AS is a highly malignant soft tissue sarcoma originated from vascular endothelial cells, accounting for less than 1% of soft tissue sarcoma[1]. It often occurs in the skin, subcutaneous tissue of the head and face[9],breast, but also in the mouth[10], mediastinum[11], kidney[12], thyroid[13], lung and other anatomical sites[14]. AS in digestive system is rare, but in solid organs such as liver and spleen is relatively common[15]. Small intestine AS is particularly rare, to the best of our knowledge, only 66 cases of small intestinal angiosarcoma including primary or metastatic were reported in the current English literature. The most common sites of small intestinal AS were ileum and jejunum[2–8]. Our case was located in jejunum.
The etiology of AS remains unclear.It may be associated with long-term exposure to thorium oxide, vinyl chloride, arsenic and other chemicals. Radiation export may also be the cause of AS,such as radiotherapy treatment for prostate cancer, colorectal cancer, endometrial cancer or cervical cancer[2–4]. Chemotherapy,chronic lymphedema, chronic inflammation,and trauma may also be associated with angiosarcoma.It had been reported that angiosarcoma was probably associated with long-term taking of calcium channel blocker to control blood pressure,such as levamlodipine besylate[2]. It may occur around arteriovenous fistula or persistent foreign body. In addition, there is a certain relationship with hemodialysis or genetic factors.The average time from exposure to these factors to the diagnosis of angiosarcoma was 18 years (range of 4 to 30 years) [3]. Our patient did not have any of these aforementioned medical histories.
Li et al. reviewed the literature found 66 cases of small intestinal AS[4]. There were 24 patients diagnosed before the year 2000, and 42 patients were diagnosed after 2000. Patient age ranged from 24 to 92 years, with an average age was 64 year old, and 70% of patients were over 60 years old. The female:Male ratio was 1:2.4. The clinical manifestations of small intestine AS were extremely variable and nonspecific. The main clinical features included gastrointestinal bleeding (black stool, hematochezia or occult bleeding), abdominal discomfort/pain, and abdominal mass. Other symptoms included intestinal obstruction, diarrhea and weight loss, nausea/vomiting, acute abdomen,bowel perforation,skin pallor/ anemia, etc[2–8]. Some early cases were even asymptomatic and were occasionally found in routine endoscopy[16]. Our patient developed black stool for 7 days without obvious inducement, and gradually felt dizzy and weak for 3 days.Because the clinical symptoms are nonspecific,and may be confused with other gastrointestinal diseases, it is easy to misdiagnose. To some extent biopsy is helpful to definite diagnosis, but postoperative pathological examination is still the most effective way to definite diagnosis.
Endoscopy reveals that AS is generally nodular, polypoid or protuberant mass, most are solid, a few may be spongy, diffuse or ulcerative. Cross-sections of the tumor are usually soft, accompanied by hemorrhage, necrosis and fish-like change. Pathological examination tumor diameter was 1.5cm ~ 12.0 cm, with an average diameter of 5.0 cm. It is usually a single nodule, occasionally a multiple nodule[6].Histologically, AS can be classified into well-differentiated, poorly differentiated,and epithelioid tumors. 42 reports provided detail pathological description, of which 17 cases were epithelioid, 10 cases were well differentiated,11 cases were poorly differentiated[4].Microscopically, the tumor cells are spindle, epithelioid or irregular in shape, with marked heteromorphism, common mitosis,necrosis, prominent nucleoli and rich eosinophilic cytoplasm,forming slit-shaped or pseudoglandular or papillary structures. The most significant diagnostic features are irregular vascular anastomosis and atypical endothelial cells, with red blood cells in the lacuna. In addition, the formation of blood lake is of great significance for diagnosis.
Immunohistochemistry is the better way to make an accurate diagnosis of the epithelioid AS. AS immunohistochemistry expresses more than one vascular endothelial markers, including: CD34, CD31, ERG, FLI-1,factor VIII, UEA-1 and so on[17]. The factor VIII-associated antigen and UEA-1 are considered to be the most sensitive and reliable markers in evaluating the origin of epithelioid cell. Factor VIII has a high specificity for the diagnosis of AS, but is not very sensitive to poorly differentiated AS. UEA-1 has high sensitivity but low specificity[18].The expression rate of CD34 in gastrointestinal tract AS is significantly higher than that in skin AS. In the diagnosis of AS, the sensitivity of CD31 is better than the factor VIII, and its specificity is higher than UEA-1[18]. Usually one or more vascular markers are positive, and AS is diagnosed when the epithelial markers are negative. Although some vascular endothelial cell markers can also stain histiocytes, megakaryocytes, myeloid cells, or some other types of cells, our experience is that more than two strong and diffusely stained endothelial markers appear simultaneously in malignant solid tumors. At this time, the diagnosis of AS has high specificity (except epithelioid sarcoma and myeloid sarcoma). Recently, the ETS family transcription factors ERG and FLI-1 have been considered as relatively specific markers of vascular endothelium[19]. Without these markers, AS is easily misdiagnosed as differential cancer. It should be pointed out that the expression rate of ERG in well-differentiated AS is higher, while in poorly-differentiated or epithelioid AS, the expression may be lost due to the dedifferentiation of the tumor. However, epithelioid AS can focally express epithelial markers (CK7 and CK), and can also express CK when AS metastasizes to lymph nodes, which may bring some pitfalls in biopsy. In addition, CD117 is not routinely used as a vascular-derived marker, but when AS is positive, it suggests that patients receiving imatinib treatment may be effective[20].
Some results showed that the amplification of C-MYC gene on chromosome 8q24.21 had high sensitivity and specificity for secondary AS (including radiation-related AS and lymphedema related AS), and there was overexpression of C-MYC protein simultaneously, while the amplification of C-MYC gene was rare in primary cutaneous AS[21]. The overexpression of C-MYC protein in immunohistochemistry is not specific to primary or secondary AS. Different mechanisms (any link including gene amplification, gene rearrangement, transcription, translation or post-translational modification) may lead to the overexpression of C-MYC protein[22]. Therefore, we can not differentiate primary or secondary AS by the overexpression of C-MYC protein by immunohistochemistry alone, we must detect whether there is amplification of C-MYC gene by FISH. Our patient had no medical history of AS or the other tumor in other anatomical site. Immunohistochemistry C-MYC protein was negative, and showed no amplification of C-MYC gene by FISH, all of the above results supported primary small intestine AS.
Before diagnosing primary small intestinal AS, it is necessary to exclude metastatic AS firstly. The clinical history is very important. The differential diagnosis mainly includes (1) gastrointestinal stromal tumor (GIST): The simultaneous expression of CD117 and DOG1 has higher sensitivity and specificity for GIST. CD34 is also positive in GIST, but its specificity is relatively low. (2) Poorly differentiated cancer: tumor cell nuclear polymorphism is more obvious, and vascular fissure-like structures and blood lake phenomena are rarely seen. Immunohistochemistry expressed CK but did not express vascular markers. (3) Epithelioid sarcoma: sometimes it also can produce pseudohemangioma-like morphology, which can express Vimentin, CK, CD34,it has immunophenotype overlap with epithelioid AS, but usually INI-1 is negative, and CD31 and ERG are not expressed. (4) Kaposi's sarcoma(KS): It is usually associated with immunosuppression such as AIDS. The small intestinal KS is usually multifocal. The fissure-like space contains red blood cells between the spindle cells, PAS positive eosinophilic transparent bodies can be seen, it can also express vascular endothelial markers, but HHV8 positive can help diagnosis[23].(5) Malignant mesothelioma: It expresses mesothelial markers such as CK5/6, WT-1, D2-40, Calretinin,etc, but does not express vascular endothelial markers. (6) Carcinosarcoma: It's composed of cancer and sarcoma, the component of sarcoma can be for AS. Cancer and sarcoma have different immunophenotypes[24].
The factors influencing the poor prognosis include age, tumor size, TNM stage, surgical margin, and metastasis[3]. The patients' age is less than 50 years old, tumor diameter is less than 5.0 cm, low TNM stage and negative surgical margin are all relatively good prognostic factors. The small intestinal AS commonly metastasizes to regional lymph nodes,the liver, lungs, and bones. Metastases at presentation occur in 40% of the cases[3, 4].
Because small intestinal AS is rare, there is no standard treatment guidelines. Usually surgery or postoperative radiotherapy and chemotherapy is the treatment option. Surgical resection is the first choice for focal resectable tumors, which may also be used for palliative treatment in patients with metastatic disease. For localized AS, complete radical resection with wide margins is the primary treatment of choice[3, 4]. Early recognition of the clinical signs and symptoms with early diagnosis and complete surgical resection should be beneficial. Whether neoadjuvant therapy is useful for advanced diseases remains controversial. Prognosis in advanced diseases is very poor despite the use of surgery, chemotherapy and even radiotherapy. Surprisingly, there is a case of spontaneous regression of pulmonary metastatic EAS from the small intestine[5].Because of the limited scope of tumor involvement and negative surgical margin, our patients had relatively good prognosis. No radiotherapy and chemotherapy was given after operation, without recurrence or metastasis after 2 years follow-up.