Radiation-induced colon angiosarcoma: a case report
Article information
Abstract
Angiosarcomas are rare malignant neoplasms derived from vascular endothelial cells, characterized by hyperproliferation of these particular endothelial cells. These rare and aggressive neoplasm entities represent only 2% of all soft-tissue tumors and mainly occur in the skin and other subcutaneous tissues, particularly in the head, neck region, and breast. Various factors such as trauma, some chemical toxins, familial syndromes, and radiotherapy have been implicated in the development of angiosarcoma. Post-radiation gastrointestinal angiosarcomas are very rare with an extremely poor prognosis. Only a few cases of radiation-induced gastrointestinal angiosarcomas have been reported in the literature, particularly in the small bowel. Herein, we present a case of a 55-year-old woman who developed colon angiosarcoma 16 years after receiving radiotherapy for squamous cell carcinoma of the cervix.
Introduction
Angiosarcomas are uncommon malignant tumors that develop from endothelial cells of blood vessels or lymphatic vessels. It’s an aggressive neoplasm representing only 2% of all soft-tissue sarcomas. The most common site of primary angiosarcoma is usually found in the cutaneous and breast, such as the neck and head region, accounting for approximately two-thirds of all angiosarcomas [1]. However, primary angiosarcoma of the gastrointestinal is extremely rare with a poor prognosis and accounts for less than 2% of all digestive malignancies. Likewise, colorectal angiosarcoma is estimated less than 0.001% for all colorectal cancers [2,3].
On the other hand, secondary angiosarcoma is mainly related to exposure to different risk factors including chemical toxic, chronic lymphedema, radiotherapy, and familial syndromes such as hemochromatosis, neurofibromatosis type 1 bilateral retinoblastoma, and Maffucci syndrome. Radiotherapy and chronic lymphoedema are the most common risk factors [4]. Although post-radiation angiosarcoma of the gastrointestinal tract is unusual and rare, the small bowel is the most common site in most reported cases. As far as we know, a few cases of radiotherapy-induced colon angiosarcoma have been reported in the literature [5].
This paper reports an uncommon case of angiosarcoma of the colon after radiotherapy.
Case Report
This case is about a 55-year-old female admitted to the Emergency Department for abdominal pain, ascites, intermittent rectal bleeding, and a progressive deterioration in her overall health status, with loss of appetite and weight. She had a medical history of squamous cell carcinoma of the uterine cervix 16 years earlier, for which she underwent a total hysterectomy with salpingo-oophorectomy followed by receiving a series of 24 postoperative radiotherapy sessions and cisplatin-based chemotherapy (we did not have the information on both the radiation dose and the field). She denied taking any new medication/tobacco or changes in regimen, and we did not notice any other personal history or a family history of cancer.
A physical examination revealed a conscious patient with blood pressure within normal range, but she was pale, with tachycardia at 120 bpm, and she had significant abdominal distension with ascites. There was no lymphadenopathy, splenomegaly, or hepatomegaly, and rectal examination was normal. Laboratory tests at admission revealed severe anemia at 6.3 g/dL, hypoalbuminemia, normal kidney function, and no evidence of infection (activated protein C level 6 mg/L. There were no elevated levels of the tumor markers carcinoembryonic antigen and carbohydrate antigen 19-9 (CA19-9), although CA125 levels were elevated. A large-volume abdominocentesis was performed, which revealed hematic fluid with a protein concentration level of 45 g/L. Cytological examination of the abdominal fluid was negative for tumor cells.
Given the hematic fluid aspect, a computed tomography (CT) of the pelvic and abdomen was performed, which showed symmetrical and circumferential wall thickening of the cecum and ileum with abundant hyperdense ascites without extravasation of contrast product. There were no hepatic or splenic lesions or profound lymphadenopathies with no signs of aorta or mesenteric thrombosis (Fig. 1). During her hospitalization, she was transfused with three units of packed red blood cells after undergoing a colposcopy, which revealed an ulcerative circumferential mass in the cecum and right colon that was bleeding on contact with complete colonic obstruction, as well as signs of post-radiation rectitis (Fig. 2). Several biopsies were taken from the mass for further analysis.
A computed tomography scan showed (A, B) circumferential thickening of both the cecum and the right colon (yellow arrows) and (C) an abundance of ascites (blue arrows).
A colonoscopy revealed a stenosing, hyperemic, hemorrhagic, and friable circumferential mass of the right colon and cecum.
Pathological examination of the specimen showed a malignant, highly vascularised, poorly differentiated tumor, lined vessels by large endothelial cells. Nuclei had dense chromatin with irregular outlines and scanty cytoplasm. Additional immunohistochemical analysis confirmed the endothelial nature of the mass, with positive staining of the tumor cells on both CD34 and CD31. In addition, the tumor had a Ki67 proliferation index of 40%. There was no mass expression for CK, CD3, CD20 or HHV8. These findings supported the diagnosis of colonic angiosarcoma (Figs. 3, 4). At the multidisciplinary meeting, it was decided that surgical resection should be considered. Unfortunately, our patient developed a massive bilateral pulmonary embolism and died within 7 days after admission. The informed consent was waived.
A poorly differentiated angiosarcoma of the colon involving lamina propria and showing cords and sheets of atypical endothelial cells: (A) hematoxylin-eosin staining ×10, (B) hematoxylin-eosin staining ×20.
(A) Angiosarcoma showing diffuse and strong immunoreactivity for CD31. (B) Angiosarcoma shows a significant increase in Ki67 expression.
Discussion
Angiosarcoma is an uncommon malignant neoplasm arising from vascular or lymphatic endothelial cells and represents only 2% of all soft-tissue sarcomas. This highly aggressive tumor usually arises in the skin or soft tissue, with less frequent occurrences in the breast, bone, and internal organs. The liver, spleen, adrenal glands, and ovaries are common intra-abdominal locations of angiosarcoma. On the other hand, gastrointestinal tract angiosarcoma is considered an exceedingly infrequent site with a poor prognosis. A systematic review conducted by Schizas et al. [5] identified 110 cases of angiosarcoma, with the small bowel being the most common site (44,5%), followed by the colon and rectum in 35,5%. However, only a small number of cases were identified as post-radiation angiosarcoma, with 15 cases in the small bowel and 7 cases in the large intestine [1,2].
In the study of Li et al. [6], 66 cases of small bowel angiosarcoma were collected between 1970 and 2017, of which only 17 cases were related to angiosarcoma radiation. The mean age at diagnosis was 64 years ranging from 47 to 88 years, and the majority of the patients were female (ratio female/male = 6), and had received radiotherapy for malignant genital tract cancers. The interval between exposure to radiation and the development of angiosarcoma ranged from 3 to 24 years with a mean of 13 years. The terminal ileum was the most frequent localization followed by the jejunum. At diagnosis, distant metastases such as the liver, lungs, and peritoneal surface were found in most cases.
Only 39 cases of colorectal angiosarcoma have been described as case reports, including our patient. The mean age was 58.7 ± 18.9, with 19 cases of males and 20 females [3,5]. Our patient is a 55-year-old woman. Various risk factors such as chronic lymphedema, radiation, thorium dioxide (Thorotrast) exposure or vinyl chloride, and several familial syndromes have been documented to develop soft tissue, liver, and bone angiosarcoma. Most cases of post-radiation angiosarcoma were reported in the soft tissue, and breast with only a few reported cases of small bowel angiosarcoma. Nevertheless, post-radiation colorectal angiosarcoma remained exceedingly rare. Out of 39 cases of colorectal angiosarcoma, only seven patients have a history of exposure risk factors, including our patient who has received radiotherapy for her cervix carcinoma. The interval between radiation therapy to diagnosis of tumor onset ranged from 4 to 20 years, with an average of 13 years [4,5,7,8]. Our patient received radiotherapy 16 years before the diagnosis of colon angiosarcoma. A previous follow-up study showed that the overall risk of angiosarcoma after radiotherapy ranged from 0.01% to 0.30% [6].
The primary clinical manifestation of colorectal angiosarcoma is lower gastrointestinal bleeding, constituting 65.7% of cases, with melena presented in 51% and hematochezia in 14.3% associated with abdominal or perianal pain and weight loss. There have been reports of unusual presentations including intraperitoneal bleeding, intestinal obstruction, and chief complaints related to metastatic diseases. Most reported cases of angiosarcoma were located at the sigmoid colon in 43.6%, followed by the rectum in 23.1%, the cecum in 17.9%, and six involved an unspecified part of the colon. In our case, the location of angiosarcoma was in the right colon. The diagnosis of colorectum angiosarcoma was based on endoscopy with biopsies in most cases (69.5%) and confirmed by histology. For the remaining patients, the diagnosis was made after exploratory laparotomy, accounting for 11% of cases. Endoscopically, this vascular neoplasm appeared as an ulcerated mass with or without active bleeding, hypervascular mucosa, and obstructing mass. In another review, endoscopic biopsies were performed in 37.5% of cases. Reasons for not performing endoscopic biopsies included active bleeding, appearance of hypervascularity, or failure to perform the endoscopy. Imaging modalities including CT and magnetic resonance image exhibit low diagnostic efficiency and are mainly utilized to confirm the existence of the malignancy. At diagnosis, 53.8% of cases presented distant metastasis, with the most common sites being the liver, bones, and lungs [5,7,9]. In our case, the endoscopy found an obstructing ulcerated mass suggesting a colonic adenocarcinoma. However, histopathological examination revealed a colonic angiosarcoma.
In terms of histology, angiosarcoma is usually characterized by a highly vascularized with an abundance of endothelial cells, atypical vascular channels with plump, and areas of solid and spindled cell tumors with an infiltrative and destructive growth pattern. Furthermore, malignant endothelial cells are the hallmark of angiosarcoma, it is described as epithelioid cells, spindle cells, or a mixture of both [7]. In terms of immunohistochemistry, angiosarcoma typically expresses a variety of endothelial cell markers, including anti-CD31, anti-CD34, vascular endothelial growth factor, von-Willebrand factor (Factor VIII), vimentin, and ERG (ETS-related gene). Immunohistochemistry is crucial in confirming the diagnosis of angiosarcoma. Anti-CD31 and anti-CD34 are the most positive markers in almost all reported cases, as in our patients. Factor VIII, anti-CD31, and Ulex europaeus agglutinin-1 are the most useful markers in poorly differentiated cases. Other, antibodies have been shown to identify endothelial cell angiosarcomas, such as thrombomodulin (CD141), vascular endothelial growth factor receptor type 3, Fli-1, and podoplanin, but they have a low sensitivity. In addition, other studies show the positive expression of C-MYC antibody in MYC amplification analysis for post-radiation angiosarcoma more often than primary angiosarcoma. However, MYC protein expression as a specific marker of secondary angiosarcomas is still debated, and further studies will be needed to investigate its role in the oncogenesis of secondary angiosarcoma [10,11]. In the present case, immunohistochemical studies showed that the tumor cells were positive for CD31 and CD34 and negative for CK, CD3, CD20, and HHV8. CD117 is not available. Furthermore, the Ki67 proliferation index was 40%. According to these results, colon angiosarcoma was definitively established.
The treatment approach for this uncommon malignant colon tumor is based on the case reports and strategies employed for angiosarcoma occurring in other locations. Generally, surgery treatment with complete resection is the approach of choice whenever feasible. Given the rarity of post-radiation colon angiosarcoma, there is no guidance for systemic chemotherapy. It is suggested that adjuvant chemotherapy in the treatment of angiosarcomas such as paclitaxel, doxorubicin, docetaxel, and thalidomide may be used but its effects on outcomes are also limited due to non-randomized studies to value this chemotherapy for post-radiation angiosarcoma. Therefore, it is recommended that a multidisciplinary team of experts meet to decide on the optimal therapeutic approach [7,9].
The prognosis of patients with colorectal angiosarcoma is very poor, with a reported survival rate of only 29% at 5 years, and median survival of 23 months. However, radical resection may increase the 5-year survival rate to 39%. Some experts suggest that tumor size over 5 cm and high tumor grade may indicate a poor prognosis, while others disagree. Moreover, advanced age over 65 and the presence of metastatic disease at diagnosis have both been linked to a poor prognosis. Most patients die within a few months of diagnosis and those who survive over one year after diagnosis are extremely rare [8,12-14].
In conclusion, a few cases of radiation-induced colon angiosarcoma are reported in the literature, including our clinical case. These cases usually present with gastrointestinal bleeding, and are associated with a poor prognosis. Diagnosis relies on endoscopy and is subsequently confirmed through histological examination. As there is currently no widely recommended adjuvant treatment, surgical excision, when feasible, remains the primary treatment approach.
Notes
Statement of Ethics
The IRB review has been waived as it does not involve subjects. Data were anonymously registered in the database of our department and written informed consent was obtained.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author Contributions
Conceptualization, AZ, CB, OEM. Investigation and methodology, AZ, GK, ZI. Project administration, AZ, GK, ZI. Resources, AB, NK, HK, OEM. Supervision, GK, ZI. Writing of the original draft, AZ. Writing of the review and editing, AZ. Software, CB, HK, OEM. Validation, GK, ZI. Formal analysis, AZ, CB, HK, OEM. Data curation, AZ, AB, GK, ZI. Visualization, AZ, GK, ZI. All the authors have proofread the final version.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.