Methods
Six prior case reports of angiosarcoma of the testis were found in the English language medical literature in a MEDLINE search. Of these, 2 were excluded from the analysis because they were retroperitoneal [
5] and paravertebral [
6] angiosarcomas (did not involve the testis) arising 5 and 10 years after radiotherapy for testicular teratoma and seminoma, respectively. Additionally, the computerized medical archival records of the University of Pittsburgh Medical Center (1986 to present) was searched and 1 additional unreported case of testicular angiosarcoma was found. Formalin-fixed, paraffin-embedded tissue sections and the following immunohistochemical stains from this case were reviewed: Ulex Europaeus lectin (1:50, EY Lab, San Francisco, California), CD31 (1:20, DakoCytomation, Carpinteria, California), CD34 (1:20, Becton Dickinson, San Jose, California), AE1/AE3 (AE1/AE3, 1:500, Dako), and Pancytokeratin cocktail (AE1/AE3, 1:500, Dako; CAM5.2, 1:50, Becton Dickinson; MNF116, 1:50, Dako; and UCD/PR-10.11, 1:25, Zymed, San Francisco, California). Tissue sections that had been shown to be positive or negative for each marker were used as controls.
The histologic diagnosis was based on the morphologic spectra defined by Meis-Kindblom and Kindblom [
7]. The architectural categories were: classic, a proliferation of anastomosing blood-filled channels; solid, a proliferation of sheets or nests without evidence of lumen formation; and primitive, a nearly solid proliferation with angulated small capillary-sized lumina reminiscent of tubules but filled with blood. The cytologic categories were: typical, plump hyperchromatic, tufted endothelial cells with scant amphophilic cytoplasm; epithelioid, endothelial cells with open chromatin, prominent nucleoli, and abundant eosinophilic cytoplasm; and spindled, fusiform or elongated cells with tapered ends.
Discussion
Angiosarcomas are rare, highly aggressive tumors of vascular and lymphatic endothelial cell origin, that comprise less that 2% of all sarcomas and less than 1% of all vascular tumors[
7,
8]. Angiosarcomas are known to be associated with chronic lymphedema, radiotherapy, and exposure to arsenic, thorium dioxide, or vinyl chloride [
7,
8]. It is frequently described in upper limb lymphedema as a result of mastectomy and radiotherapy for breast carcinoma. Other commonly reported sites include breast, liver, spleen, bladder, and bone, but very rarely in the testis. Approximately 10% of the cases of vascular sarcomas are associated with postmastectomy lymphoedema [
7,
8]. The overall prognosis of angiosarcoma is poor, with a mean survival of 24 months and a 5-year survival of 10–24% [
7‐
9]. Although data are limited, deep soft tissue and visceral angiosarcomas appear to have an even higher mortality, with up to 53% of patients succumbing to disease within a year [
7,
8]. Less than one third of deep angiosarcomas arise in visceral organs, with the liver, spleen, and heart being the most common sites of involvement [
7]. The mainstay of treatment for testicular angiosarcoma is surgery. Chemotherapy is only palliative, and the value of high-dose radiotherapy is limited in radiation-induced angiosarcoma because of the tumour bed having been previously irradiated to near-normal tissue tolerance doses [
10]. The reported actuarial disease-free survival was 43% when adjuvant radiotherapy is given in angiosarcomas, as compared to 17% without [
8].
To our knowledge, only 4 cases of true primary testicular angiosarcomas have been previously reported in the English language medical literature [
1‐
4]. Hence the characterization of the etiology and clinicopathologic features of primary testicular angiosarcoma is not well defined in the medical literature. Indeed, the clinical, gross, histopathologic, and immunophenotypic features of angiosarcomas of the testis have not been previously reviewed comprehensively. Initially, 6 prior case reports of angiosarcoma of the testis were found in the English language medical literature in a MEDLINE search. Of these, 2 were excluded from the analysis. These 2 were excluded because they were not true primary testicular angiosarcomas [
5,
6]. The case reported by Ulbright et al [
5] in a 17-year old male was a retroperitoneal angiosarcoma arising 5 years after pre-operative radiotherapy of 45 Gy to the retroperitoneum for metastatic testicular mature teratoma. Of note, both the resected retroperitoneal metastasis that occurred synchronous with the testicular mass 5 years earlier were diagnosed as mature teratoma, after thorough sampling. Therefore the retroperitoneal angiosarcoma arising 5 years later was most probably de novo radiation-induced, and not arising from or a remnant of an unsampled angiosarcoma in the testicular and/or retroperitoneal mature teratoma 5 years earlier [
5]. Similarly, the case reported by Lee et al [
6] in a 35-year old man was a thoracic paravertebral angiosarcoma arising 10 years after prophylactic post-operative radiotherapy to the mediastinum following orchiectomy for a 8 cm stage I pure seminoma. Of note, computerized tomography scans of the chest, abdomen, and pelvis were negative at the time of diagnosis of the pure seminoma of the testis 10 years earlier. This confirmed the absence of metastasis of the seminoma to the mediastinum or para-aortic region 10 years earlier, and hence the estimated dose of 28 to 54 Gy to the mediastinum was given only prophylactically. Therefore the paravertebral angiosarcoma arising 10 years later was most probably de novo radiation-induced [
6]. Thus previously published data was available on only 4 cases of true primary testicular angiosarcoma for our review.
With the inclusion of our current case, 5 cases of true primary testicular angiosarcoma formed the basis of our analysis and subsequent comments. Clinically, primary testicular angiosarcomas occurred across the age spectrum for adult men, in both young and old men (mean age, 43.4 years; respective ages were 16, 23, 24, 74, and 80). The biologic behavior and prognosis of true primary testicular angiosarcoma may be much better than previously thought. None of the 5 patients died with metastatic disease, though follow-up was incomplete for 2 cases. The remaining 3 patients with complete follow-up were alive and well at the time of their respective publications (mean follow-up, 17 months). Hence, although definitive conclusions cannot be drawn from such a small set of patients without long term 5-year follow-up, the ultimate biologic behavior of true primary testicular angiosarcomas may not be as abysmal as previously thought on comparison with visceral and deep soft tissue angiosarcomas [
7‐
9].
Visceral angiosarcomas are conventionally regarded as deep soft tissue angiosarcomas because they typically present as hemorrhagic masses [
7]. The vast majority of true primary testicular angiosarcomas presented as hemorrhagic masses, typical of visceral and deep soft tissue angiosarcomas. In a review of 80 cases involving deep soft tissues, most of these angiosarcomas were found to be heterogeneous in morphology and the most common pattern seen was the epithelioid cytologic pattern (70%) [
7]. Epithelioid cytologic pattern was found in a comparable percentage (80%) of cases of primary testicular angiosarcoma in this series [
2‐
4]. Classical architectural pattern of relatively well-differentiated areas of anastomosing blood-filled channels lined by atypical cells and infiltrating soft tissue, classic for cutaneous or mammary angiosarcomas, were observed in only 8% of their cases of deep soft tissue angiosarcomas [
7]. This classic architectural pattern with typical cytology was found in 2 (40%) of the 5 cases of primary testicular angiosarcoma herein reviewed [
1], although the most common (60%) pattern reported in the 5 cases of primary testicular angiosarcoma was classic architectural pattern with epithelioid cytologic features [
2‐
4]. However, 40% of the 5 cases of primary testicular angiosarcoma had a focal solid growth component in addition to the classic architectural pattern [
4] and 20% had a spindled cytology in addition to the epithelioid cytology [
4].
Our further definition of the histopathologic spectrum of testicular angiosarcoma is important from a diagnostic standpoint, especially when faced with small biopsy specimens. Epithelioid cytology and solid architectural patterns are apparently not an uncommon finding in testicular angiosarcomas and may be mistaken in some cases for a poorly differentiated carcinoma, as illustrated by the case report of Sahoo et al [
4] where the angiosarcoma was mistaken for an embryonal carcinoma by the primary pathologist. Other differential diagnoses of angiosarcoma include melanoma, anaplastic large cell lymphoma, other sarcomas, and other vascular lesions, particularly reactive posttherapy changes. Based on our review, the most useful histomorphologic characteristics to raise one's suspicion of an angiosarcoma is the presence of blood-filled spaces lined by atypical, often epithelioid, endothelial cells. Angiosarcomas with epithelioid cytology mimics carcinoma. Since both angiosarcomas and carcinomas can be cytokeratin positive, it is important to perform immunohistochemistry using a large panel of markers including CD31, CD34, and Ulex Europaeus lectin. For the distinction between a carcinoma and angiosarcoma in a rare location such as the testis, a single immunohistochemical stain may not be sufficient to confirm the diagnosis. Although no testicular angiosarcoma has been reported to have cytokeratin reactivity to date [
2‐
4], overall up to one third of angiosarcomas have been reported to have cytokeratin reactivity, including those without epithelioid histology [
7]. Some authors [
7] suggest that Factor VIII-related antigen is the most sensitive marker in deep soft tissue and visceral angiosarcomas, including testicular angiosarcomas. In this review, testicular angiosarcomas showed positive immunoreactivity to Factor VIII-related antigen, CD31, CD34, and Ulex Europaeus lectin in all the cases in which they was used. Conversely, testicular angiosarcomas showed negative immunoreactivity to Pancytokeratin, AE1-AE3, Placental Alkaline Phosphatase, CD68, and Leucocyte Common Antigen in all the cases in which they was used. However, because of the variability among immunohistochemistry laboratories, more than one endothelial marker would be necessary to support the diagnosis of angiosarcoma in a site such as the testis where the entity is extremely rare.
The known angiosarcoma risk factors of antecedent radiation therapy, and prior exposure to arsenic, thorium dioxide, or vinyl chloride [
7‐
10] were absent in all 5 cases of true primary testicular angiosarcoma herein reviewed. However, the associated ipsilateral chronic hydrocele in our current case may be a risk factor for the development of primary testicular angiosarcoma, though this association has not been previously reported. Chronic lymphedema, specifically scrotal edema and postmastectomy lymphedema of upper limb, are risk factors for the development of angiosarcoma of the scrotum and upper limb, respectively [
7,
8]. Approximately 10% of the cases of vascular sarcomas are associated with postmastectomy lymphoedema [
7,
8]. Hydrocele is the most common cause of scrotal swelling [
11]. It is a common, benign condition manifesting as fluid collection between the wall layers of the tunica vaginalis. It usually results from a patent processus vaginalis that communicates with the peritoneal cavity. Less frequently, a non-communicating hydrocele can be found in the inguinal canal or the scrotum secondary to tumor, trauma, inflammation or infection [
11]. Post-traumatic hydroceles are seen mainly in older men, as was the case in our current 80-year-old patient whose primary testicular angiosarcoma did not arise from a teratoma. Although an association has not been reported between testicular angiosarcoma and hydrocele, other testicular and paratesticular sarcomas (namely leiomyosarcomas, rhabdomyosarcomas, and osteosarcomas) have been associated with hydrocele [
12‐
16]. Williams and Banerjee reviewed 13 cases of leiomyosarcoma in the scrotum, 3 of which were associated with hydrocele, and suggested that the presence of hydrocele in association with paratesticular tumor is usually an indication that the tumor is malignant [
15]. Hence, the ipsilateral chronic hydrocele may be a risk factor for the development of the testicular angiosarcoma in the current case. Although it is well recognized that hydroceles may also develop secondarily to the presence of a testicular mass, the 7-year history of hydrocele prior to the discovery of the testicular mass and the diagnosis of the testicular angiosarcoma makes it unlikely that the testicular mass resulting from the angiosarcoma preceded the hydrocele, unless the testicular mass was present and went unnoticed by the patient for well over 7 years.
Three of the 5 cases of primary testicular angiosarcoma were associated with the concurrent presence of multilocular cystic areas diagnosed as mature teratoma in the same testicular tumor[
1,
3,
4]. These 3 cases were mature testicular teratoma admixed with primary testicular angiosarcoma as a malignant component within the testis. These 3 cases represent heterologous sarcomatous differentiation in a testicular germ cell neoplasm. Therefore, it seems there are two groups of testicular angiosarcomas: one group (3 of the 5 cases) that occurs in young people that represent a malignancy derived from teratoma; and a second group (2 of the 5 cases) that occurs in the elderly and is not associated with germ cell neoplasm, but may be associated with chronic hydrocele. The current WHO terminology for the first group is somatic-type malignancy from teratoma or teratoma with malignant transformation. The presence of angiosarcoma as a component of testicular teratoma is extremely rare [
1,
3,
4], and may be misdiagnosed as embryonal carcinoma [
4]. The most frequent malignant components associated with testicular germ cell tumors are sarcomas, of which rhabdomyosarcoma is the most common subtype [
17]. Two cases of therapy-related angiosarcoma of the retroperitoneum and gut have been documented in the English language medical literature in patients who were treated with radiotherapy with or without chemotherapy for testicular teratoma or seminoma [
5,
6]. Sahoo et al [
4] recently described a rare association of angiosarcoma with teratoma in a patient who had received no treatment prior to surgery.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
HBA participated in the histopathological evaluation, performed the literature review, acquired photomicrographs and drafted the manuscript. UNMR and AVP conceived and designed the study, gave the final histopathological diagnosis and revised the manuscript for important intellectual content. All the authors read and approved the final manuscript.