Primary Small Intestinal Angiosarcoma: Epidemiology, Diagnosis and Treatment

Case

A 73-year-old man presented with chest pain, dyspnea, melena, weakness, and fatigue for 3 days, and melena for 7 days since the discharge from a prior 3-month-long hospitalization for GI bleeding. No fever, chills, abdominal pain, nausea, or vomiting was reported. During the previous hospitalization, patient had received multiple blood transfusions and undergone endoscopy and push enteroscopy that revealed Los Angeles Grade A erosive esophagitis, small sliding hiatal hernia, two erosions in the bulb, two cratered ulcers with adherent clots in D1 and D2, a fungating mass in D3. The biopsy of the mass showed acute-on-chronic inflammatory cells with granulation tissue. Patient had no prior radiation or polyvinyl exposure and no family history of GI malignancy. He was a former smoker. Vital signs were within normal limits on admission and physical exam showed a non-distended, non-tender abdomen with decreased bowel sounds and no organomegaly.

After admission, the patient received blood transfusions, and underwent multiple enteroscopy, with the biopsy from a bleeding ulcer in D3 revealed poorly differentiated high grade sarcoma. Subsequently, a pylorus-preserving pancreaticoduodenectomy was performed; the pathology demonstrated multiple ulcerated mucosal and submucosal nodules up to 1cm in size of high grade angiosarcoma involving duodenum and jejunum, and metastatic angiosarcoma in 10 of 14 peripancreatic and mesenteric lymph nodes. The positivity for CD34, vimentin, Wilm’s tumor-1, and vWF supported the angiosarcoma diagnosis. Postoperative chest computed tomography (CT) showed masses in both lungs highly suspicious for metastasis that was absent 1 month prior. Patient survived 16 days after surgery on mechanical ventilation before family decided to discontinue treatment.

Age and gender distribution

There are 29 male and 18 female included in this study, the male to female ratio is 1.6:1. The ages of 18 female and 28 male patients are obtainable. The ages of female patients range from 25 to 85 years, with median value of 63.5 years; the ages of male patients range from 25 to 87 years, with median of 69.5 years (Fig. 1, Table 1). There was no significant difference in the age distributions between the two genders (n = 28 female vs. 18 male; P = 0.772, Wilcoxon two-sample test).

Figure 1

Age distribution in male and female patients of small intestinal angiosarcoma. There is no significant difference in age distribution between male and female genders (P = 0.677, Wilcoxon two-sample test, n = 28 and 18, respectively; the age of one male patient is missing).

The presenting clinical characteristics

The clinical symptoms and signs on initial presentation are nonspecific. The common clinical features (in descending order of frequency) include abdominal pain, anemia, GI bleeding, fatigue/weakness, weight loss, dyspnea, abdominal distension/bowel obstruction, anorexia, nausea/vomiting, acute abdomen, and bowel perforation (Table 2).

Risk factors

The development of angiosarcoma has been related to history of radiation exposure, certain environmental toxins or foreign bodies, chronic lymphedema, and genetic factors [3, 4]. There are 17 patients who had previous radiation exposure, among which 16 with therapeutic radiation, one with a 30-year-long exposure to both occupational radiation and polyvinyl chloride. The onset of radiation exposure is available in14 cases, ranging from 3 to 30 years prior to the diagnosis of angiosarcoma, with median latency of 9.5 years. In addition, there was one case with hemodialysis for 21 years (Table 3). Therefore, based on the current data, previous heavy radioactive exposure is likely the most common preventable environmental risk factor for small intestinal angiosarcoma.

Anatomical distribution and stages of small intestinal angiosarcoma

The location of the angiosarcoma in small bowel as reported were (percentage of the 47 cases, in descending order): ileum only (29.8%), jejunum only (27.7%), unspecified small intestine (23.4%), duodenum/jejunum (10.6%), duodenum only (4.3%), jejunum/ileum (2.1%) and duodenum/jejunum/ileum (2.1%) (Table 4). The jejunum and ileum are the most common locations for small intestinal angiosarcoma.

Among the 47 patients reported, 26 had metastatic disease, three patients with stage III, and four patients with stage II, others indeterminate. The metastatic sites include liver (11/26, 42.3%), lung (11/26, 42.3%), peritoneum (5/26, 19.2%), spleen (4/26, 15.4%), bone (3/26, 11.5%), stomach (3/26, 11.5%), mesentery (3/26, 11.5%), two cases of kidney (2/26, 7.7%), abdominal wall (2/26, 7.7%) and retroperitoneal (2/26, 7.7%); and one case for each of these sites: brain, oropharynx, thoracic cavity, pleura, pancreas, omentum, gall bladder, urinary bladder, appendix and skin (1/26, 3.8%).

Biomarkers for diagnosis

The diagnosis of small bowel angiosarcoma may be very challenging due to the non-specific clinical, radiological and histopathological features as seen in our and previously reported cases [1, 5-45]. Imaging studies including CT, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and ultrasound can be used to define the extent of abdominal angiosarcoma prior to operation. Endoscopy and enteroscopy help detect the source of bleeding. Although the biopsy done by endoscopy and/or enteroscopy may lead to the appropriate diagnosis, it may be overlooked initially as in our case. Surgical resection and subsequent immunohistochemical studies are therefore required for a definitive diagnosis [3, 4].

Histological characteristics of angiosarcoma may provide useful clues for diagnosis. Angiosarcoma can be classified into different subtypes based on the cytologic appearance: spindle-shaped endothelial cells, epithelioid with large rounded or polygonal cells, and pleomorphic or mixed phenotypes as in most angiosarcoma [21]. Areas of irregular anastomosing vasculature lined by atypical endothelial cells are readily identifiable in histology study. However, the existence of anaplasia in most of angiosarcomas makes it challenging to distinguish such tumors from other undifferentiated ones such as melanoma or carcinoma. Therefore immunohistochemistry is mandatory to establish the definitive diagnosis of angiosarcoma. Expression of endothelial markers CD31, CD34, von Willebrand factor (vWF), Ulex europaeus agglutinin 1 (UEA-1), Friend leukemia integration 1 (Fli-1), endothelin-1, vascular endothelial growth factor (VEGFR), and erythroblast transformation specific related gene (ERG) can help identify angiosarcomas, each with different sensitivity and specificity (Table 5, [2, 46-51]), among which the vWF, UEA-1 and CD31 are considered the most useful for the diagnosis of poorly differentiated cases [1].

However, some of these markers may be lost due to progressive tumor dedifferentiation. Otherwise, epithelioid angiosarcoma may express cytokeratins, which makes it difficult to distinguish it from poorly differentiated carcinomas. Therefore, a number of other markers with different tissue specificity including lymphatic endothelial (lymphatic vessel endothelial hyaluronan receptor-1/Lyve-1 or podoplanin/D2-40), smooth muscle (desmin), neural (S100, SOX10), epithelial (keratin), stromal (CD117, DOG1), melanocytic (HMB-45, melan-A), human herpes virus 8 (HHV-8), and mesothelial (calretinin, CK5/6, HBME-1 and WT-1) can be used to distinguish angiosarcoma from other tumors such melanoma [3, 26, 48].

The markers used in the reported cases of small intestinal angiosarcoma are summarized in Table 6. Among which, collagen IV, a marker for basal lamina collagen has proven to be a powerful tool in the identification of endothelial neoplasm in combination with other markers [52]. Overexpression of vimentin, a marker for epithelial-mesenchymal transition, is linked to accelerated tumor growth, tissue invasion, and poor outcome [53].

The expression of those endothelial markers is heterogeneous in different types of vessels of various organs [49, 54]. Also, unusual expression patterns and loss of endothelial markers are common findings in angiosarcomas [55]. Therefore, a combination of multiple markers may markedly improve the sensitivity and specificity in the diagnosis in challenging angiosarcoma cases (Table 7, [2, 50, 56-58]).

Treatment and outcome

The treatment modalities are available in 45 patients with small intestinal angiosarcoma (Table 8), among which 31 patients underwent resection alone (26 cases with obtainable survival times); eight had resection/chemotherapy (seven with survival times); two with surgery/chemotherapy/radiation therapy (both with survival times reported); one patient received surgery, but it is unclear if other treatment modality was added subsequently (with survival time); one patient received chemotherapy only (with survival time); one had chemotherapy/radiation (with survival time), and one patient treated was Argon plasma coagulation (APC, with survival time), the treatment for two patients are unavailable (with survival time). The chemotherapy agents used as single or in combination are anthracycline (three cases), paclitaxel (three cases), dacarbazine (two cases), cisplatin (one case), thalidomide (one case), vincristine (one case), and cyclophosphamide (one case).

Among the 26 patients treated with surgery alone and included for survival analysis, 16 had metastatic disease at diagnosis, two with stage III, while the stages of the other eight patients indeterminate. Six out of the seven patients treated with surgery plus chemotherapy were found to have metastatic lesions at diagnosis, while the other one was indeterminate. Furthermore, almost all of the patients with metastatic small bowel angiosarcoma underwent surgical resection with or without additional treatment modalities: surgery alone (18/26, 69.2%), surgery plus chemotherapy (6/26, 23.1%), surgery plus chemotherapy and radiation (1/26, 3.8%), and only one patient was treated with APC (1/26, 3.8%).

The median survival times are obtainable for 41 patients (as reported or from personal communications). The median survival time is 150 days (range 9 to more than 3,720 days) days after diagnosis (Fig. 2a). The median survival times are 300 days for female (n = 15) and 120 days for male patients (n = 26), with no significant difference between the genders (log-rank test: z = 0.17; P = 0.86; Fig. 2b). The overall 1-, 2-, 3-, and 5- year survival rates are 36.6%, 14.6%, 12.2%, and 2.4% respectively. The survival rates are markedly lower than that of the primary soft-tissue sarcomas (5-year survival of 50-60%), and overall angiosarcomas (5-year survival of about 35%) [1].

Figure 2

(a) Survival analysis of patients with small intestinal angiosarcoma. (b) There is no gender difference in the survival times between male and female patients (0 = female, 1 = male; Log-rank test, z = 0.17, P = 0.86, n = 15 and 26, respectively).

The survival times in different treatment groups are further summarized (median survival time) as showed in Figure 3. There is a significant difference in the survival times between patients treated with surgical resection only (range 8 - 3,720 days; median 96.5 days, n = 26) compared with surgery/chemotherapy (range 150 - 1,080 days, median 420 days, n = 7; log-rank test, z = 2.2; P = 0.0275). Due to the small number of cases for other treatment modalities, only range and median survival times are provided here: surgery/chemotherapy/radiation (range 1,020 - 1,440 days, median 1,230 days, n = 2); upfront surgery but with unknown subsequent therapy (1,080 days, n = 1); chemotherapy only (median 120 days, n = 1); chemotherapy/radiation (540 days, n = 1), APC (42 days, n = 1); unspecified treatment (range 120 - 510, median 315 days, n = 2).

Figure 3

Survival times in different treatment groups. The survival time is longer in patients received resection/chemotherapy compared to that in patients underwent surgery alone (*P = 0.0275; Log-rank test; n = 7 and 26, respectively). The survival times in other treatment groups are not compared due to the limited case numbers. *Compared to treatment with patients treated with surgery only. APC: argon plasma coagulation; Chemo: chemotherapy; NA: the other modality not available; Rad: radiation therapy; Surg: surgery.