Indian Journal of Pathology and Microbiology
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Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 3-4
Use of smooth muscle markers is better than the endothelial cell markers for identification of tumor venous invasion and extramural tumor deposits in gastrointestinal tract tumors

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

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Date of Web Publication31-Jan-2020

How to cite this article:
Das P, Baloda V. Use of smooth muscle markers is better than the endothelial cell markers for identification of tumor venous invasion and extramural tumor deposits in gastrointestinal tract tumors. Indian J Pathol Microbiol 2020;63:3-4

How to cite this URL:
Das P, Baloda V. Use of smooth muscle markers is better than the endothelial cell markers for identification of tumor venous invasion and extramural tumor deposits in gastrointestinal tract tumors. Indian J Pathol Microbiol [serial online] 2020 [cited 2022 Jan 24];63:3-4. Available from: https://www.ijpmonline.org/text.asp?2020/63/1/3/277372

Tumor invasion into the endothelial-lined spaces (lymphatics and medium/large veins) is a poor prognostic marker in various malignancies. As per the AJCC tumor-node-metastasis (TNM) staging system (AJCC Cancer Staging Manual, 8th edition), one has to look for and comment on the extramural venous invasion (VI) to predict distant tumor metastasis. Presence of VI also qualifies a patient to receive systemic adjuvant chemotherapy in TNM stage II and stage III colorectal carcinomas (CRCs).[1] Tumor invasion in the small vessels, comprising lymphatics, capillaries, and postcapillary venules (all considered under 'L' classification in current TNM staging system) is also a marker of higher lymph node (LN) metastasis.[2] Tumor deposits (TD) [tumor satellites] are the discrete macroscopic or microscopic tumor cell nodules, in the pericolorectal adipose tissue, discontinuous from the primary tumor without any histological evidence of residual LN, or vascular or neural structures. If a vessel wall can be demonstrated around a TD, the same should be classified as either a venous invasion (V1/2) or lymphatic invasion (L1), respectively. Like the VI, the presence of TDs also does not change the primary tumor 'T' category, but changes the LN status (N) to pN1c, in a regional LN-negative CRC. In stage II CRC presence of pN1c further, upstage it to stage III. Though in previous editions of AJCC size of TDs (in TNM5) and their outer contour (in TNM6) were taken into account to differentiate them from pericolorectal metastatic LNs, neither size nor contour is part of the current definition of TD in AJCC 8th edition.[1],[2]

Though histologic criteria are known for assessment of VI in the standard H and E stained sections, at times, it may be challenging, especially when there is the presence of retraction artifacts around the tumor cell clusters. As a result, VI is an underreported finding in histopathology reports and there is marked interobserver and intraobserver variability.[3] Histologically, VI can be identified as a round/tubular cluster of tumor cells in an endothelium-lined space either surrounded by a rim of smooth muscle or containing red blood cells.[2] Paying attention to the 'orphan arteriole' [presence of a well-circumscribed tubular cluster of tumor cells without any appreciable venous wall adjacent to a medium size thick-walled arteriole] and 'protruding tongue' sign [presence of an elongated smooth cluster of tumor cells in the pericolorectal adipose tissue, not in direct continuity with the advancing tumor margin] increases the yield of VI detection. However, many times, histological examination is not confirmatory enough, and ancillary markers are needed. The Royal College of Pathologists (RCPath) dataset recommends taking a minimum of four tumor sections per specimen and performing elastic tissue stain to identify peritumoral elastic tissue in vessel wall with a standard target for detection of extramural VI at 25%.[4] However, the College of American Pathologists (CAP) does not provide specific recommendations on the number of sections to sample, though, advocates using elastic tissue stains to increase yield up to three times compared to routinely stained slides.[5] However, some authors think that elastic tissue as is present in the submucosal and subserosal stroma; mere detection of elastic tissue around a tumor cell cluster may not indicate VI resulting in overdiagnosis. Though neither CAP nor RCPath currently advocates the use of immunohistochemistry (IHC) for detection of VI, its use may improve the detection rate. Among the IHC markers, lymphatic endothelial markers are lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), D2-40 (podoplanin), vascular endothelial growth factor receptor 3 (VEGFR-3), and vascular endothelial markers as CD34 and CD31 are in use for detection of LVI in tumors. However, with these markers also interpretation can be challenging as CD31, being a platelet endothelial adhesion molecule, can also show immunoreactivity in histiocytes and platelets; and D240 stain can show background staining in myofibroblasts and nerves.[6] Moreover, the elastic tissue stain gained popularity for detection of LVI over the endothelial markers because the invading tumor cells may destroy the vascular endothelial cells resulting in poor interpretability in cases of LVI.[7]

In this issue, an article compared the utility of the vascular wall smooth muscle markers over the endothelial markers and demonstrated that the smooth muscle stains are superior to the endothelial stains for identifying the VI in various gastrointestinal tract (GIT) carcinomas. The advantage of smooth muscle markers, as smooth muscle myosin (SMM), h-caldesmon, and desmin is that they stain the vessel wall smooth muscles accurately and not the surrounding fibrous stroma. Among these, the former two markers were found to be superior, while desmin stain may result in misinterpretation as it also stains the mesothelial cells.[8] In the index article, the authors also studied transgelin, an actin filament binding protein, and found that it is superior for identifying smooth muscles in the vein wall than the SMM. Their results are quite promising and resolve the dilemma of detection of VI and TDs in various malignant tumors. However, the authors found that application of transgelin or SMM as a marker of VI can be limited around the muscularis mucosae, muscularis propria, and in periampullary regions.[9]

In conclusion, both VI and TDs are stage-independent prognostic markers in GIT carcinomas, and there is a growing interest to improve the methods of detecting them. The use of smooth muscle markers as transgelin and smooth muscle myosin seems superior for the detection of VI than the elastic tissue stain and endothelial markers as described above.

   References Top

Van Wyk HC, Foulis AK, Roxburgh CS, Orange C, Horgan PG, Mcmillan DC. Comparison of methods to identify lymphatic and blood vessel invasion and their prognostic value in patients with primary operable colorectal cancer. Anticancer Res 2015;35:6457-63.  Back to cited text no. 1
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing; 2017.  Back to cited text no. 2
Messenger DE, Driman DK, Kirsch R. Developments in the assessment of venous invasion in colorectal cancer: Implications for future practice and patient outcome. Hum Pathol 2012;43:965-73.  Back to cited text no. 3
Loughrey MB, Quirke P, Shepherd NA. Standard Datasets for Reporting Cancers: Dataset for Colorectal Cancer. 2nd ed. 2018. Document G049. Available from: https://www.rcpath.org/uploads/assets/uploaded/0d5e22ce-be66-474c-ba3097adae84121d.pdf. [Last accessed on 2019 Apr 05].  Back to cited text no. 4
Washington MK, Berlin J, Branton P, Burgart LJ, Carter DK, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 2009;133:1539-51.  Back to cited text no. 5
Weber SK, Sauerwald A, Pölcher M, Braun M, Debald M, Serce NB, et al. Detection of lymphovascular invasion by D2-40 (podoplanin) immunoexpression in endometrial cancer. Int J Gynecol Cancer 2012;22:1442-8.  Back to cited text no. 6
Kirsch R, Messenger DE, Riddell RH, Pollett A, Cook M, Al-Haddad S, et al. Venous invasion in colorectal cancer: Impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists. Am J Surg Pathol 2013;37:200-10.  Back to cited text no. 7
Ekinci Ö, Öǧüt B, Çelik B, Dursun A. Compared with elastin stains, h-caldesmon and desmin offer superior detection of vessel invasion in gastric, pancreatic, and colorectal adenocarcinomas. Int J Surg Pathol 2018;26:318-26.  Back to cited text no. 8
Betul Ogut, Ozgur Ekinci, Bulent Celik, Emel Rodoplu Unal, Ayse Dursun. Comparison of The Efficiency of Transgelin, Smooth Muscle Myosin, and CD31 Antibodies for the Assessment of Vascular Tumor Invasion and Free Tumor Deposits in Gastric, Pancreatic and Colorectal Adenocarcinomas 2020;63:25-30.  Back to cited text no. 9

Correspondence Address:
Prasenjit Das
Department of Pathology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_284_19

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