Radiotherapy‑associated intra‑abdominal angiosarcoma after prostatic adenocarcinoma: Case reports
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- Published online on: October 5, 2018 https://doi.org/10.3892/mco.2018.1738
- Pages: 592-596
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Copyright: © Parada Domínguez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Angiosarcomas is a malignant tumour that recapitulate the functional and morphologic features of normal endothelium. Angiosarcomas are rare forms of soft tissue neoplasm, comprising less than 1% of all soft tissue tumours (1–3). The majority of these tumours develop as subcutaneous lesions, usually at head and neck region (1). Also, these vasoformative soft tissue tumours arise in a number of well-defined clinical settings such as chronic lymphedema, usually post mastectomy (Stewart-Treves Syndrome) and rarely congenital lymphedema (Milroy's disease) or filarial lymphedema (4).
The risk of developing cancer is increased among persons who already have had cancer previously, which may be caused by both the joint causal factors for the first primary cancer and the treatment of the first cancer, as both chemotherapy and radiotherapy are known to increase the risk (5–9). Excess risks of developing soft tissue sarcoma have been reported in relation to radiation treatment for cancers such as of breast, ovary, cervix, and Hodgkin's and non-Hodgkin lymphoma. For breast and ovary cancer, during a follow-up of over 10 years, the soft tissue cancer risk increased to 8–25-fold, and latency time has varied between 2 and 40 years (5–9).
To our knowledge, we report the first two cases of intra-abdominal angiosarcoma eight and five years after therapeutic prostate adenocarcinoma radiation. We discuss previous literature regarding intra-abdominal angiosarcoma and radiation treatment.
Case reports
Case 1
A 71-year-old man presented in June 2016 with diffuse abdominal pain. The patient's history was significant for pT2a prostatic adenocarcinoma (Gleason score 7) in 2011 treated with external radiation therapy (70 Gy) and hormonal treatment six months. In 2015 the patient was diagnosed with in-situ urothelial carcinoma treated with BCG six cycles. He received regular follow-up, and his latest serum prostate-specific antigen level (March 2016) was 0.0023 ng/ml (normal 0–0.04 ng/ml). His past medical history was not relevant. He had no history of exposure to chemicals. Physical examination revealed ascites and peritoneal fluid liquid was obtained. Computed tomographic scan of the abdominal cavity showed peritoneal carcinomatosis. An exploratory laparoscopy was performed with peritoneal biopsy. After diagnosis the patient received palliative chemotherapy with Paclitaxel. He died five months after the diagnostic. No autopsy was performed.
Case 2
An 82-year-old man presented in July 2016 with diarrhea and generalized weakness. The patient's history was significant for pT3a prostatic adenocarcinoma (Gleason score 7) in 2008 treated with external radiation therapy (75 Gy) and hormonal treatment. In 2012 the patient was diagnosed with colonic adenocarcinoma pT4aN0 Mx. In 2016 the diagnosis of invasive high-grade urothelial carcinoma was performed, with posterior cistoprostatectomy. His past medical history revealed systemic arterial hypertension, type 2 diabetes mellitus, and chronic renal failure. He had no history of exposure to chemicals. Physical examination was unremarkable. After admission, abdominal CT was performed with compatible diagnosis of local recurrence at the sigmoid level by urothelial carcinoma, and laparoscopic resection was performed. He died seven days after the diagnostic. No autopsy was performed.
Peritoneal fluid liquid was processed by liquid cytology using ThinPrep 2000 System (Cytyc Corp, Marlborough, MA) and stained according to the Papanicolau technique and hematoxylin-eosin staining (H&E). The surgical specimens from case 1 and 2 were fixed in 10% buffered formalin for at least 24 h. After fixation, biopsied sections from the peritoneal and sigmoidectomy were embedded in paraffin, cut at 2 µm, and stained with H&E. In addition, 2-µm sections were obtained from the paraffin-embedded samples and were placed in an automatic processor VENTANA® Benchmark ULTRA/LT immunohistochemistry, Ventana Medical Systems, USA, using the previously standardized protocol for CD31 (pre-diluted), CD34 (pre-diluted), FVIII (pre-diluted), cytokeratin AE1/AE3 (pre-diluted), calretinin (pre-diluted), Kaposi sarcoma herpes virus (pre-diluted) and c-Myc (pre-diluted), including retrieval solution pH9 and detection kit for Immunohistochemistry Optiview® DAB (VENTANA®). The primary antibodies (Roche Pharmaceutical, Inc) were incubated for 32 min. Finally, the immunohistochemical sections were revealed with Diaminobenzidine, contrasted with Meyer's hematoxylin. For each immunohistochemical study cecal appendix was used as positive and negatives control.
Results
Case 1
The cytology sample consisted of 20 ml haemorrhagic fluid, which was processed for liquid cytology and cell block. The surgical biopsy specimen consisted of 20×15 mm of tan-yellow soft tissue mixed with clotted blood. The entire specimen was submitted for histopathologic examination. Cytological smears were cellular and showed a population of spindle and pleomorphic cells with ill-defined cell borders. The nuclei were oval and hyperchromatic with irregular nuclear membranes. Branching papillary clusters and pseudoacini or rosettelike groups were also seen. The tumour cells were positive by immunocytochemistry for cytoplasmic endothelial markers CD31 (Fig. 1), CD34 and factor VIII, confirming the endothelial origin of sarcoma (10). The tumor cells were negative for keratin and Kaposi sarcoma herpes virus. The tumour cells were also positive for c-Myc (Fig. 1).
Microscopically, the epiplon showed an irregular proliferating vascular channels, with nodular appearance, lined by atypical endothelial cells, which in turn were surrounded by spindle-shaped cells and epithelioid areas. The tumour cells varying from elongated and spindle-shaped to large and plump. The epithelioid morphology showed large rounded cells, arranged in small nests, cords or rudimentary vascular channels. Mitoses were fairly frequent and some were atypical. The tumour cells were positive by immunocytochemistry for cytoplasmic endothelial markers CD31 (Fig. 1), CD34 and factor VIII, confirming the endothelial origin of sarcoma (10). The tumor cells were negative for keratin and Kaposi sarcoma herpes virus. The tumour cells were also positive for c-Myc (Fig. 1).
Case 2
The surgical specimen consisted of a sigmoidectomy of 280 mm in length. The serosa showed congestive zones, alternating with necro-haemorrhagic areas and fibrin deposits. The mucosa presented oedematous aspect. Representative material was submitted for histopathologic examination. Microscopically, a neoplastic lesion located on the serous surface and affecting the colonic muscle layer was observed. Neoplasia consisted of vasoformative areas consist of ramifying channels lined by atypical endothelial cells forming intraluminal buds and focal papillar formations. The tumour cells were pleomorphic, varying from elongated and spindle-shaped to large and plump. The nuclei were large and pleomorphic with clumped chromatin and prominent nucleoli (Fig. 2). The tumour cells were positive by immunocytochemistry for cytoplasmic endothelial markers CD31 (Fig. 1), CD34 and factor VIII, confirming the endothelial origin of sarcoma. The tumor cells were negative for the Kaposi sarcoma herpes virus, keratin and calretinin. The tumour cells were also positive for c-Myc (Fig. 2).
Discussion
Radiation therapy is a routinely used therapeutic modality for prostate cancer and may predispose to the appearance of secondary neoplasms such as bladder, lung and rectum cancer (10,11). It has also been reported that sarcomas increase their incidence after radiotherapy for prostate carcinoma, being 6% within the radiation field and 2% outside the radiation field (11). In this regard, few cases of angiosarcoma have been reported following radiotherapy for carcinoma of the prostate (12–16). To the best of our knowledge we describe the first two cases of intra-abdominal angiosarcomas secondary to radiotherapy treatment for prostate carcinoma.
Our cases met the suggested diagnostic criteria described by Cahan et al (17) for the development of radiotherapy-induced sarcomas (Table I), such as: the sarcoma should arise in the area previously subjected to irradiation, (2) a latent period (in years) must exist between the time of irradiation and development of the sarcoma and (3) the sarcoma must be confirmed histologically. In both cases, the latency period was 5 to 8 years, they were developed in the areas where the radiotherapy was performed and finally, the diagnosis was confirmed from the cytological and histopathological points of view.
Additionally, one of the pathways related to the development of radiotherapy-induced angiosarcomas may be c-Myc. c-Myc is a well-established proto-oncogene, which when overexpressed drives cell proliferation, blocks cell differentiation, promotes angiogenesis and genetic instability (18–20). Some studies have shown that c-Myc amplification is a recurrent genetic alteration in secondary angiosarcomas, but not in primary angiosarcomas, suggesting distinct pathogenetic mechanisms between them (1,3,6,20–25). In our cases, the immunohistochemical expression of c-Myc could be correlated with genetic amplifications and this mechanism of c-myc c-Myc seems to be key for the development of secondary angiosarcomas. This finding supports the possibility of relating the angiosarcomas studied with the radiant pre-effect. To our knowledge, we describe two cases of intra-abdominal angiosarcoma with c-myc post-radiotherapy expression for prostatic adenocarcinoma.
After an exhaustive bibliographic review, we found no cases of secondary angiosarcomas located in the abdominal region in patients treated with prostate cancer radiotherapy. This indicates that the risk for the development of these sarcomas after radiotherapy in this group of patients with prostate cancer is practically absent. Thus, given the large number of patients who can be cured or who receive palliative treatment with radiation therapy, concern regarding post irradiation sarcoma should not be a major factor influencing treatment decisions in patients with cancer (26). Different population studies have shown that the appearance of secondary angiosarcomas is frequently observed related to breast or gynaecological cancers (5–9). This suggests an association between female hormonal factors and secondary angiosarcoma.
In summary, secondary angiosarcomas of the abdominal cavity are exceedingly rare. They may pose considerable diagnostic difficulty in a partial sampling or cytology study. Awareness of the possibility of angiosarcomas occurring in this location, particularly with a history of prostate cancer radiation, and use of appropriate immunohistochemical studies are crucial to establish a correct diagnosis.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
DP and KP contributed to the cytological diagnosis and manuscript preparation. DP and KP performed the immunocytochemical and immunohistochemical staining and the histopathological diagnosis. DP contributed to the collection of patient data. The final version of the manuscript has been read and approved by all authors.
Ethics approval and consent to participate
The authors obtained consent from the Ethics Committee of the Sant Joan University Hospital in Reus (registration no. CEIM: 034/2018) for publication of the case details.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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