Laterally spreading features of gastrointestinal stromal tumors: A clinicopathological study
- Authors:
- Published online on: April 10, 2018 https://doi.org/10.3892/or.2018.6360
- Pages: 2681-2687
Abstract
Introduction
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and arise from interstitial cells of Cajal (ICCs) or their precursor cells (1–5). GISTs tend to form well-circumscribed, protruding nodules without diffuse infiltration, so that local resection is often initially an adequate therapy (3,6–8). A 1–2 cm surgical safety margin is thought to be required for grossly and microscopically complete resection of GISTs (8–10), referred to as an R0 resection in the Union for International Cancer Control (UICC) system (11). Novitsky et al (9) demonstrated that all 50 surgically removed GISTs with a grossly 1–2 cm margin beyond the tumors exhibited microscopic negative margins ranging from 0.2 to 4.5 cm. Based on this, Everett et al (10) deduced a possible 0.5-cm length microscopic extension of GISTs. To the best of our knowledge, however, detailed histopathological examination of such laterally extending or spreading lesions of GISTs has not been previously conducted. Therefore, we examined the incidence and the histopathological features of these laterally spreading lesions of GISTs in the present study.
Materials and methods
Patients and GISTs
We examined a total of 52 GISTs grossly completely removed from 50 patients, which were retrieved from the surgical pathology files (1994–2016, October) of the Department of Pathology, Japan Self-Defense Forces Central Hospital, and the surgical pathology files (1996–2017, April) of the Division of Pathology, Mishuku Hospital, Tokyo, Japan. All GISTs were confirmed to be immunohistochemically positive for KIT (1:100; polyclonal; cat. no. A4502; Dako; Agilent Technologies, Inc., Santa Clara, CA, USA) and CD34 (1:100; NU-4A1; cat. no. 413361; Nichirei Biosciences, Inc., Tokyo, Japan). Clinical findings were obtained from medical charts and request forms for surgical pathology examination. Patients consisted of 39 men and 11 women, and ranged in age from 33 to 88 years (mean, 63.9 years). GISTs were located on the esophagus (2), stomach (38), small intestine (11 in total: Duodenum, 2; jejunum, 2; ileum, 1; and not otherwise specified, 6) and cecum (1). Sixteen minute or small GISTs were incidentally detected in other diseases. The present study was a retrospective study, which was performed according to the Declaration of Helsinki, and was approved by the Medical Research Ethics Committees of the Japan Self-Defense Forces Central Hospital (approval no. 28-014) and Mishuku Hospital (approval no. 2016-04).
GIST examination
In the present study, we defined ‘exophytic’ GISTs, as those with serosal protruding extramural components constituting >50% of the tumor volume. ‘Dumbbell’ -shaped GISTs were also found (2), but were re-classified in this study as either exophytic or non-exophytic, according to the aforementioned definition. Exophytic GISTs attached to the GI wall with a relatively narrow pedicle were called ‘pedunculated’ GISTs. When a laterally spreading lesion was present, we calculated its length from the outline of the main GIST or from the pedicle of the pedunculated GIST. Histology of GISTs was divided into 2 types, that is, spindle- or epithelioid-cell predominant. The risk category of each GIST was evaluated using the Joensuu criteria (12). All 10–20% buffered formalin-fixed and paraffin-embedded representative specimens were available. Select serial 4 µm-thick sections were re-cut and immunostained for discovered on GIST 1 (DOG1) (1:100; clone no. K9; cat. no. NCL-L-DOG-1; Leica Biosystems, Newcastle, UK), α-smooth muscle action (SMA) (clone no. 1A4; cat. no. 412021; Nichirei Biosciences, Inc., Tokyo, Japan; prediluted) and S-100 protein (S-100) (polyclonal; cat. no. 422091; Nichirei Biosciences, Inc.; prediluted).
Statistical analysis
Associations between the laterally spreading features and other clinicopathological findings were analyzed using the Chi-square test with the Yates' correlation and the unpaired t-test. Significance was set at P<0.05.
Results
Table I summarizes the clinicopathological findings of the 52 GISTs. Of the 52 GISTs, 29 (56%) were exophytic, 8 (15%) were pedunculated, 8 (15%) were dumb-bell shaped, 13 (25%) exhibited ulceration, 43 (83%)/9 (17%) were spindle-cell/epithelioid-cell predominant, 13 (25%) had a high mitotic rate (>5/50 high-power fields), 14 (27%) exhibited mucosal invasion, and 8 (15%) contained skeinoid fibers. Focal SMA and S-100 positivity was found in 14 (27%) and 4 (8%) GISTs, respectively. In 38 GISTs immunostained for DOG1, 37 (97%) exhibited positivity. Eleven (21%) and 10 GISTs (19%) were assessed as intermediate and high risk, respectively. Laterally spreading features were identified in 7 GISTs (13%). In 2 GISTs, the laterally spreading tumor cells involved the surgical margin, and were referred to as an R1 resection according to the UICC system (11). No other R1 cases were found.
A summary of the clinicopathological findings of laterally spreading GISTs is provided in Table II. Of these, 1 arose in the jejunum, while the other 6 were present on the gastric walls, including the posterior wall of fundus (2 cases), corpus (3 cases) and antral anterior wall (1 case). Five (71%) were exophytic, while 4 exhibited pedunculated features. Endoscopically, submucosal tumor-like protrusions or mildly elevated features were observed in 4 GISTs (Fig. 1A; cases 1, 3, 5 and 6) and concomitant ulceration was found in one (case 6). However, these endoscopic features did not appear to be different from those of other GISTs without laterally spreading lesions. The other 3 laterally spreading GISTs (cases 2, 4 and 7) exhibited no elevated tumorous features endoscopically (Fig. 1B and C), although one of them (case 7) had well-demarcated, depressed lesions (Fig. 1C). Histologically, the laterally spreading features were not found in the mucosa or submucosa, and were localized within the muscularis propria without significant thickening adjacent to the main GISTs (Figs. 2–4). The lengths of these spreading lesions ranged from 0.12 to 0.7 cm (mean, 0.3 cm). In the 2 R1 resection cases, the removed muscular layers adjacent to the main GISTs were relatively limited, and their surgical margins were involved by the spreading lesions (Fig. 2C and F). These spreading cells histologically resembled those of tumor cells of the main GISTs in 4 cases (Figs. 2G and H, and 3B, F and I). In another 3 cases, the spreading cells consisted of more slender spindle cells with smaller nuclei, compared with tumor cells of the main GISTs (Fig. 4D and F). Compared with immunohistochemical features of the main GISTs, KIT+ and DOG1 staining of the spreading lesions were similar in 4 cases (Fig. 4E and G), but were weaker or diminished in the other 3 cases (Fig. 2G, inset and H, inset). There were no differences of CD34+ staining between the main GISTs and the spreading lesions (Figs. 2E and 4C). No SMA or S-100 positivity was found in the spreading spindle cells. One patient (case 6) succumbed to the disease 2.5 years after the surgery. In this case, the autopsy revealed a 5.5-cm recurrent growth of the GIST at the gastric excision site and multinodular peritoneal seeding in the upper abdominal cavity. The other 6 patients with laterally spreading GISTs were alive 0.4–19.2 years after the surgery, with no evidence of disease.
The laterally spreading features were significantly associated with pedunculated GISTs (P=0.006), but not with older age (P=0.312), sex (P=0.969), tumor location (gastric or non-gastric) (P=0.725), tumor size (P=0.430), exophytic type (P=0.626), dumb-bell shape (P=0.634), ulceration (P=0.977), microscopic type (spindle- or epithelioid-cell predominant) (P=0.757), high mitotic rate (P=0.815), mucosal invasion (P=0.666), skeinoid fibers (P=0.634), or higher risk category (high and intermediate risk category) (P=0.872) (Table III).
Table III.Relationship between the laterally spreading GISTs and other clinicopathological variables. |
Discussion
The present study revealed unique laterally spreading features in 13% of a total of 52 GISTs. These spreading lesions were harbored within the otherwise normal-looking adjacent muscularis propria, so that recognition would be challenging either radiologically, endoscopically, or surgically. In fact, the present study did not reveal endoscopic features or signs specific to the laterally spreading lesions. These spreading lesions were not extensive (range, 0.12–0.7 cm), but infrequently (29% of the 7 cases) involved the muscular surgical margins. These findings not only support the generally accepted concept that R0 resection requires a 1 to 2-cm safety margin (8–10), but also indicate that such safety margins should be applied to the muscularis propria, not the mucosa or submucosa. In addition, the present study demonstrated a close relationship between laterally spreading lesions and the pedunculated shape of GISTs. Therefore, surgeons should pay attention to the ≥1-cm muscular safety margins for R0 resection, particularly for pedunculated GISTs, even if these muscular walls are not thickened or tumorous.
In some cases, laterally spreading tumor cells were somewhat different from those of the main tumors. Compared with the pathological features of the main GISTs, laterally spreading lesions consisted of more slender tumor cells with smaller nuclei (in 3 cases), and showed weaker or diminished KIT/DOG1+ staining (in 3 cases). However, the former 3 cases were not identical to the latter 3 cases, and the slender morphological features of laterally spreading tumor cells did not appear to be associated with the weaker or diminished KIT/DOG1+ staining. On the other hand, the more slender morphological features of laterally spreading tumor cells somewhat resembled those of ICC hyperplasia (4,6,13). It is known that ICCs can be positive for DOG1 (14,15). These findings raise the possibility that some laterally spreading lesions may represent a hyperplastic reaction of ICCs caused, secondarily, by torque from the stalk of the pedunculated GISTs. However, the other 4 spreading lesions identified were composed of tumor cells resembling those of the main GISTs, suggesting true intramuscular extension of the tumor cells.
The most important risk factors associated with GISTs are anatomic location, tumor size, and mitotic activity, all of which are included in the widely accepted risk-stratification criteria (1–6,12). Tumor rupture is another independent risk factor of GISTs, despite its rarity (3–7,12). Mucosal invasion, high cellularity, and increased microvessel density may be additional indicators of poor prognosis (1,3,4,6). Some authors noted high recurrence or poor prognosis in incomplete resection cases of GISTs compared with complete resection cases (8,16). However, DeMatteo et al (17) concluded that microscopically positive surgical margins did not influence patient outcomes. Zhi et al (18) demonstrated that a microscopically positive surgical margin can impact the disease-free survival of patients with GISTs, but had no influence on overall survival. Therefore, the prognostic significance of incomplete GIST resection remains controversial (6,9,10,19). In the present study, both patients that had laterally spreading-related R1 resection were alive without recurrence 1–2.3 years after surgery, demonstrating that they were not associated with unfavorable outcomes. However, the recurrence or metastases of GISTs may occur many years later (6), so that further follow-up is required. In addition, one patient with a laterally spreading GIST succumbed to the disease 2.5 years after surgery, although the surgical margin in this case was free of tumor cells and the spreading lesions exhibited ICC hyperplasia-like slender morphology. Therefore, regarding the clinicopathological significance of the laterally spreading lesions, further investigations of a larger series of GISTs are needed.
To the best of our knowledge, the present study is the first to histologically describe the laterally spreading features of GISTs, which occurred in 13% of the GISTs evaluated. These spreading lesions may contribute to R1 resection, albeit uncommonly. For R0 resection, the ≥1-cm muscular safety margin should be required, particularly in cases of pedunculated GISTs.
Acknowledgements
The authors thank Mr. Kenji Okada and Mr. Shin-ichi Katori for their excellent technical assistance.
Funding
No funding was received.
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
SM conceived and designed the study. MM provided examined materials. SM, KM, and HT performed the histopathological examination. SM and YU collected appropriate references. SM wrote the paper. SM, MM, YU, KS, KM and HT reviewed and edited the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Ethics approval and consent to participate
All experimental protocols were approved by the Medical Research Ethics Committees of the Japan Self-Defense Forces Central Hospital (Tokyo, Japan) and Mishuku Hospital (Tokyo, Japan).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
DOG1 |
discovered on GIST 1 |
GI |
gastrointestinal |
GIST |
gastrointestinal stromal tumor |
ICCs |
interstitial cells of Cajal |
S-100 |
S-100 protein |
α-SMA |
α-smooth muscle actin |
UICC |
Union for International Cancer Control |
References
Miettinen M and Lasota J: Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diag Pathol. 23:70–83. 2006. View Article : Google Scholar | |
Miettinen M, Fletcher CD, Kindblom LG and Tsui WM: Mesenchymal tumours of the oesophagus; mesenchymal tumours of the stomach; mesenchymal tumours of the small intestine; mesenchymal tumours of the colon and rectumWHO Classification of Tumours of The Digestive System. Bosman FT, Carneiro F, Hruban RH and Theise ND: 4th edition. International Agency for Research on Cancer; Lyon: pp. 35–36, pp74-79, pp115-116, pp181-182. 2010 | |
Rosai J: Rosai and Ackerman's surgical pathology. 10th edition. Mosby/Elsevier; Philadelphia, PA: 2011, View Article : Google Scholar | |
Rubin BP: GIST and EGISTEnzinger and Weiss's soft tissue tumors. Goldblum JR, Folpe AL and Weiss SW: 6th edition. Elsevier/Saunders; Philadelphia, PA: pp. 569–590. 2014 | |
Miettinen MM, Corless CL, Debiec-Rychter M, Fletcher JA, Lasota J, Rubin BP and Sciot R: Gastrointestinal stromal tumorWHO Classification of Tumours of Soft Tissue and Bone. Fletcher CDM, Bridge JA, Hogendoorn PCW and Mertens F: 4th edition. International Agency for Research on Cancer; Lyon: pp. 164–167. 2013 | |
Grant NG and Noffsinger AE: Mesenchymal tumorsFenoglio-Preiser's Gastrointestinal Pathology. Noffsinger AE: 4th edition. Wolters Kluwer; Philadelphia, PA: pp. 1141–1222. 2017 | |
Dematteo RP, Heinrich MC, El-Rifai WM and Demetri G: Clinical management of gastrointestinal stromal tumors: Before and after STI-571. Hum Pathol. 33:466–477. 2002. View Article : Google Scholar : PubMed/NCBI | |
Gouveia AM, Pimenta AP, Capelinha AF, de la Cruz D, Silva P and Lopes JM: Surgical margin status and prognosis of gastrointestinal stromal tumor. World J Surg. 32:2375–2382. 2008. View Article : Google Scholar : PubMed/NCBI | |
Novitsky YW, Kercher KW, Sing RF and Heniford BT: Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg. 243:738–747. 2006. View Article : Google Scholar : PubMed/NCBI | |
Everett M and Gutman H: Surgical management of gastrointestinal stromal tumors: Analysis of outcome with respect to surgical margins and technique. J Surg Oncol. 98:588–593. 2008. View Article : Google Scholar : PubMed/NCBI | |
Brierley JD, Gospodarowicz MK and Wittekind C: TNM classification of malignant tumours. 8th edition. Wiley-Blackwell; Hoboken: 2017 | |
Joensuu H: Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 39:1411–1419. 2008. View Article : Google Scholar : PubMed/NCBI | |
Agaimy A and Wünsch PH: Sporadic Cajal cell hyperplasia is common in resection specimens for distal oesophageal carcinoma. A retrospective review of 77 consecutive surgical resection specimens. Virchows Arch. 448:288–294. 2006. View Article : Google Scholar : PubMed/NCBI | |
Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgomery K, Varma S, Corless CL, Heinrich MC, Smith KS, et al: A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 32:210–218. 2008. View Article : Google Scholar : PubMed/NCBI | |
Miettinen M, Wang ZF and Lasota J: DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: A study of 1840 cases. Am J Surg Pathol. 33:1401–1408. 2009. View Article : Google Scholar : PubMed/NCBI | |
Langer C, Gunawan B, Schüler P, Huber W, Füzesi L and Becker H: Prognostic factors influencing surgical management and outcome of gastrointestinal stromal tumours. Br J Surg. 90:332–339. 2003. View Article : Google Scholar : PubMed/NCBI | |
DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM and Brennan MF: Two hundred gastrointestinal stromal tumors. Recurrence patterns and prognostic factors for survival. Ann Surg. 231:51–58. 2000. View Article : Google Scholar : PubMed/NCBI | |
Zhi X, Jiang B, Yu J, Røe OD, Qin J, Ni Q, Sun L, Xu M, Zhu J and Ma L: Prognostic role of microscopically positive margins for primary gastrointestinal stromal tumors: A systematic review and meta-analysis. Sci Rep. 6:215412016. View Article : Google Scholar : PubMed/NCBI | |
McCarter MD, Antonescu CR, Ballman KV, Maki RG, Pisters PWT, Demetri GD, Blanke CD, von Mehren M, Brennan MF, McCall L, et al: Microscopically positive margins for primary gastrointestinal stromal tumors: Analysis of risk factors and tumor recurrence. J Am Coll Surg. 215:53–60. 2012. View Article : Google Scholar : PubMed/NCBI |