Gastrointestinal stromal tumors (GIST) are rare. Mean annual incidence in the world is 1.0 — 1.5 cases per 100 000 [1]. Stromal tumors are usually localized in stomach (about 60%) and small intestine (about 25%). Lesion of esophagus (up to 5%) and colon (up to 5%) is rarer. Other localizations of tumors are observed in 4% — 5% of cases (greater omentum, mesentery, retroperitoneal space) [2, 3].

Duodenal stromal tumors are very rare and make up only 3-5% of all patients with GISTs [4]. The most common site is descending part of the duodenum (D2), less common — lower horizontal segment (D3), ascending part (D4) and duodenojejunal junction. Stromal tumors are extremely rarely localized in proximal segment (D1) [5]. Considering low morbidity and complexity of anatomical zone, symptoms of duodenal GISTs are very diverse. There are few data in the world literature regarding treatment approaches and prognosis in these patients. Most often, duodenal GIST is asymptomatic. The most common symptoms are gastrointestinal bleeding and abdominal pain, less common — obstructive jaundice and back pain [6 — 8].

Morphologically, duodenal GISTs do not differ from stromal tumors of other localizations. In contrast to gastric stromal tumors, duodenal GIST is more often characterized by spindle cell structure correlating with KIT gene mutation. PDGFRA gene mutations and WT wild type are less common. Similar to small bowel GIST, there is a high incidence of exon 11 deletions and exon 9 duplications in KIT gene [8, 9]. In this regard, duodenal GISTs have more unfavorable prognosis compared to gastric GISTs. Moreover, duodenal GISTs determine unfavorable prognosis in schemes for assessing the risk of disease progression [10, 11].

Targeted therapy with tyrosine kinase inhibitors (TKI) is preferred for disseminated GISTs. To date, there are 3 lines of treatment with TCIs: imatinib, sunitinib and regorafenib. Surgical treatment is considered as an adjuvant approach in patients with favorable response to TKI therapy [12 — 14].

Surgery is preferred in patients with localized duodenal GISTs. Gastropancreaticoduodenectomy (GPDE) is standard procedure. However, this operation is very traumatic and associated with high morbidity, mortality and poor functional outcomes.

Postoperative complications after GPDE occur in 30-70% of patients. Mortality rate is up to 5% [12, 13]. The most common complication is leakage of pancreatojejunostomy and biliodigestive anastomoses (30% and 9%, respectively). Pancreatic fistulas after GPDE occur in 10% — 15% of cases [15, 16].

According to literature data, local resections are justified in patients with GISTs if tumor cells are absent within resection margin (R0) [17, 18]. These procedures significantly improve early results and quality of life. At the same time, overall survival is similar to that after extended resections [17 — 20]. Negative resection margin and intact tumor capsule are mandatory requirements for surgery [18, 19]. Local duodenal resections are associated with low postoperative morbidity, favorable functional outcomes and better quality of life, as well as less hospital-stay compared to extended surgeries. Considering similar long-term results, local resections are preferred for duodenal GISTs.

The most significant predictors of tumor progression are dimension, mitotic index and mutation profile of tumor [11, 17]. Similar to other localizations, combined treatment with neoadjuvant and adjuvant imatinib therapy is required in patients with duodenal GISTs and high risk of progression [22, 23]. However, it is necessary to expand the indications for neoadjuvant imatinib therapy including patients with low-to-moderate risk of progression to ensure optimal technical conditions for local resections.

Thus, targeted TKI therapy is preferred in patients with metastatic disease, surgery — in patients with localized duodenal GISTs. GPDE is associated with high morbidity, mortality and poor functional outcomes. Considering favorable immediate results and functional outcomes, as well as similar long-term results, local resections are preferred for duodenal GISTs.

The objective of our study was to evaluate the immediate and long-term results of surgical and combined treatment of patients with duodenal stromal tumors.

Material and methods

There were 50 patients with non-epithelial duodenal tumors for the period 2002 — 2019 at the Blokhin National Cancer Research Center. Two patients had leiomyoma, 1 — leiomyosarcoma, other 47 patients — stromal tumors. Mean age of patients was 58.2 years. There were 29 women and 18 men. For duodenal GISTs, descending duodenal segment (D2) was the most common site (n=24, 51.1%), lower horizontal part (D3) — 15 (31.9%) patients, ascending segment (D4) and duodenojejunal junction — 6 (12.7%) patients. Proximal (D1) tumors were observed in 2 (4.3%) patients. Spindle-cell structure of duodenal GIST was found almost in 90% of cases. Mutational profile of KIT and PDGFRA genes was determined in 26 patients. Except for 2 patients with GIST syndrome associated with NF1, KIT gene mutations were detected in all cases (exon 11 — 20 (76.9%) cases, exon 9 — 4 (15.4%) cases) (Table 1).

Table 1. Characteristics of patients with duodenal stromal tumors

Note. * — risk of disease progression according to the modified NIH (National Institutes of Health) scheme in patients with localized and locally advanced GIST.

Disseminated process was initially diagnosed in 6 out of 47 patients with GISTs. In 2 cases, GIST syndrome was associated with neurofibromatosis type 1 (NF1). Other 39 patients had localized and locally advanced process. Patients with metastatic disease underwent TKI therapy. Patients with localized and locally advanced process underwent surgical or combined treatment depending on risk of progression.

Results

Five out of 6 patients with metastatic disease underwent therapy with imatinib 400 mg/day, one patient with KIT exon 9 mutation — 800 mg/day. Therapy resulted clinical effect in all patients (partial regression in 4 patients and stabilization of disease in 2 patients). Progression-free period under imatinib therapy was 21 months. Disease progression was noted in 4 patients. Two patients are still taking imatinib. In 2 patients with progression of disease, higher dosage of imatinib (800 mg/day) did not result any clinical effect. Two patients with progression under imatinib therapy underwent treatment with sunitinib 50 mg/day for 4 weeks with a 2-week interval. Stabilization of disease within 8 months was observed in 1 patient, 2-month stabilization — in another one (the patient continues treatment). Surgical treatment was considered in patients with effective targeted therapy and performed in 4 patients including 2 cases of double cytoreductive surgeries. Overall 5-year survival rate was 40%.

Surgical treatment was carried out in 37 out of 39 patients with localized and locally advanced process. Two patients refused surgery.

Considering anatomical features of the duodenum, the following procedures are possible: gastropanreaticoduodenectomy (GPDE), atypical resection (AR), proximal resection, distal segmental resection (DSR) and distal resection (DR), pancreas-sparing duodenectomy. Local resections include:

1. Atypical (wedge-shaped) resection — excision of tumor and duodenal wall segment within intact tissues (negative resection margin). This procedure is possible when tumor with narrow base is localized on anterior, lateral and posterior walls of the duodenum (Fig. 1A, B). Suturing of duodenal wall defect is performed using double-row sutures in transverse direction to prevent duodenal stenosis (Fig. 1C).

Fig. 1. Stages of duodenal wedge resection.

a — computed tomogram of the abdominal cavity organs, b—d — intraoperative photographs. Explanations in the text.

Contraindications for atypical resection are wide base of tumor (associated with resection of extensive duodenal flap and high risk of duodenal stenosis), lesion of medial wall and peripapillary neoplasms.

We performed 13 atypical resections in patients with non-epithelial duodenal tumors including 11 ones with localized GIST and 2 patients with leiomyoma (Table 2). Postoperative complications Clavien-Dindo grade 1 occurred in 2 (15.3%) patients (postoperative wound suppuration). No postoperative impairment of quality of life was noted.

Table 2. Characteristics of patients with localized and locally-advanced duodenal stromal tumors

2. Upper (proximal) duodenectomy — resection of duodenal bulb (D1) with proximal part of descending duodenal segment (D2). Stapler suture on the duodenal stump is covered with a purse-string suture. Plastic stage implies gastroenterostomy and inter-intestinal anastomoses in various modifications. We observed proximal duodenal tumor only in 2 (4.3%) patients. In both cases, local resections of duodenal bulb were carried out. The possibility of this procedure is determined by the distance between inferior edge of the tumor and major duodenal papilla.

3. Distal segmental resection — excision of tumor with circular resection of distal segment (D4) in patients with lesion of ascending duodenum or duodenojejunal junction (Fig. 2A, B). Resection is followed by duodenojejunostomy in "side-to-side" or "end-to-side" fashion. Anastomosis is usually located to the left or below superior mesenteric vessels (Fig. 2C).

Fig. 2. Stages of distal segmental duodenectomy.

a — computed tomogram of the abdominal cavity organs, b—d — intraoperative photographs. Explanations in the text.

GIST of ascending part (D4) and duodenojejunal junction was observed in 6 (12.7%) patients. Distal segmental resection was performed in 5 patients. This procedure was associated with acceptable postoperative morbidity and quality of life. Postoperative complication occurred only in 1 patient (paracaudal abscess followed by ultrasound-assisted drainage) (Table 2).

4. Distal pancreatectomy — circular distal resection of descending (D2), lower horizontal (D3) and ascending (D4) duodenal segments in patients with lesion of descending and lower horizontal duodenal segments (Fig. 3A, B). The final stage was duodenojejunostomy in side-to-side fashion between residual descending duodenal segment (D2) and jejunum (Fig. 3C). In this case, jejunum loop can be passed behind and anterior to small bowel mesentery [21].

Fig. 3. Stages of distal duodenectomy.

a — computed tomogram of the abdominal cavity organs, b—d — intraoperative photographs. Explanations in the text. Anatomical conditions. A — computed tomogram of the abdominal cavity organs, B—D — stages of distal resection of the duodenum (intraoperative photos). Explanations in the text.

Technical limitation for this procedure is tumor localization near major duodenal papilla. The minimum necessary distance for distal resection is 3 cm (Fig. 3A) [21].

We performed distal duodenectomy in 9 patients (leiomyosarcoma — 1, duodenal GIST — 8). Postoperative complications developed only in 3 patients (Clavien Dindo grade 1 — 1 (11,1%) patient, grade 2 — 2 (22.2%) patients). These were postoperative wound suppuration and external pancreatic fistula ISGPF type A and B (Table 2). No postoperative impairment in quality of life was observed.

5. Pancreas-sparing duodenectomy (PSD) is performed in case of distance to major duodenal papilla < 3 cm. Total mobilization and excision of duodenum are carried out. Reconstructive stage includes choledochointestinal, gastrointestinal and inter-intestinal anastomoses. There are 2 types of PSD. These are typical procedure described by L.F. Sillin in 1984 [24] and papilla-sparing PSD with preserving of major duodenal papilla and sphincter of Oddi. Typical PSD does not differ from PDE regarding postoperative morbidity and quality of life [25]. Considering postoperative morbidity and functional outcomes, papilla-sparing PSD has an advantage over GPDE [26]. We performed GPDE in all patients with tumor localized near major duodenal papilla.

Localized process was diagnosed in 25 out of 37 patients, locally advanced process — in 12 cases. Considering preferable local resections for duodenal GIST, we considered expanding the indications for neoadjuvant imatinib therapy to achieve the most convenient technical conditions for these procedures.

Neoadjuvant imatinib therapy was performed in 10 (27.1%). As a result, local resections were carried out in 24 out of 37 patients. Other 13 patients underwent GPDE (Table 2). Postoperative complications developed in 6 (22.2%) and 8 (61.5%) patients after local resections and GPDE, respectively. Similarly, incidence of severe complications (Clavien Dindo grade 3) was significantly lower after local resections (4.2% (1/24) vs. 15.3% (2/13), respectively). Postoperative mortality was absent in both groups.

There were no significant differences in long-term relapse-free and overall survival after GPDE and local resections.

Overall 5-year survival was 91% and 70% after PDE and local resections, respectively (p = 0.5960); 5-year relapse-free survival — 65% and 70%, respectively (p = 0.6226) (Fig. 4). There were no local relapses in both groups.

Fig. 4. Long-term results of surgical and combined treatment of patients with localized and locally-advanced duodenal stromal tumors.

Thus, local resection is preferred for duodenal GIST considering similar survival rates, better immediate results and quality of life.

Discussion

Surgery is the main approach for localized and locally advanced duodenal GIST.

Historically, GPDE was considered standard procedure for duodenal tumor. However, this surgery is very traumatic and associated with high morbidity, mortality and poor functional outcomes.

According to various data, postoperative complications after GPDE occur in 30-70% of patients, mortality rate is up to 5% [12, 13]. The most common complication is leakage of pancreatojejunostomy and biliodigestive anastomoses (30% and 9%, respectively). Pancreatic fistula after GPDE develops in 10% — 15% of cases [15, 16].

Currently, optimal surgical strategy is discussable in these patients. Local resections are preferred for GIST considering similar long-term results, fewer postoperative complications and better functional outcomes. Negative resection margin and intact tumor capsule are mandatory criteria of R0 local resection [18, 19]. Considering anatomical features of the duodenum, the following types of local resections are possible: atypical resection, proximal resection, distal segmental resection and distal resection.

Indications for neoadjuvant imatinib therapy should be extended in patients with large tumors and locally advanced process to ensure the most convenient technical conditions for local resections. According to our data, neoadjuvant imatinib therapy was performed in 10 (27.1%) out of 37 patients that increased percentage of local resections (24 (64.9%) patients). Other 13 patients underwent GPDE.

Early results after local resections were significantly better compared to GPDE. Postoperative complications occurred in 6 (22.2%) and 8 (61.5%) patients after local resections and GPDE, respectively. Incidence of severe complications (Clavien Dindo grade 3) was significantly lower after local resections (4.2% (1/24) vs. 15.3% (2/13), respectively). Postoperative mortality was absent in both groups. Relapse-free and overall survival was similar. Overall 5-year survival was 91% and 70% after PDE and local resections, respectively; 5-year relapse-free survival — 65% and 70%, respectively (p = 0.6226). There were no local relapses in both groups.

Thus, local duodenal resections are associated with low postoperative morbidity, favorable functional outcomes and quality of life, as well as less hospital-stay compared to extended surgery (GPDE). Local duodenal resections are preferred for localized and locally advanced GIST considering similar long-term results.

The authors declare no conflicts of interest.