gI9VqIeg

Open References

 Gastric cancer: Classification, histology and application of molecular pathology. Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. J Gastrointest Oncol. 2012 Sep;3(3):251-61. doi : 10.3978/j.issn.2078-6891.2012.021 PMID: 22943016 [Free]

 Genetics and molecular pathology of gastric malignancy: Development of targeted therapies in the era of personalized medicine. Van Ness M, Gregg J, Wang J, Chen M. J Gastrointest Oncol. 2012 Sep;3(3):243-51. doi : 10.3978/j.issn.2078-6891.2012.017 PMID: 22943015 [Free]

References

 Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, Rajasegaran V, Heng HL, Deng N, Gan A, Lim KH, Ong CK, Huang D, Chin SY, Tan IB, Ng CC, Yu W, Wu Y, Lee M, Wu J, Poh D, Wan WK, Rha SY, So J, Salto-Tellez M, Yeoh KG, Wong WK, Zhu YJ, Futreal PA, Pang B, Ruan Y, Hillmer AM, Bertrand D, Nagarajan N, Rozen S, Teh BT, Tan P. Nat Genet. 2012 May;44(5):570-4. doi : 10.1038/ng.2246 PMID: 22484628

 Milne AN, Sitarz R, Carvalho R, Carneiro F, Offerhaus GJ. Early onset gastric cancer: on the road to unraveling gastric carcinogenesis. Curr Mol Med. 2007 Feb;7(1):15-28. PMID: 17311530

 Yang S, Jeung HC, Jeong HJ, Choi YH, Kim JE, Jung JJ, Rha SY, Yang WI, Chung HC. Identification of genes with correlated patterns of variations in DNA copy number and gene expression level in gastric cancer. Genomics. 2007 Jan 15; PMID: 17229543

 Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;(157):327-49. PMID: 15055305

 Simpson AJ, Caballero OL, Pena SD. Microsatellite instability as a tool for the classification of gastric cancer. Trends Mol Med. 2001 Feb;7(2):76-80. PMID: 11286759

 Weiss MM, Kuipers EJ, Postma C, Snijders AM, Pinkel D, Meuwissen SG, Albertson D, Meijer GA. Genomic alterations in primary gastric adenocarcinomas correlate with clinicopathological characteristics and survival. Cell Oncol. 2004;26(5-6):307-17. PMID: 15623941