jacobs journal of nephrology and urology › uploads › article_pdf › 18 ›...

Citation : Anthony Kodzo-Grey Venyo. Primary Angiosarcoma of the Urinary Bladder: A Review and Update of the Literature.J J Nepho Urol 2019; 6(1):038.

Review ArticlePrimary Angiosarcoma of the Urinary Bladder: A Review and Update of the

LiteratureAnthony Kodzo-Grey Venyo1

1Department of Urology, North Manchester General Hospital, United Kingdom

*Corresponding author: Anthony Kodzo-Grey Venyo, North Manchester General Hospital, Department of Urology, De-

launay’s Road, Crumpsall, Manchester, M8 5RB Lancashire, UK; E-mail: [email protected]

Received Date: 02-28-2019

Accepted Date: 03-12-2019

Published Date: 03-15-2019

Copyright: © 2019 Anthony Kodzo-Grey Venyo

Jacobs Journal of Nephrology and Urology

AbstractPrimary angiosarcomas of the urinary bladder (PAUB) are very rare; in view of this their clinical and pathological features have not been extensively described. To the knowledge of the author, only 36 cases of primary angiosarcoma of the urinary bladder have been reported in the literature. Primary angiosarcoma of the urinary bladder has been reported in individuals whose ages had ranged between 32 years and 89 years. PAUB has been reported in men and women but PAUB has been reported more often in men. PAUB has presented most often with haematuria but other symptoms had included: Lower urinary tract symptoms, urinary frequency, loin pain, weight loss, weakness, lethargy, cachexia, and swelling of the lower extremities. In some cases, a past history of radiotherapy or exposure to industrial chemicals had been documented. Diagnosis of PAUB has been based upon cytology, histopathology and immunohistochemistry features of a tumour and occasionally bladder washings which may show: Anastomosing vascular channels which are lined by plump hyperchromatic cells, as well as solid growth and epithelioid cytology. Typically the tumour invades the muscularis propria and the tumour may also involve the urinary bladder muscle; immunohistochemistry staining studies would tend to show positive staining for CD31, CD34, and Cytokeratin can be focally positive, especially in cases of epithelioid tumours. Treatment options that had been undertaken in various cases of PAUB included trans-urethral resection of a bladder tumour, partial cystectomy, radical cystectomy plus lymphadenectomy, cysto-prostatectomy with lymphadenectomy, anterior pelvic exenteration, and these procedures were undertaken as sole procedures, or with adjuvant therapy in the form of radiotherapy alone, chemotherapy alone or chemotherapy and radiotherapy. With regard to outcome generally, the prognosis had tended to be poor and even though very few cases of short-term to medium-term survival have been reported, there was hardly any case of long-term disease-free survival. There was the development of early metastases even with cases of a tumour confined to the submucosa of the urinary bladder. There was no case report of disease-free survival of any patient who was initially diagnosed with metastases or any patient who subsequently developed metastasis pursuant to initial treatment of the disease and even though some patients were alive with the stable disease there was no report of complete destruction of tumour cells by chemotherapy or radiotherapy. Considering that some cases of PAUB developed pursuant to radiotherapy it would appear as if radiotherapy might not be the most appropriate adjuvant treatment for patients who have post-radiotherapy PAUB. Considering that the available chemotherapy agents have not been reported

2

to have completely destroyed metastatic PAUB lesions, it would be most appropriate for pharmacotherapy researchers, oncologists, and urologist to identify a specific chemotherapeutic regimen that would effectively destroy metastatic PAUB tumour cells and prolong the long-term disease-free survival of patients who have PAUB. Finally, a global multi-center trial of treatment options for PAUB should be undertaken.

Keywords: Angiosarcoma; Primary, Urinary Bladder; Immunohistochemistry, Trans-Urethral Resection Of Bladder Tumour; Radiotherapy; Chemotherapy; Cystectomy; Cystoprostatectomy;CD31; CD34; Cytokeratin; Poor Prognosis.

IntroductionMajority of vascular lesions in the urinary bladder

are haemangiomas which comprise 0.6% of all urinary bladder cancers and this makes primary angiosarcoma of the urinary bladder very rare. [1] Jungano [2] referred to an older report from 1905 of a “telangiectasia fibrosarcoma” of the bladder in a 64-year-old man, which by modern criteria may have truly been the first case of angiosarcoma of the urinary bladder. It had been stated that primary angiosarcomas of the urinary bladder are typically rare tumours of middle-aged and elderly men that present with locally advanced disease and show a wide histological spectrum. [3] It had also been stated that considering the rarity of angiosarcomas of the urinary bladder, the biological behaviour of these tumours, have not been clearly and extensively clarified. Furthermore, the pathological features of primary angiosarcomas of the urinary bladder (PAUB) have not been well described and as a result, establishment of a diagnosis of primary angiosarcoma of the urinary bladder (PAUB) may be extremely difficult to give. [3]The ensuing paper on primary angiosarcoma of the urinary bladder (PAUB) is divided into two parts (A) Overview and (B) miscellaneous narrations, and discussions related to case reports, case series, and studies related to primary angiosarcoma of the urinary bladder (PAUB).

AimTo review and update the literature on primary

Methodangiosarcoma of the urinary bladder (PAUB).

Various internet data bases were searched including Google, Google Scholar, Yahoo and PUBMED. The search words that were used included: Primary angiosarcoma of bladder, bladder angiosarcoma. Thirty nine references related case reports, case series, review papers and studies related to primary angiosarcoma of the urinary bladder were used to ascertain the presentation, investigation, diagnosis, management and outcome of patients following treatment and these references were used to write the review and update.

Result(A) OverviewDefinition: Angiosarcoma of the urinary bladder (PAUB) is a rare vascular tumour with anastomosing vascular channels in which endothelial cells are seen to exhibit marked cytologic atypia [4]. Part of the tumour may contain spindled cells and epithelioid cells and anastomosing vascular channels.

Epidemiology: Angiosarcoma of the urinary bladder is more common in the male with 89% occurrence. The mean age of occurrence of this tumour is 64 years. [4] The ages of the patients have ranged between 32 years and 89 years. Aetiology: A number of factors have been associated with the development of angiosarcoma of the urinary and these include:• Radiotherapy for pelvic malignancy in 1 out of 3 cases [4]

• Exposure to arsenic [4]

• Exposure to thorium chloride [4]

• Exposure to polyvinyl chloride [4]

• Exposure to chemotherapeutic agents [4]

Angiosarcoma of the urinary bladder had been reported in bladder with pre-existing haemangioma. [4] Presentation• Angiosarcoma of the urinary bladder usually

Jacobs Publishers

3

presented with haematuria. [4] • They may also present with lower urinary tract symptoms including dysuria. • Some patients may additionally present with loin pain.Clinical Examination Findings

The general and systematic examination findings may be normal but in cases of severe haematuria there may be clinical evidence of pallor and if there is blood clot induced retention of urine, then the urinary bladder would be palpable in the suprapubic region. There is also the possibility that a palpable urinary bladder mass could be found on clinical examination on rare occasions if an individual has an extensive invasive urinary bladder tumour in the dome of the urinary that has invaded the bladder and infiltrated beyond the urinary bladder.

Laboratory investigations Urine• Urine microscopy and culture and sensitivity are general tests that are carried out in the general assessment of patients who have primary angiosarcoma of the urinary bladder. The results would usually be normal but if there is evidence of urinary tract infection the infection would be treated to help improve the general state of the patient with utilization of the most appropriate antibiotic based upon the sensitivity pattern of the cultured organism. At times there may be evidence of non-visible or visible haematuria.• On rare occasions cytology examination of the urine specimen or urine washings obtained at cystoscopy may reveal cytological features of angiosarcoma tumour.

Haematology• Full blood count, and coagulation screen are general routine tests that are undertaken in the general assessment of patients who have primary angiosarcoma of the urinary bladder but the results would not establish the diagnosis of the disease. Most often the results would be normal but at times when there had been excessive loss of blood in the urine or there is disseminated disease at the time of diagnosis of the disease there could be severe anaemia to require blood transfusion.

Biochemistry• Serum urea, blood glucose, and liver function tests are routine tests that are undertaken in cases of primary angiosarcoma of the urinary bladder and generally the results would tend to be normal; however, the results could be impaired because the individual has some underlying medical problem that needs to be appropriately managed to improve the general condition of the patient. On the other hand in cases of disseminated disease with extensive metastases in the liver and dehydration there may be impairment of liver function and dehydration which could be seen as impaired renal function. If there is obstruction of the ureter this could also be associated with impaired renal function.

Radiology investigationsUltrasound scan • Ultrasound scan of renal tract, abdomen and pelvis can be done initially in the assessment of patients who have primary angiosarcoma of the urinary bladder and this would tend to show the lesion within the urinary bladder, its size, location, and whether or not there is any hydronephrosis. If there are any enlarged lymph nodes in the pelvis, abdomen or retroperitoneum the ultrasound scan would show it. • Ultrasound scan of abdomen and pelvis can be undertaken in the follow-up assessments of patients who have undergone treatment for primary angiosarcoma of the urinary bladder. However, CT scan of thorax, abdomen, and pelvis or magnetic resonance imaging (MRI) scan of thorax, abdomen and pelvis are most often undertaken these days in the developed countries where the facilities are available as well as because these radiology imaging options provide more detailed information in comparison with ultrasound scan and their interpretation does not tend to be operator dependent. • If there is obstruction of the ureter with hydronephrosis, ultrasound-guided insertion of nephrostomy can be undertaken to preserve renal function.

Computed Tomography Scan• Contrast CT Urogram tends to be undertaken for

Jacobs Publishers

4

the initial investigation of the haematuria , and this would show the lesion in the bladder, its size as well as position in the urinary bladder. The CT scan would also show if there is muscle involvement by the tumour and if there are any lymph node enlargements or metastatic lesions within the abdomen as well as if the pelvic and the abdominal/retroperitoneal lymph nodes are enlarged. Furthermore if there is any hydronephrosis the CT scan will show it. • Contrast CT scans of thorax, abdomen, and pelvis tend to be undertaken for the initial staging of the disease, and for the follow-up assessment of patients at regular intervals to assess whether there is local recurrence of tumour or metastases.

Magnetic Resonance Imaging Scan • Contrast MRI scans of renal tract / abdomen and pelvis tends to be undertaken for the initial investigation of the haematuria , and this would show the lesion in the bladder, its size as well as position in the urinary bladder. The MRI scan would also show if there is muscle involvement by the tumour and if there are any lymph node enlargements or metastatic lesions within the abdomen as well as if the pelvic and the abdominal/retroperitoneal lymph nodes are enlarged.Furthermore if there is any hydronephrosis the MRI scan will show it.• Contrast MRI scans of thorax, abdomen, and pelvis tend to be undertaken for the initial staging of the disease, and for the follow-up assessment of patients at regular intervals to assess whether there is local recurrence of tumour or metastases.

Positron Emission Tomography (PET-CT)• PET-CT scan undertaken in the investigation of another problem could incidentally identify a lesion in the urinary bladder and also if there are any metastatic lesions but this would be an extremely rare way of initially diagnosing the lesion but PET-CT scan can also be utilized in the follow-up assessment of patients following treatment of their tumours to see if they have developed any recurrences or metastases.

Isotope Bone Scan • Isotope bone scan can be undertaken to investigate

whether a patient has developed bone metastasis or not.

Macroscopic Appearance• Angiosarcoma of the urinary bladder typically is seen as haemorrhagic raised mass with a mean diameter of about 7 cm of the trigone or dome. [4] They may also look solid at times.

Microscopic Appearance• Microscopic examination of angiosarcoma of the urinary bladder typically shows the following features: Anastomosing vascular channels which are lined by plump hyper-chromatic cells, as well as solid growth and epithelioid cytology. Typically the tumour invades the muscularis propria. [5]

Immunohistochemical Staining CharacteristicsAngiosarcoma of the urinary bladder on immunohistochemistry, stain positively with: • CD31 [4]

• CD34 [4]

• Cytokeratin can be focally positive, especially in cases of epithelioid tumours. [4]

Differential DiagnosisThe differential diagnosis of angiosarcoma of the urinary bladder, include the following:• Haemangioma – It is typically 1 cm or less, 80% are cavernous, exhibits no atypia, not associated with anastomosing or solid areas. [4] • Kaposi’s sarcoma – It is associated with Human Immunodeficiency virus (HIV) and HHV8, presence of extravasated red blood cells, usually associated with less atypia than angiosarcoma. [4] • Sarcomatoid variant of urothelial carcinoma – It exhibits undifferentiated spindle cells, has an associated urothelial carcinoma, vascular makers are negative in it. [4]

Treatment• Treatment of angiosarcoma of the urinary bladder is by wide resection and perhaps radiotherapy and chemotherapy may have a role. [4]

Jacobs Publishers

5

• Muscle-invasive tumour would need to be treated by means of surgery in the form of cystectomy plus adjuvant therapy including chemotherapy alone, chemotherapy plus radiotherapy, or cystectomy and radiotherapy. Considering angiosarcomas of the urinary bladder tends to be associated with radiotherapy perhaps most clinicians would argue that radiotherapy alone may not be effective. • Even though there is no consensus opinion of the management of angiosarcomas of the urinary bladder, the fact that it is known that the long-term outcome of the disease following surgery alone would tend to be poor with patients dyeing of disease quickly it would be argued that utilization of adjuvant chemotherapy or neo-adjuvant chemotherapy should be encouraged as well as discussed by a multi-disciplinary team of oncologists, urologists, and pharmacotherapy researchers.

Prognosis• Traditionally angiosarcoma of the urinary bladder has been considered to be associated with poor prognosis, however, Seethala et al [3] recently indicated that their prognosis may be better than previously conjectured. [3] Furthermore, survival 6 years after initial presentation has been reported recently. [6] • Other authors had reported very short period of survival of 6 weeks. [7]

(B) Miscellaneous narrations, discussions and salient points from some case reports, case series, reviews as well as studies related to angiosarcoma of the urinary bladder.Pazona et al. [6] reported the long-term disease free survival of one patient who was treated by means of multi-modal therapy whom they had previously reported on. Six years, pursuant to the patient’s initial presentation, the patient died and the post-mortem examination showed no evidence of residual disease. They stated that their case represented the longest reported survival of a patient with angiosarcoma of the urinary bladder. [6]. Seethala et al. [3] reported that based upon the context that primary angiosarcomas of the bladder are typically rare and their clinical and pathologic features had not been well described, they identified relevant sources using MEDLINE

and a subsequent bibliographic search of all case reports and reviews on primary angiosarcoma of the urinary bladder. They also searched the M.D. Anderson centre pathology archives. Seethala et al. [3] extracted data on the following demographics: clinical presentation, predisposing factors, gross pathology, microscopic pathology, immunophenotype, therapy, and outcomes. Seethala et al. [3] stated that:• Primary bladder angiosarcoma was found at a mean age of 64.2 years, with a male to female ratio of 8:1.

• Two cases arose in a post-irradiation setting.

• Primary bladder angiosarcoma typically presented with haematuria and were grossly- haemorrhagic -raised masses (mean size 6.7 cm), of the trigone / and of the dome.

• Histologically, most of the tumours exhibited classic anastomosing channels lined by plump hyperchromatic cells, although many exhibited variant histology such as solid growth and epithelioid cytology.

• Three (43%) of 7 patients died within a year, but only 1 patient with evidence of disease. The remaining patients were alive at the time of publication of their respective cases (mean, 22 months).

Seethala et al. [3] concluded that primary angiosarcoma of bladder are typically rare tumours of middle-aged and elderly men that present with locally advanced disease and show a wide histologic spectrum. However, their prognosis may be better than previously thought. Tavora et al. [5] retrospectively identified vascular tumours of the urinary bladder from the consultation files from one of the authors. They identified 13 lesions which included 3 haemangiomas, 3 intravascular papillary endothelial hyperplasias (Masson vegetant haemangioendotheliomas), 2 arteriovenous malformations (AVMs), 1 epithelioid haemangioendothelioma (EHE), and 4 angiosarcomas. Tavora et al. [5] stated the following:• One of the angiosarcomas was associated with conventional high-grade urothelial carcinoma (sarcomatoid variant of urothelial carcinoma.

• All the patients were adults with a range in age from 18 to 85 years old (mean 63.3).

Jacobs Publishers

6

• There was no statistical difference among the various lesions in terms of age, although angiosarcomas tended to arise in older patients (mean 71 years vs. 60 years of the remainder).

• Haematuria was the most common presentation of both benign and malignant lesions.

• Some of the other symptoms included voiding irritation, pelvic pain, and obstruction.

• Histologically, benign and malignant lesions were similar to their counterparts in other organ systems.

• Two haemangiomas were of the capillary type and a third one was of the cavernous sub-type. They measured 1.1 cm, 2.4 cm, and 3.2 cm.

• Both arteriovenous malformations (AVMs) were clinically large broad-based masses which measured 5.5 cm and 5.8 cm in greatest diameter. One of the arteriovenous malformations (AVMs) was associated with pseudo-epitheliomatous hyperplasia of the urothelium.

• All of the 3 patients with Masson lesion had history of radiation therapy for other causes. These presented as raised lesions and they were all <1.0 cm.

• Patients with haemangiomas, papillary endothelial hyperplasias, and arteriovenous malformations (AVMs) had an invariably benign prognosis and they needed no further therapy. These benign lesions had consistent involvement of the sub-mucosa and spared the muscularis propria of the organ.

• All the cases of angiosarcoma and epithelioid haemangioendothelioma (EHE) involved the muscularis propria.

• Two of four patients with angiosarcoma had a history of prior radiation therapy and all the four patients were dead of disease at 6 months.

• The angiosarcomas measured 3 cm, 4.5 cm, 5 cm, and 5.8 cm in greatest diameter at cystoscopy.

• The patient with epithelioid haemangioendothelioma (EHE) had a single nodule which was treated by trans-urethral resection of the bladder lesion and no evidence of disease at 4 years of follow-up was found.

• None of the patients experienced marked visible haematuria that resulted in morbidity or mortality.

• A wide spectrum of benign, intermediate- malignant, and malignant vascular lesions primarily involved the bladder.

• Despite the potential for marked haemorrhage, none of the tumours resulted in marked haematuria.

They concluded that papillary endothelial hyperplasia occurs in the bladder and must be differentiated from angiosarcoma, which has a rapidly fatal outcome.Kulaga et al. [7] in 2007, reported a woman who developed epithelioid angiosarcoma of the urinary bladder which she developed after she had received radiation treatment for endometroid adenocarcinoma. [7]

In 2008, Williams et al. [8] reported a 71-year-old man, who presented with a single episode of visible painless haematuria. He had undergone external beam radiotherapy for prostate cancer 10 years earlier. His clinical examination revealed a palpable left pelvic mass. He had a computed tomography (CT) scan which confirmed the presence of a left-sided bladder wall mass with unilateral hydronephrosis. At cystoscopy the tumour was found to arise from the left hemi-trigone, and bimanual examination under anaesthesia revealed a mass which appeared to be fixed to the pelvic sidewall. A trans-urethral resection of the tumour was undertaken and a left indwelling ureteral stent was placed. Histological examination of the resected specimen was consistent with epithelioid angiosarcoma infiltrating the muscularis propria. Subsequently, the patient underwent a radical cystoprostatectomy, pelvic lymph node dissection, and construction of an ileal conduit. Intra-operatively, there was a large extravesical mass which extended to and invaded the pelvic sidewall. A wide resection was carried out, which revealed no residual gross tumour behind. The pathological

Jacobs Publishers

7examination revealed a mass with mucosal ulceration. The lesion involved the bladder wall and invaded through the detrusor muscle. It also involved the peri-vesical soft tissue, prostate, and seminal vesicle (see figure 1 which illustrates the histopathology and the immunohistochemistry staining features of the tumour).

Figure 1: (A–C) Haematoxylin-eosin stained sections at 10, 20, and 40×, respectively, showing the bladder wall invaded by a vascular tumour, in which vascular channels are lined by atypical endothelial cells. (D–F) CD31 staining at 10, 20, and 40× magnification respectively, enhancing the vascular aetiology of the tumour with the atypical endothelial cells staining for this endothelial marker. Reproduced from: [8] Williams S K, Romaguera R L, Kava B. Angiosarcoma of the Bladder: Case Report and Review of the Literature The Scientific World JOURNAL (2008) 8, 508–511. DOI: 10.1100/tsw.2008.79 under the Creative Commons Attribution License which allows reproduction of figures from the journal provided the original source is properly cited.

The patient recovered from surgery, and was

referred for adjuvant chemotherapy and radiotherapy. Despite a reasonably good appetite, he continued to lose weight post-operatively. He developed malignant ascites and bilateral lower extremity oedema. He had a repeat computed tomography (CT) scan 2 months following surgery which revealed diffuse carcinomatosis. The patient subsequently opted for hospice care and died 3 months post-operatively.

Williams et al. [8] stated that:

• Very little is known regarding the natural history, optimal treatment, and prognosis of urinary tract angiosarcomas. • Engel et al. [9] reported on 10 cases with angiosarcoma of the bladder. They found an almost universally poor prognosis, with an overall mean survival of only 8.5 months.• Mark et al. [10] iterated that these tumours are usually high-grade and they have a reported 5-year survival rates of between 10% and 35%.• At the time of the report of their case, 13 cases of bladder angiosarcomas had been reported. Three of these patients had an antecedent history of pelvic radiotherapy. Two cases were reported after radiation therapy for a gynaecologic malignancy [11], [12] while one appeared after therapeutic irradiation for prostate cancer [13].• None of these patients had an antecedent history of exposure to arsenic, thorium dioxide, or vinyl chloride. • The most common presentation of these patients was haematuria [3] while dysuria and flank pain were less common symptoms. • There was a marked male predilection, with reports of male to female ratio of 8:1.• The tumours tended to arise from all areas of the bladder. As with most sarcomas, the lung and the liver were common sites for metastases, with a haematogenous metastatic pattern the rule. • The development of a secondary malignancy is a recognized risk of radiation therapy as reported by a number of authors [9], [11], [13], [14].• In considering the diagnosis of a radiation-induced sarcoma, Cahan et al. [15] suggested the following

Jacobs Publishers

8criteria: (1) the sarcoma should arise in the area previously subjected to irradiation, (2) a latent period (at least 7 years) must exist between the time of irradiation and development of the sarcoma, and (3) the sarcoma must be confirmed histologically. [15] • The association of angiosarcoma with therapeutic radiation has been previously described [11], [13]. Williams et al. [8] furthermore, stated that:

• Their reported case satisfied all of the aforementioned criteria and, thus, could be considered radiation related. • In addition to the direct oncogenic effect of ionizing radiation, prolonged cellular stimulation during repair of tissue damage resulting from radiation-induced ischemic change may play a role in development of angiosarcoma [16]• The management of these patients is surgical resection of the tumour with generous circumferential margins whenever possible. Radical cystectomy and ileal conduit was performed on this patient. Negative margins are crucial for cure and improved local control has been demonstrated in high-grade lesions with adjuvant radiotherapy [8].• Mark et al. [10] reported an actuarial disease-free survival of 43% when adjuvant radiotherapy was given in angiosarcomas compared to 17% without. In general, randomized trials have failed to show a survival benefit for chemotherapy in the treatment of soft-tissue sarcomas [17]. • Multimodal approaches with chemotherapy and radiotherapy had shown promising results in high-grade sarcomas of the head and neck [18] • Pazona et al. [6] reported on long-term survival after multimodal therapy for bladder angiosarcoma. They reported on a patient treated with radical cystectomy with adjuvant chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]) followed by pelvic irradiation. The patient died of a cardiac event 6 years after surgery with no evidence of disease at autopsy. • Likewise, Engel et al. [9] reported on a patient with primary angiosarcoma of the bladder who was treated with combined cystectomy, MAID chemotherapy, and external beam radiation. They reported that at 32 months after

diagnosis and initial treatment, the patient had no evidence of disease.

Williams et al. [8] stated that their patient had rapid disease progression after surgery, and was therefore not a candidate for adjuvant therapy. Williams et al. [8] concluded that:• Angiosarcoma of the bladder is an extremely aggressive tumour with a short disease course. • If an attempt at cure is feasible, a multi-modal approach consisting of radical surgery followed by high-dose adjuvant radiotherapy and chemotherapy would seem most effective.

Warne et al, [19] reported a 32-year-old woman who presented initially with left flank pain and visible haematuria throughout her urinary stream. She had computed tomography scan of her kidneys, ureter and urinary bladder (CT KB) which revealed ureteric dilatation down to the level of the bladder without evidence of renal calculus. She subsequently underwent insertion of left ureteric stent. She re-presented a month later with contra-lateral flank pain and a trans-urethral resection of bladder tumour was performed. Histopathological examination findings of the resected bladder tumour were consistent with a diagnosis of angiosarcoma. Magnetic resonance imaging (MRI) scan of the pelvis was done which revealed that the tumour arose from the posterior wall of the urinary bladder with local invasion and regional lymph node metastasis. Ifofosfamide and epirubicin chemotherapy, with single-fraction radiotherapy induced significant reduction in tumour bulk, though the initial response was ensued by symptoms suggestive of disease progression. She died 19 months after her initial diagnosis with persistent pulmonary and vertebral metastases, though autopsy was not performed.

Ravi [20] reported the case of primary angiosarcoma of the urinary bladder in a man who did not have exposure to any aetiological factors and who was disease free 8 months after he had undergone partial cystectomy and adjuvant post-operative pelvic irradiation.

Engel et al. [9] reported a case of angiosarcoma

Jacobs Publishers

9of the bladder, and they reviewed 9 other previously reported cases. Engel et al. [9] stated that of the 10 cases, 2 were considered to have arisen from a pre-existing bladder haemangioma. Two patients had a history of prior gynaecologic malignancies treated with external beam radiotherapy, with subsequent sarcoma formation within the past treatment field. Two other patients presented with skin lesions that predated the discovery of bladder lesions. Only 4 patients presented with primary bladder lesions and no pre-existing disease or previous carcinogenic exposure (except for tobacco use). Haematuria was a universal presentation, and treatment was widely-variant. Of the 10 patients, 8 died during a period of follow-up of 23 months. Five patients died of tumour-related causes. The mean survival of these 5 was 10.6 months. The 2 most recent patients (including their patient) were alive and tumour free at 8 and 32 months, respectively. Both of these patients underwent multimodality oncologic approaches as part of their treatment regimen.Engel et al. [9] concluded that:• Angiosarcoma of the bladder is exceedingly rare and usually fatal. • Prognosis is poorer than that of angiosarcomas in more traditional sites. • Regional lymph nodes are typically spared, but local recurrence with eventual distant metastasis is the rule. Optimal therapy has not been determined, but it most likely should involve a multimodal approach combining radical surgery with chemotherapy and radiotherapy.Aragona et al [21] in 1991 reported the second case of primary angiosarcoma of the bladder and they pointed out the immunohistochemical characteristics of these neoplasias. They stated that using immunoperoxidase staining techniques, Ulex lectin had proved to be a more sensitive marker for endothelial cells than factor VIII-related antigen, and that it should be used as an additional marker for endothelial cell-derived tumours. Schindler et al. [22] also reported a 47-year-old man who had angiosarcoma of the urinary bladder.Spiess et al. [23] assessed the histologic subtypes, clinical presentations, treatment approaches, and treatment-related outcomes of patients with bladder sarcoma. They

stated that between January 1985 and July 2004, 19 patients (12 men and 7 women) with primary bladder sarcoma were evaluated at the University, of Texas M.D. Anderson Cancer Center. Median follow-up duration was 72 months (range 3-141). Spiess et al. [23] reported that:• The median age of patients at presentation was 57 years (range 22-94). The histologic subtypes of bladder sarcoma were leiomyosarcoma (N = 14), angiosarcoma (N = 3), and unclassified sarcoma (N = 2). • The clinical presentation consisted of gross, painless haematuria in 79% of patients, lower urinary tract symptoms in 16%, and microhematuria in 5%.• The primary treatment modalities used were surgery in 16 (84%) patients, chemotherapy in 2 (11%), and palliation in 1 (5%). • The rate of local and distal recurrence was 16% and 53%, respectively. The most common sites of distant metastases were the lungs, bone, brain, and liver. The 5-year disease-specific survival rate was 59%, with the median- survival duration of 6 years. There was no statistically significant difference in disease-specific survival between patients with bladder leiomyosarcoma compared to other sarcoma subtypes (P = 0.149).• Lymphovascular invasion (P = 0.03) and lymphatic metastasis (P = 0.03) were associated with disease-specific survival, and surgical margin status was associated with recurrence-free (P = 0.04), disease-specific (P = 0.03), and overall survival (P = 0.005).Spiess et al. [23] concluded that: Bladder sarcoma is a highly aggressive malignancy, regardless of its histologic subtype. Surgical margin status is an important determinant of survival.

Ojerholm et al.[24] reported a 61-year-old man who had been diagnosed as having carcinoma of the prostate gland following investigation of his raised level of his serum prostate-specific antigen on routine testing. He did have an organ-confined and intermediate-risk group carcinoma of prostate, T1c, Gleason 4 + 3 = 7 adenocarcinoma of prostate for which he did undergo radical radiotherapy as treatment of curative intent. At his 7-year post radiotherapy treatment follow-up assessment his serum PSA level had remained within the controlled level. Nevertheless, he did report

Jacobs Publishers

10having had one episode of visible haematuria. He had contrast computed tomography scan (CECT scan) which showed a filling defect in his urinary bladder. He then underwent cystoscopy plus biopsy / resection of an erythematous papillary lesion on the lateral wall of the urinary bladder. Histology examination of the biopsied specimen obtained from the urinary bladder did confirm a malignant tumour for which he underwent a radical cystoprostatectomy. Upon pathology examination of the surgically excised specimen, a 3.5 cm radiotherapy induced primary angiosarcoma of the urinary bladder that had invaded the peri-vesical tissue was made. The surgical resection margins and all the lymph nodes that were examined were free of tumour. At his 4-month post-operative follow-up, he had a PET-CT scan which did not demonstrate any evidence of local recurrence or distant metastasis. A multi-disciplinary team meeting decided at that stage that the management of the patient should involve close radiology imaging surveillance and chemotherapy should be given only when there is radiology imaging evidence of metastatic disease. Ojerholm et al. [24]recommended that physicians must remain vigilant with regard to patients who had undergone radiotherapy for carcinoma of the prostate gland who subsequently develop urinary symptoms including haematuria. [24] With regard to fuel for discussion, even though the multi-disciplinary team decided that adjuvant therapy should not be given, some people could argue that adjuvant chemotherapy should have been given because angiosarcoma is an aggressive tumour and if clinicians wait till tumour recurrence develops the tumour load or tumour burden would be big for the chemotherapeutic medicaments to quickly and effectively destroy and that if adjuvant combination chemotherapy is given pursuant to the cystoprostatectomy when there is no radiology imaging evidence of metastasis the tumour load in the presumed microscopic metastasis would be small enough for the chemotherapy medicaments to effectively destroy and thus preventing the development of overt recurrence in the future.

Matoso et al. [25] stated that primary angiosarcoma of the urinary bladder is very uncommon, with about 30 cases reported in the literature and that angiosarcomas that have epithelioid morphology are even more uncommon, with only one reported case at the time of publication of their

article. Matoso et al. [25] described the histopathological features and clinical follow-up data of 9 patients who had epithelioid angiosarcoma (EA) of the urinary bladder retrieved from their surgical pathology files from 1998 to 2014. Matoso et al. [25] Summated their findings as follows: • Eight cases were consults. • The mean age of the patients at the time of their initial presentations was 65 years and the ages had ranged from 39 years to 85 years.• The male to female ratio of the angiosarcoma of the urinary bladder was 8:1.• The clinical manifestation was haematuria and urinary bladder mass with regard to all cases. • Six patients did have a history of having had radiotherapy to the pelvic region; 5 of them for the treatment of carcinoma of the prostate gland and 1 to treat carcinoma of the cervix. The interval between the radiotherapy treatment to the diagnosis of the epithelioid angiosarcoma (EA) of the urinary bladder had ranged between 6 years to 15 years. • The size of the epithelioid angiosarcoma (EA) tumour of the urinary bladder had ranged between 1 cm and 8 cm with an average tumour size of 4 cm.• The submitting diagnoses that were documented included:o

o

Poorly differentiated carcinoma in 5 cases,

o

High grade invasive urothelial carcinoma in 3 cases,Atypical vascular proliferation in 1 case.

• With regard to morphology, the tumours had consisted of nests and sheets of highly atypical cells that had a high nuclear to cytoplasmic ratio, rare or occasional intracytoplasmic lumens, and a haemorrhagic background. Atypical vascular proliferation was identified in 1 case. None of the 9 cases did show any evidence of any urothelial carcinoma component. Three patients did show in addition usual angiosarcoma within the resected specimen.• Immunohistochemistry studies of the tumours showed the following: Five cases out of the 9 cases were positively stained for cytokeratins that included CK 7 in 3 cases, AE1/AE3 in 3 cases, and Cam 5.2 in 1 case. All of the 9 tumours were positively stained for at least 1 endothelial marker, positive staining for CD31 in 7 cases, positive staining for CD34 in 2 cases, positive staining for

Jacobs Publishers

FVIII in 3 cases, and positive staining for ERG in 2 cases. Immunohistochemistry staining studies of the tumours also showed that the tumour cells of all the 9 patients had consistently stained negatively for p63 and for GATA3.• Various treatment options were undertaken including: o Trans-urethral resection of bladder tumour (TURBT) only in 5 cases.o

o

TURBT followed by cystoprostatectomy in 2 cases. TURBT followed by partial cystectomy in 1 case.

• Pathology examination of the tumours showed that the tumour did involve the muscularis propria in 5 out of 9 patients, the per-ureteric adipose tissue in 1 patient, and the prostate gland in 1 patient. • With regard to outcome, five out of the 9 patients had died of their angiosarcoma disease, with a median survival of 7 months but the individual survivals had ranged between 6 months and 14 months. Two of the patients were alive with disease at 3 months and 6-months of follow-up. One patient who had undergone radical cystoprostatectomy was alive without any evidence of disease at his 12-month follow-up pursuant to his operation. Matoso et al. [25] also made the ensuing iterations:• Epithelioid angiosarcoma (EA) of the urinary bladder is an uncommon malignant tumour which is frequently misdiagnosed as high-grade carcinoma, especially in view of the positive immunohistochemistry staining of the tumour for cytokeratin.• The tumour tends to be more frequently encountered in older men who have a history of having had radiotherapy to the pelvis. • Morphological features that should alert the pathologist to the diagnosis of tumour of vascular origin include highly atypical nuclei associated with interspersed erythrocytes, haemorrhagic background, and occasional intracytoplasmic lumens. • Patients who have angiosarcomas of the urinary bladder tend to present with muscle-invasive disease and the prognosis of angiosarcomas of the urinary bladder is dismal. The lessons learnt from this article include that the diagnosis of angiosarcoma of the urinary bladder can be difficult for the pathologist and for this reason a possibility

of misdiagnosis does exist. Additionally realizing that angiosarcomas of the urinary bladder tend to ensue previous radiotherapy to the pelvis and radiotherapy is regarded as a cause of angiosarcoma of the urinary bladder there should be no place for utilization of radiotherapy as adjuvant therapy for the disease. Realizing that utilization of TURBT, partial cystectomy after TURBT, TURBT and subsequent radical cystectomy as well as radical cystectomy alone had been associated with a very poor prognosis, it would be argued that utilization of neoadjuvant or adjuvant combination chemotherapy should be the only other additional treatment to radical cystectomy which could help improve the prognosis with regard to long-term disease free survival. For this reason it would be recommended that a global multi-centre trial treatment of angiosarcomas of the urinary bladder should be established which should include chemotherapy and radical cystectomy.

Wang et al. [26] stated that angiosarcoma of the lower urinary tract is very rare and in the urinary bladder only 34 cases had been reported in the English literature. [3, 5, 7, 12, 13, 25] Wang et al. [26] also stated that prior to the report of their case only two cases of post-radiotherapy epithelioid angiosarcoma of the urinary bladder had been reported in the literature but no case of angiosarcoma of the prostate following radiotherapy had been report. Wang et al. [26] reported a case of primary angiosarcoma that had involved both the urinary bladder and the prostate gland following a previous radiotherapy for adenocarcinoma of the prostate gland. Wang et al. [26] reported a 79-year-old man who in 2007 had undergone external beam radiotherapy for adenocarcinoma of prostate. In 2013, he developed irritative lower urinary tract symptoms and visible haematuria. He underwent cystoscopy and trans-urethral resection of urinary bladder tumour. Histology examination of the specimen showed a widely infiltrating, poorly differentiated tumour which had epithelioid cytological features, with areas of haemorrhage, and spindled pattern which was adjudged to be consistent with a diagnosis of high-grade urothelial carcinoma with sarcomatoid dedifferentiation. He underwent 2 months subsequently, radical cystoprostatectomy and the microscopic examination features as well as the immunohistochemistry studies features of the specimen were adjudged to be

11Jacobs Publishers

consistent with epithelioid angiosarcoma of the bladder and prostate gland. One of 34 excised pelvic lymph nodes contained tumour with extra-nodal tumour involvement. He had remained well at his 20 month post-operative follow-up. An important lesson to learn from this case report is the fact that primary angiosarcoma of the urinary bladder may not be easy to diagnose and could be easily mis-diagnosed as a poorly differentiated carcinoma of the urinary bladder. Secondly careful re-examination of previously resected specimen and utilization of angiosarcoma detecting immunohistochemistry studies would help in

confirming the diagnosis of angiosarcoma (see table for the immunohistochemistry features of the tumour). Even though the patient was well at his 20-month follow-up, some people could argue that considering the aggressive biological behaviour and poor prognosis associated primary angiosarcoma perhaps, in retrospect utilization of adjuvant chemotherapy would have been an additional attempt to destroy possible microscopic metastatic lesions and thus help prevent future development of overt metastasis and death of the patient. This argument is only conjectural taking into consideration there is no consensus global

Table 1: List of reported cases of primary angiosarcoma of the urinary bladder (PAUB) with relevant summation of vari-ous features.

Author &Year

Age Sex Predisposing factor & relevant history

Presentation Histology / im-munohistochem-istry

Treatment Outcome Num-ber

Jumgano et al. [2] 1907

54 M Haemangioma Haematuria & urinary tract ob-struction

Anastomosing vascular chan-nels / No immu-nohistochemistry studies under-taken

Surgery Information not available

1

Casal et al [35].1970

85 M Haemangioma Haematuria Anastomosing channels / no im-munohistochem-istry undertaken

Surgery Myocardial in-farction; he died 3 days pursuant to his diagnosis

2

Stroup & Chang [34] 1987

68 M Data not available Haematuria Anastomosing vascular chan-nels, immunohis-tochemistry not undertaken

Surgery He developed liver and pulmo-nary metastases & also myocar-dial infarction, he died 8 months pursuant to his diagnosis.

3

Aragona et al. [21] 1991.

78 M Information not available

Haematuria Anastomosing vascular channel & positive stain-ing for Factor VIII, & ULEX but keratin was negative

Surgery(Diverticulec-tomy)

He developed myocardial infarction & he died 2 months pursuant to his diagnosis

4

Ravi et al. [20] 1983

55 M No information available

Haematuria Anastomosing vascular chan-nels, Immuno-histochemistry not performed

Partial cys-tectomy & adjuvant ra-diotherapy(5500 cGy)

Alive with no evidence of local recurrence or metastasis at his 8-month fol-low-up

5

12Jacobs Publishers

Navon et al. [13] 1997

78 M Had radiotherapy 13 years preced-ing the diagnosis of angiosarcoma of urinary bladder

Haematuria Anastomosing vascular chan-nels & positive staining for CD34 & Factor VIII.

Radical cysto-prostatectomy

Alive and with no recurrence or metastasis 30 months pursuant to his diagnosis.

6

Engel et al. [9] 1998

47 M No information available

Haematurria, flank pain, supra pubic pain

Solid tumour, primitive epi-thelioid tumour cells & no im-munohistochem-istry staining undertaken or not available

Radical cysto-prostatectomy, & 5 cycles of chemotherapy & radiother-apy to pelvic region

Alive and free of recurrence and metastasis 29 months pursuant to his diagnosis

7

Schindler et al. [22] 1999

47 M None Left flak/loin pain & dysuria & su-prapubic pain

Solid tumour & microscopy examination showed anasto-mosing vascular channels, and epithelioid tu-mour cells & positive staining for CD31, posi-tive staining for vimentin, CD34 negative, keratin negative, factor VIII neg-ative


Lymphatic spread

8

Seethala et al. [3] 2006

66 M Radiotherapy 4 years preceding the diagnosis

Haematuria Solid tumour & primitive looking epithelioid & spindled cells that stained posi-tive for CD34 & CD31 but keratin was negative

Radical cysto-prostatectomy & 5 cycles of Gemcitabine and Docetaxel chemotherapy

Questionable metastasis in the peritoneum but he was alive & well 19 months pursuant to his diagnosis.

9

Kulaga et al. [7] 2006

83 F Radiotherapy 14 years preceding the diagnosis of angiosarcoma of urinary bladder for adenocarci-noma of endome-trium

Non visible Hae-maturia

Epithelioid tumour cells ant features of angiosarcoma & positive staining for CD31,Vimentin posi-tive, Factor VIII negative, CD34 negative

Trans urethral resection of bladder tumour (TURBT)

-died 3 months post-operatively with no post mortem exanina-tion

10

Williams et al. [8] 2008

71 M Radiotherapy for carcinoma of the prostate 10 years preceding the diagnosis of an-giosarcoma of the urinary bladder

Haermaturia Epithelioid tumour cells & features of angiosarcoma & positive staining for CD34, CD31, & Factor VIII

Radical cysto-prostatecto-my & was referred for radiotherapy & chemother-apy but was apparently not well enough to receive adju-vant therapy

He developed diffuse abdomi-nal carcinomen-tosa and died 3 months pursuant to his operation.

11

13Jacobs Publishers

Warne et al. [19] 2011 ;

32 F None, diagno-sis was made 6 months post-par-tum

Haematuria Epithelioid tu-mour cells and features of an-giosarcoma with positive staining for CD31, Fac-tor VIII-related antigen, Ulex, CD34, AE1/AE3, Cam5.2, CK8, MN-F116,CK20

Surgery & paclitaxel che-motherapy

She developed pulmonary metastasis and died 19 months pursuant to her diagnosisBut no autopsy undertaken.

12

Bahouth et al. [30] 2015

89 M Radiotherapy for carcinoma of the prostate gland 12 years preceding the diagnosis of angiosarcoma of the urinary blad-der.

Haematuria Anastomosing vascular chan-nels & positive staining for CD34, CD31, and Factor VIII. but keratin stained negative

Surgery & palliative radiotherapy

He developed metastasis to the pelvic bone and spinal vertebrae and died 3months pursuant to his diagnosis

13

Nawar et al [38] 2016.

68 M None hypospa-dias

Urinary obstruc-tion

Sheets of spin-dled cells, epi-thelioid tumour cells, and osteo-clast-like multi-nucleated giant cells & positive staining for CD31 & CD68.

Surgery He died 3 weeks pursuant to his operation.

14

Wang et al [26] 2016

79 M External beam radiotherapy for carcinoma of prostate 6 years earlier

Irritative lower urinary tract symp-toms and visible haematuria

Solid epithelioid pattern resem-bling poorly differentiated carcinoma and vascular differ-entiation with anastomosing vascular, angu-lar, blood filled spaces, lined by elongated, hyperchromatic tumour cells.Positive staining for CD31, CD34, FL11, ERG, focal staining for CK7, 20 to 60% nuclear positive staining for c-Myc.

Cystoprosta-tectomy. (sur-gery alone)

Alive and well 20 months pursuant to the surgery with no recurrence.

15

14Jacobs Publishers

Nizam et al. [27]

57 M No predisposing factor

Visible haema-turia, anaemia, urinary frequency, dysuria, weakness, pallor, cachexia, bilateral lower extremity oedema, pallor, cachexia, scattered ecchy-mosis, anaemia,

Epithelioid an-giosarcoma with full thickness of muscularis pro-pria of bladder with tumour at resection margin, positive staining for AE1/AE3, CK8/18, FLI-1, CD31, Factor VIII, Focal stain-ing weak stain-ing for CD34 and ERG. The tumour stained negative for GATA-3, p63, S100, CK903, and pax-8.

Blood transfu-sion for anae-mia, insertion of vena cava filter due to pulmonary embolism and lower limb swelling plus ecchymosis and partial cystectomy there was re-sidual tumour at resection margin and tumour in up-per left renal pelvis down to upper ureter, pulmonary embolism, and a possible tumour focus in acetabulum / ischium. Pa-tient declined to have further treatment, therefore palli-ative care.

1-month alive in poor state with disease

16

Gerbaud et al [28] 2016

72 M Industrial chemi-cal exposure

Haematuria Epithelioid angiosarcoma tumour cells plus necrosis, pos-itively stained for: CD31, FLI-1, ERG, and 90% Ki67 stain-ing but negative for CD34.

Trans-urethral resection of tumour which was in sub-mucosa, radiotherapy initially and total pelvecto-my and uri-nary diversion, he developed liver and lung metastases

He died at 5 months of angio-sarcoma diag-nosis.

17

Rallabandi et al. [29]

65 F Haematuria Had radiotherapy following hyster-ectomy 22 years for carcinoma of cervix.

Vascular tumour with spindled to ovoid cells, pleomorphic cells with ve-sicular nuclei, prominent nucle-oli, and osseous metaplasia. Positive staining for CD31 and vimentin and negative staining for pancytokera-tin, desmin, and CD34.

Trans urethral resection of bladder tu-mour.

No follow-up data available

18

15Jacobs Publishers

Matoso et al. [25] 2015

73

77

71

85

39

64

43

73

64

F

M

M

M

M

M

M

M

M

Haematuria

Haematuria

Haematuria

Haematuria

Haematuria

Haematuria

Haematuria

Haematuria

Haematuria

CD31 positive Factor VIII pos-itive.

CD31 positiveCD34 positiveFactor VIII neg-ative

CD31 positiveFactor VIII pos-itive

CD31 positiveCD34 positiveFactor VIII pos-itive

CD31 positive

CD31 positiveERG positive

CD31 positiveFactor VIII pos-itiveERG positiveCD34 negative



TURBT en-sued by partial cystectomy

TURBT


TURBT



TURBT

TURBT.

TURBT

Died 6 months after diagnosis


Died 7 months pursuant to diag-nosis

He died 6 months pursuant to his diagnosis

He died 13months pursu-ant to his diag-nosis

Alive 12 months pursuant to his initial diagnosis

Alive 6 months pursuant to the initial diagnosis

Died 3 months pursuant to ini-tial diagnosis

Alive 3 months pursuant to ini-tial diagnosis

19

20

21

22

23

24

25

26

27

Bahouth et al. [30] 2015

89 M Massive haema-turia

External beam radiotherapy for adenocarcinoma of prostate 12 years earlier

Angiosarcoma invading the muscularis pro-pia of the blad-der with anasto-mosing vascular channels positive staining for CD31 and CD34. Focally positive for factor VIII. Negative stain-ing for P63/

Trans-urethral resection of bladder tumour and palliative ra-diotherapy to back pain due to metastasis [He refused chemotherapy]

He died 3months after diagnosis

28

16Jacobs Publishers

Spina et all [31] 2013

67 F Haematuria None Infiltrated poorly differentiated tumour that was interpreted as high-grade papillary urothe-lial carcinoma. Immunohis-tochemistry staining features not available to author.

Trans-urethral resection of bladder tu-mour, radical cystectomy, pelvic lymph adenectomy, hysterectomy bilateral sal-pingo-oopho-rectomy (an-terior pelvic exenteration),

Patient died within a short time post-opera-tively.

29

Bevazal et al. [32] 2014

20 M Details not avail-able

Haematuria and disseminated pel-vic pain

CD34 positive Partial cystec-tomy

Alive 1 ear pursuant to diag-nosis

30

Abbasov et al. [33] 2011


Haematuria Keratin positive,Factor VIII pos-itiveVimentin pos-itiveCD31 positiveCD34 negative


Died 5 weeks after diagnosis

31

Schindler et al. [22]1999

47 M Dysuria followed later by left loin pain

None documented Cytological examination of bladder washings showed features of angiosarcoma

Details not available

Details not avail-able

32

Ravi [20] 1993

Not avail-able

M Details not avail-able

None Features con-sistent with angiosarcoma of bladder details not available

Partial cys-tectomy & adjuvant post-operative radiotherapy

Was alive dis-ease-free at his 8 month follow-up but no long-term outcome data

33

Morgan et al. [12]1989

72 F Vaginal bleeding & haematuria

Previous radio-therapy

Features of an-giosarcoma of bladder, she also had angiosarco-ma of the vaginaFactor VIII pos-itive



34

Stroup and Chang [34] 1987

68 M Haematuria Details not avail-able

Features of an-giosarcoma & positive immu-nohistochemistry staining for Factor VIII, & cytokeratinKeratin negative

Partial cystec-tomy followed by radical-cystoprosttec-tomy later

He developed local recurrence 3 months after partial cystec-tomy,

He died 8 months after initial diagnosis autopsy did show liver and lung metastases

35

Casal et al. [35] 1970

85 F Details not avail-able

Haematuria,dy-suria, weight loss

Classic focally solid angiosar-coma


Details are not available

36

Schwartz et al. [39] 1983


Haematuria en-larging cutaneous nodules


10 courses of chemotherapy: cisplatinum, doxorubicin, & cyclophos-phamide

He died 23 months after diagnosis with angiosarcoma in the brain, lung, and scrotum

37

17Jacobs Publishers

opinion on the best option of managing the disease. Nizam et al. [27] reported a 57-year-old man who presented with a 4-week history of visible haematuria, urinary frequency and dysuria and who was found to be pale and cachectic, and who also had bilateral lower extremity oedema and some ecchymosis. His blood test results showed evidence of anaemia, hyponatraemia, borderline impairment of renal function as well as hypoalbuminemia. He had CT scan of thorax, abdomen and pelvis which showed a mass in the left upper pole calyx down to the left upper ureter and a mass that comprised of blood clot and tumour in his urinary bladder. He was found to have pulmonary embolism. He had 2 units of blood transfusion and insertion of inferior vena cava filter. He also had partial cystectomy and pathology examination of the specimen showed epithelioid angiosarcoma with involvement of the full thickness of the muscularis propria of the urinary bladder and tumour at the resection margin. He declined to have further surgical treatment one month later because he was in a poor state of health and required palliative care with the knowledge that his prognosis was poor. The lesson learnt from this case report include the fact that primary angiosarcoma of the urinary bladder may present with a

short history of haematuria and urinary symptoms but at presentation the tumour may be advanced with metastatic disease and occasionally there may be pulmonary embolism, impaired renal function, impaired liver function, and anaemia. The case also illustrates the aggressive biological behaviour of the tumour. In this particular case surgery alone could not be undertaken to cure the disease. Furthermore, with the realisation that the patient had extensive disease, if there was a well known chemotherapy medicament or regimen that could effectively destroy the angiosarcoma tumour cells this could have been discussed and utilized. It would appear as if there is a global need for a global multi-centre trial of various chemotherapy regimens that would destroy effectively angiosarcoma tumour cells with the aim of prolonging lives. There is need for oncologists, urologists and pharmacotherapy researchers to identify chemotherapy medicaments that would destroy angiosarcoma tumour cells through further research work. Gerbaud et al. [28] reported a 72-year-old man who presented with visible haematuria. He had cystoscopy which revealed a large tumour in the left side of the bladder for which he underwent trans-urethral resection of bladder tumour. Histopathology examination of the

Pazona et al. [6] 2007


Haematuria & suprapubic pain

CD31 positive Radical cysto-prostatectomy & 5 cycles of chemotherapy & pelvic irra-diation

Died 6 years after diagnosis from myocardial infarction, autop-sy no evidence of recurrent tumour.

38

Tavora et al. [5] 2008

73

77

71

63

F

M

M

F

Haematuria


Haematuria

Haematuria

Details not avail-able for all 4 cases to author

Haematuria

CD31 positive and CD34 pos-itive for 3 cases but keratin was negative for all 4 tumours

Radical cys-tectomy




She died 2 months after diagnosis

Died 5 months after diagnosisDied 4 months after diagnosis


39

40

41

Ojerholm et al [24] 2015


Haematuria Details not avail-able


Alive 4 months after diagnosis

42

18Jacobs Publishers

tumour showed features that were characteristic of epithelioid angiosarcoma of the urinary bladder that had involved the submucosa bulging the mucosa of the bladder. CT scan undertaken 3 weeks after the complete resection TURBT showed local recurrence but no metastases. He also had initial radiotherapy followed by total pelvectomy and urinary diversion due to evidence of thickening of his bladder wall on CT scan. He developed liver and pulmonary metastasis and died 5 months after his diagnosis (see figures 2, 3, and 4, for pathology finding images and CT scans). The lesson learnt from this case report is that even though the tumour was in the submucosa, liver and pulmonary metastases developed quickly which would indicate that angiosarcomas of the urinary bladder whether they are superficial or not they could quickly metastasize as well as it should be assumed that any angiosarcoma of the urinary bladder that is diagnosed initially should be presumed to be associated with microscopic metastases and hence for most cases surgical operation alone would not be adequate. It would therefore be argued that patients who have primary angiosarcoma of the urinary bladder whether superficial or not should be treated by surgery and adjuvant systemic chemotherapy to destroy microscopic metastatic tumours before they develop into large metastatic lesions. This suggestion is conjectural and would require a global consensus opinion decision on which chemotherapy options should be utilized perhaps after further research work has been undertaken by pharmacotherapy research workers, oncologists, and urologists.

Figure 2: Malignant epithelioid cells. HES stain. Reproduced from: [28] Gerbaud E, Ingels A, Ferlicot S, Irani J. Angiosarcoma of the Bladder: Review of the Literature and Discussion About a Clinical Case. Urol. Case Rep; 2017 Jul; 17: 13: 97 – 100 DOI: 10.1016/j.eucr.2016.12.007 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412009/

Accessed 2019 Jan 26.Rallanandi et al. [29] reported a 65-year old woman

who had presented with haematuria. She had ultrasound scan and CT scan of abdomen and renal tract which showed a tumour in the urinary bladder with calcification. He had cystoscopy which showed a calcified urinary bladder mass. She had 22-years earlier undergone hysterectomy and radiotherapy for carcinoma of the cervix. She had cystoscopy and trans urethral resection of the bladder tumour mass and pathology examination of the specimen showed features of epithelioid sarcoma with extensive osseous metaplasia. Immunohistochemistry staining studies of the tumour did show positive staining for CD31 and vimentin and negative staining for cytokeratin, desmin, and CD34. Rallabandi et al. [29] stated that up to the time of the report of their case in 2016, only 16 cases of angiosarcoma of the urinary bladder had been reported in the English literature and out of the 16 reported cases, 6 of them had occurred pursuant to radiotherapy and that their reported case was the first case of angiosarcoma of the urinary bladder to occur 22 years after radiotherapy and to be associated with extensive osseous metaplasia. Whilst the case report did illustrate that angiosarcoma of the urinary bladder can occur 22 years pursuant to radiotherapy for carcinoma of the cervix and it can be associated with osseous metastasis, unfortunately there was no long-term follow-up outcome reported. Considering that generally angiosarcomas tend to be aggressive tumours associated with development of metastases early and death of many patients some people would argue that perhaps the patient should have been assumed to possibly have microscopic metastatic disease which will eventually show up in the future hence she should have been offered systemic chemotherapy as adjuvant treatment as an effort to destroy the microscopic tumour cells and thus prolong her long-term disease free survival

19Jacobs Publishers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412009/


Figure 3: A: CD31 membranous staining of infiltrating tumour cells. We can observe also the normal vessel wall staining. B: Moderate ERG nuclear staining of tumour cells. We can observe a stronger staining of normal endothelial capillary cells. Reproduced from: [28] Gerbaud E, Ingels A, Ferlicot S, Irani J. Angiosarcoma of the Bladder: Review of the Literature and Discussion About a Clinical Case. Urol. Case Rep; 2017 Jul; 17: 13: 97 – 100 DOI: 10.1016/j.eucr.2016.12.007 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412009/ Accessed 2019 Jan 26

Figure 4: CT images show the rapid local progression of the tumour bladder. A. Day of diagnosis. B. 2 months after diagnosis. Reproduced from: [28] Gerbaud E, Ingels A, Ferlicot S, Irani J. Angiosarcoma of the Bladder: Review of the Literature and Discussion About a Clinical Case. Urol. Case Rep; 2017 Jul; 17: 13: 97 – 100 DOI: 10.1016/j.eucr.2016.12.007 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412009/ Accessed 2019

Jan 26 under copy right © 2016 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licences/by-nc-nd/4.0/)

Bahouth et al [30] reported an 89-year old man who had presented with massive visible haematuria that required urethral catheterization and bladder wash outs. He had 12 years preceding his presentation undergone external beam radiotherapy for adenocarcinoma of the prostate gland. The results of his routine blood haematology and biochemistry tests and serum PSA were normal. His urine cytology test result was normal. He had a Computerized Tomography (CT) urogram which showed a large vascular mass in the left side of the wall of the urinary bladder that had irregular edges (see figure 5a). The Computed tomography scan also did show severe left sided hydroureteronephrosis (see figure 5b) and lytic lesions within the bones of the pelvis and vertebrae suspected as metastases. He underwent cystoscopy and trans-urethral resection of a large solid bladder tumour from the base of the urinary bladder. Microscopic examination of the specimen did show features diagnostic of primary angiosarcoma that had invaded the muscularis layer with anastomosing vascular channels. Immunohistochemistry staining studies (see figure 6a). immunohistochemistry staining studies did show strongly positive staining for CD31 and CD34 and focally positive staining for factor VIII (see figures 6b and 6b and 6c). and three markers for endothelial cells, as well as immunohistochemistry studies were negative for keratin p63 (see figure 6d). No prostatic tissue was observed in the specimen. He underwent palliative radiotherapy as treatment for spinal metastasis. He was offered chemotherapy but he did not agree to have any chemotherapy. He died 3 months after his initial diagnosis. The outcome of the patient reported in this case does illustrate the aggressive biological behaviour of primary angiosarcoma of the urinary bladder which could present initially with primary and metastatic disease and for this reason the disease should be considered a systemic disease that would require utilization of systemic chemotherapy. Considering that despite utilization of chemotherapy in the treatment of cases of angiosarcomas many patients

20





generally die, there is need for pharmacotherapy researchers, urologists and oncologists to undertake research that would identify specific chemotherapy medicaments that would easily destroy angiosarcoma tumour cells to improve the long-term survival outcomes of individuals who develop angiosarcomas of the urinary bladder.

Figures 5 a and 5b: Computed tomography of our patient. (a): Highly vascular mass originating from the left bladder wall, but a prostatic origin could not be absolutely ruled out by CT. (b) Hydronephrosis on the left side and coronal view of the mass. Reproduced from: [30] Bahouth Z, Masarwa I, Halachmi S, Naliv O. Primary Angiosarcoma of Urinary Bladder: 13TH Reported Patient. Case Rep Oncol Med 2015; 2015: 652870. DOI: 10.1155/2015/652870 https://www.ncbi.nlm.nih.

gov/pmc/articles/PMC43Spina et al. [31] reported a 67-year-old white woman who had primary angiosarcoma of the urinary bladder without any apparent risk factors or an antecedent carcinogens that are typically related to such malignant tumours. She did present with visible haematuria for which she did undergo cystoscopy and trans-urethral resection of urinary bladder tumour. Histopathology examination of the specimen did show an infiltrative, poorly differentiated tumour which had been interpreted as high-grade papillary urothelial carcinoma. She did undergo radical cystectomy and regional lymphadenectomy, as well as bilateral hysteron-salpingo-oophorectomy. Pathology examination of the specimen did reveal a very large and extensive necrotic mass which had histological features that had been adjudged to be compatible to the diagnosis of angiosarcoma of the urinary bladder.

Spina et al. [31] reported that despite the patient having been managed by means of a multi-modal therapeutic approach, she died within a period of a short time. Spina et al. [31] indicated that their reported case does fall within the limited group of primary angiosarcoma of the urinary bladder with very aggressive clinical features in a patient who did not have any recognizable risk factors. Some of the lessons that need to be learnt from this case report include: (a) utilization of extensive surgical procedure of anterior exenteration to ensure complete removal of all visible tumour and all possible areas of local recurrence alone did not provide treatment of curative intent even though radiological imaging did not reveal any evidence of metastases but the patient died shortly after the extensive surgery. Even though it is conjectural it would be argued that primary angiosarcomas of the urinary bladder should be considered and recognized to be a systemic disease whether the tumour is superficial or muscle invasive because angiosarcomas of the urinary bladder would be associated with microscopic metastases which various radiology imaging scan cannot detect because the metastatic lesions are too small at the time of presentation. It would be argued that the microscopic metastases associated with primary angiosarcoma would eventually grow bigger and kill the individual subsequently. For this reason it would be argued

21Jacobs Publishers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43

that excisional surgery alone does not represent curative treatment and that treatment with curative intent should include utilization of adjuvant chemotherapy. It would also be argued that the chemotherapeutic regimens that are being utilized in the treatment of primary angiosarcomas of the urinary bladder would appear not to be effective in the treatment because long-term disease-free survivals are not being globally reported. For this reason, it is the view of the author that (a) Pharmacotherapy researchers, oncologists and urologists globally should quickly and urgently undertake research studies that would identify chemotherapy medicaments that would quickly destroy angiosarcoma tumour cells which would lead to long-term disease-free survival of patients who have primary angiosarcoma of the urinary bladder. (b) A global multi-entre trial of various adjuvant chemotherapy options for the treatment of primary angiosarcomas of the urinary bladder should be established.

Figure 6: Histopathology and immunohistochemistry. (a) Typical appearance of anastomosing vascular channels as seen with H&E. (b) Tumor cells stain positive for CD34. (c) Tumor cells do not stain for cytokeratin. Reproduced from: [30] Bahouth Z, Masarwa I, Halachmi S, Naliv O. Primary Angiosarcoma of Urinary Bladder: 13TH Reported

Patient. Case Rep Oncol Med 2015; 2015: 652870. DOI: 10.1155/2015/652870 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321076/ Accessed 2019 Jan 26]

Beyazal et al. [32] stated that published reports related to primary angiosarcomas of the urinary bladder had not featured the imaging findings of the disease. Beyazal et al. [32] reported a 20-year old man who had primary angiosarcoma of the urinary bladder with a focus on the computed tomography scan and magnetic resonance imaging findings of the disease. The details of the case report are not available to the author.

Figure 7: CT Scan of abdomen and pelvis showing bladder mass. Reproduced from: [38] Nawar N A, Olsen J, Jelic T M, He C. Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review. The American Journal of Case Reports. 2016; 17: 143 – 149. DOI: 10.12659/AJCR.896266 http://europepmc.org/articles/PMC4784551 Accessed 2019 Jan 25 under Copy Right © Am J Case Rep. 2016 This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License

22Jacobs Publishers



http://europepmc.org/articles/PMC4784551

Abbasov et al. [33] reported a case of angiosarcoma of the urinary bladder but the details of the case are not available to the author.

Schindler et al. [22] reported a 47-year old man who had had dysuria for many months which was treated as prostatitis. He subsequently developed left loin pain and following investigations a stone was found in his left ureter. A left nephrostomy was inserted and subsequently a left nephrostogram was undertaken which showed a normal left ureter. Washings obtained from his bladder urine upon cytology examination revealed features of angiosarcoma which formed the basis for the diagnosis of angiosarcoma of the urinary bladder. He had surgery for his tumour but details of the surgery are not available to the author. Pathology examination of the tumour showed Solid tumour and microscopy examination showed anastomosing vascular channels, and epithelioid tumour cells. Immunohistochemistry staining of the tumour showed positive staining for CD31 The long-term outcome of the patient was not available to the author except there was lymphatic invasion by the tumour. However, the lesson to learn from this case report would indicate that at times cytology examination of urine and or urinary bladder washings would cytological features of angiosarcoma of the urinary bladder or renal tract.

Figure 8: Representative H &E images. (A) (40 x) Atypical spindle cells and epithelioid cells with mitotic figures. (B) (60 x) Epithelioid cells with intracytoplasmic lumen. (C) (20 x) Area with numerous multinucleated giant cells. (D) (60 x) Cells with high nuclear cytoplasmic ratio. Reproduced

from: [38] Nawar N A, Olsen J, Jelic T M, He C. Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review. The American Journal of Case Reports. 2016; 17: 143 – 149. DOI: 10.12659/AJCR.896266 http://europepmc.org/articles/PMC4784551 Accessed 2019 Jan 25 under Copy Right © Am J Case Rep. 2016 This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License

Ravi [20] reported a case of primary angiosarcoma of the urinary bladder in a man who had not had any previous exposure to any predisposing factors for angiosarcoma of the urinary bladder. He was treated by means of partial cystectomy and post-operative radiotherapy. Ravi [34] stated that the predisposing factors for the development of angiosarcoma in the viscera include: exposure to thorium chloride, arsenic, polyvinyl chloride, radiotherapy, chemotherapy, and presence of foreign body material. An observation from this case report is that the patient was alive and well 8 months pursuant to his partial cystectomy and radiotherapy but there was no long-term outcome reported with regard the case. However, it would be argued that the fact that he had not had any previous exposure to radiotherapy, the angiosarcoma of the urinary bladder was therefore not radiotherapy induced. Nevertheless, considering that primary angiosarcomas tend to be associated with poor long-term follow-up, some people could argue that perhaps in retrospect the patient should also have been offered adjuvant chemotherapy as additional attempt to give him a chance to have a long-term disease-free survival.

Morgan et al. [12] stated that they had probably reported the first case of post-radiotherapy angiosarcoma that had involved both the vagina and urinary bladder. The lesson to learnt from this case report is that radiotherapy to the pelvic organ could subsequently be associated with the development of primary angiosarcoma in more than one organ. In this case the angiosarcoma could have been two separate post-radiotherapy induced de novo primary angiosarcomas. On the other hand the finding of angiosarcoma in both the vagina and the urinary bladder

23Jacobs Publishers



could have been angiosarcoma developing in one organ and then invading the other organ.

Figure 9: Features of multinucleated giant cells. (A) (60 x) Multinucleated giant cell with up to 75 nuclei (B) (60 x) Multinucleated giant cell with phagocytosed blood elements. (C) (60 x) Questionable multinucleated giant cell with intracytoplasmic lumen. Reproduced from:[38] Nawar N A, Olsen J, Jelic T M, He C. Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review. The American Journal of Case Reports. 2016; 17: 143 – 149. DOI: 10.12659/AJCR.896266 http://europepmc.org/articles/PMC4784551 Accessed 2019 Jan 25 under Copy Right © Am J Case Rep. 2016 This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License

Strout and Chang [34] reported a case of angiosarcoma of the urinary bladder in a 68 year old man who had presented with haematuria. The tumour was the classic angiosarcoma type. They stated that immunohistochemistry staining of the tumour was positive for factor VIII.

Casal et al. [35] reported in 1970 a case of angiosarcoma of the urinary bladder in an 85 year old woman who had presented with haematuria, dysuria, and weight loss in Spanish but the details are not available to the author. The tumour was however, stated to be solid and of classical angiosarcoma type.

Otsuobo et al. [36] reported a 79 -year old man who had undergone right extra-pleural lucite ball plombage for tuberculosis of the lung when he was 19 years old. He had been on medication for benign prostatic hyperplasia from 2008 and had been undergoing follow-up assessments. He did present with visible haematuria in January 2010 but at that time he had cystoscopy and CT scan of the urinary tract which did not reveal any abnormality. He was admitted in February 2010 because of fatigue and anaemia. He underwent cystoscopy 10 days later during which trans urethral resection of urinary bladder tumour was undertaken and during the procedure bleeding sites were noticed with oozing from bilateral sites on the posterior wall of the urinary bladder. Otsubo et al. [36] reported that CT scan and urine cytology examinations did not demonstrate the tumour though histological examination of the resected bladder lesion showed features that had been adjudged to reveal the possibility of malignant vasoformative tumour. He died pursuant to his admission. Autopsy was carried out which showed a very large mass within the right upper thoracic wall and the same tumour metastases within the adrenal glands, the bone, the stomach, and the urinary bladder. Microscopy pathology examination of the specimen did show that atypical cells had proliferated and had formed vascular structures which had upon immunohistochemistry staining studies stained positively for CD31 and vimentin. The final post-mortem examination diagnosis was pleural angiosarcoma with metastases to many organs including the urinary bladder. Otsubo et al. [36] additionally stated that metastatic angiosarcoma of the urinary bladder is very uncommon and difficult to diagnose; nevertheless, clinicians need to be aware of the fact that metastatic angiosarcoma of the urinary bladder does exist. The main lesson that needs to be learnt by all clinicians including urologists and pathologists is the fact that not all angiosarcomas of the urinary bladder are primary

24Jacobs Publishers



angiosarcomas because metastatic angiosarcomas of the urinary bladder also do exist. For this reason any urologist who finds that his or her patient has angiosarcoma of the urinary bladder, should ensure that a full assessment of the patient is undertaken including a thorough radiological imaging assessment to ensure there is no other tumour elsewhere in the body before the clinician or urologist and pathologist can label the tumour as primary angiosarcoma of the urinary bladder.

Figure 10: Immunohistochemistry figures, (A, B) Cell expresses CD 68, (left) and CD 31 (right), (c) patchy staining with factor X111, (D) Ki-67 is expressed in approximately 40% of cells and is not expressed by the multinucleated giant cells. Reproduced from: Reproduced from: [38] Nawar N A, Olsen J, Jelic T M, He C. Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review. The American Journal of Case Reports. 2016; 17: 143 – 149. DOI: 10.12659/AJCR.896266 http://europepmc.org/articles/PMC4784551 Accessed 2019 Jan 25 under Copy Right © Am J Case Rep. 2016 This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported

License Paner et al. [37] iterated that the pseudo-

sarcomatous pattern had been described most often in cutaneous and some visceral squamous cell carcinoma as well as it is unique with regard to its strong morphological semblance of angiosarcoma. Paner et al. [38] did describe the clinicopathological characteristics of 7 pseudo-angiosarcomatous urothelial carcinomas which occurred within the urinary bladder. Paner et al. [37] summated their findings as follows:• The patients did include 6 men and 1 woman whose median age was 70 years and whose ages had ranged between 47 years and 87 years. • The pseudo-angiosarcomatous morphology was found in 7 urothelial carcinomas that included 3 that had squamous differentiation and which had consisted of 35% to 85% of the invasive tumour. • With regard to histopathology features, the pseudo-angiosarcomatous carcinomas had been characterized by dis-cohesion of tumour cells and lysis which had created pseudo-lumen formations encompassed by attached residual tumour cells. • Detached degenerating tumour cells variably mixed with inflammatory cells had been common in false lumens.• Partly intact urothelial carcinoma nests did contain irregular or cleft-like spaces and disintegrating tumour cells that had stretched intercellular bridges. • The tumour was frequently associated with a dense collagenous matrix, often encompassing the lytic -nests,• Similar tumour cell dis-cohesion and breakdown were seen in 3 of the tumours that had foci of squamous cell differentiation, and distinguished by the presence of dyskeratosis and keratin formation.• All 7 tumours did contain other non-pseudo-angiosarcomatous carcinoma components including conventional urothelial carcinoma, squamous differentiation sarcomatoid spindled cell carcinoma, small cell carcinoma, micropapillary carcinoma, and glandular differentiation. • All 7 out of 7 pseudo-angiosarcomatous urothelial carcinomas had stained diffusely CK 7 positive. most of them, 6 out of 7 tumours were GATA3 positive, and none of the 7 tumours did express vascular - associated markers.

25Jacobs Publishers



• There was no evidence to suggest that apoptosis by TUNEL assay and cleaved caspase-3 immunostaining or loss of the adhesion molecules CD138 and e-cadherin had been possible causes for the tumour cell dis-cohesion and breakdown. • All 7 tumours were high-staged at cystectomy and had included 1 pT3a, 2 pT3b and 4pT4a, and 3 did have pelvic lymph node involvement. • Follow-up data available in 6 cases did reveal a poor outcome with an overall median survival of 8.5 months.Paner et al. [38 new 37] concluded that they had presented an unusual morphology of carcinoma of the urinary bladder which does have a striking semblance to an malignant vasoformative tumour. Their series had shown that pseudoangiosarcomatous carcinoma of urinary bladder morphology is associated with a higher tumour stage at cystectomy, commonly in association with other aggressive carcinoma variant morphologies, and they tend to be associated with a poor prognosis . Knowledge of this pattern is also important to avoid misdiagnosis, particularly in cases of limited tissue samples.

The lesson that had been learnt from this article is the fact that there are other aggressive urothelial carcinomas of the urinary bladder that resemble angiosarcomas of the urinary bladder that need to be differentiated from primary angiosarcomas of the urinary bladder by careful scrutiny of the histopathology and immunohistochemistry staining features of the tumour and quite often a second opinion from another pathologist would be required and such cases must always be discussed at a multi-disciplinary team meeting, Nawar at al. [38] reported a 68-year-old white man who had presented with symptoms of inability to micturate, pain in the abdomen, fever, and unintentional loss of weight over a period of 6 weeks. He had a history of congenital hypospadias but no history of a previous malignancy or radiotherapy. The results of his blood biochemistry tests showed he had leucocytosis and raised level of serum creatinine. He did have CT scan of his abdomen and pelvis which did show that he had a distended urinary bladder which did contain a large filling defect on the left side wall of his urinary bladder as well

as bilateral hydronephrosis (see figure 7). The features of the filling defect in the urinary bladder had suggested a bladder tumour. He was catheterized and 2000 ml of urine containing white sediment and debris was drained. He underwent cystoscopy and trans-urethral resection of bladder tumour (TURBT) for a large and necrotic tumour that had encased the urinary bladder and the prostate gland. Gross pathology examination of the specimen showed a tumour that weighed 185 grams and which had a mixture of blood and tan-pink fragments of soft tissue and with no evidence of normal looking urinary bladder mucosa or prostate. Microscopic histopathology examination of the specimen showed solid sheets of cells that had areas of acute inflammation, necrosis, and haemorrhage. Three populations of cells were found that included: spindle cells, epithelioid cells, and multi-nucleated giant cells. The spindled cells and the epithelioid cells were considered to be very atypical, and they had a high nuclear to cytoplasmic ratio, and hyperchromasia, as well as obviously prominent and multiple nucleoli and atypical mitotic figures. Some of the epithelioid cells did have intra-cytoplasmic lumens. The tumour did contain scattered multi-nucleated giant cells (see figure 8) which were osteoclast-like with up to 75 nuclei, elements of phagocytosed blood, and no evidence of activity. The multi-nucleated giant cells were noted to contain rare questionable intra-cytoplasmic lumens (see figure 9). The microscopy examination did not reveal any urothelial or prostatic tissues. The differential diagnoses that were considered upon the morphology features of the tumour included poorly differentiated carcinoma, high grade lymphoma, melanoma, and high-grade sarcoma. Immunohistochemistry studies of the tumour did show that the tumour cells including the multi-nucleated giant cells had stained diffusely positive with vimentin, C68, CD31, and they did stain focally positive for factor XIII. Ki-67 was found to be positive in 40% of the tumoural cells and Ki-67 was negative in the multi-nucleated giant cells (see figure10). The tumour cells were negatively stained for other markers including: GATA-3, CK7, prostate specific antigen (PSA), prostate specific alkaline phosphatase, CK5/6, and P63 which are epithelial markers; S-100, Mart-1, and HMB45, which are melanoma markers; LCA, CD20, CD3,

26Jacobs Publishers

CD300, and ALK-1, which are lymphoma markers. Based upon the morphology features and immunohistochemistry staining features of the tumour a diagnosis of angiosarcoma of the urinary bladder was made. Post-operatively the urethral catheter was getting blocked with necrotic tumour tissue and aggressive therapy was recommended including radical cystoprostatectomy plus adjuvant chemotherapy and adjuvant radiotherapy but the patient declined to undergo any further treatment and opted to go home with hospice care. He died 6 weeks pursuant to the diagnosis of his angiosarcoma of the urinary bladder. Lessons learnt from this case report include: (a) The case report had illustrated the careful and meticulous steps that are taken by pathologists to establish a diagnosis angiosarcoma from other differential diagnosis. (b) Primary angiosarcoma of the urinary bladder is a very aggressive tumour and patients who have localised angiosarcoma of the urinary bladder could quickly die from their disease. (c) if there are no consensus opinion documentations regarding very effective chemotherapeutic regimens that could quickly and effectively destroy angiosarcoma tumour cells that would give patients who have angiosarcoma of the urinary bladder (PAUB) the chance to have a long-term disease-free survival. (d) There is an urgent need for pharmacotherapy researchers, oncologists, and urologists globally to collaborate in finding the best chemotherapy regimens that would quickly and effectively destroy angiosarcoma tumour cells. (e) Pharmacotherapy research workers and other scientists globally need to find new chemotherapy medicaments or develop new medicaments that would effectively destroy angiosarcoma tumour cells.

Warne et al. [19] documented that Schwartz et al. [39] had in 1983 reported a 46 year old man who was diagnosed as having a cutaneous angiosarcoma which had been described as a variant of Kaposi’s sarcoma and who had presented with painless haematuria. Warne et al. [19] stated that he was diagnosed as having angiosarcoma of the urinary bladder. He received 10 courses of chemotherapy which did include a combination of Cisplatinum, doxorubicin and cyclophosphamide but he died 23 months pursuant to his initial diagnosis of angiosarcoma and at the time of his

death he had developed angiosarcomas in his brain, lung and scrotum. The lesson learnt from this case is that despite utilization of combination chemotherapy the patient died of angiosarcoma which would indicate that the available chemotherapeutic agents are not effective in destroying the angiosarcoma tumour cells. For this reason, it is the view of the author that pharmacotherapy research workers should endeavour to undertake research works that would develop or identify new chemotherapeutic medicaments that would be effective in combating angiosarcoma. ConclusionPrimary angiosarcomas of the urinary bladder (PAUBs) are rare tumours which tend to affect men and women whose ages have ranged between 32 years and 89 years. PAUB has been more often reported in the male in comparison with the female patient. Some cases of PAUB had developed pursuant to previous radiotherapy or exposure to industrial chemical agents. Some cases of PAUB are diagnosed initially with metastatic disease or locally advanced disease. Most reports had indicated that the prognosis is poor with fatal outcome. Nevertheless, few case reports had documented short-term and medium-term survival suggesting that the prognosis may be better than previously thought but there has not been reports of long-term disease-free survival. In view of the rarity of PAUBs, there is no consensus opinion regarding their treatment. There is therefore the need for a multi- centre trial to enable urologists and oncologists determine the best treatment options associated with improvement of prognosis for these tumours. Pharmacotherapy researchers, oncologists and urologists should be encouraged to develop new chemotherapy medicaments or find out the best chemotherapy options that would help in ensuring long-term disease-free survival of patients who have localized, and locally advanced as well as metastatic PAUBs.

Conflict of Interest – None

Acknowledgements: The Scientific World JOURNAL

Acknowledgements toand Hindawi Journals Group

Ltd for granting permission for reproduction of figures

27Jacobs Publishers

from their Journal under the Creative Commons Attribution Licence which grants permission for reproduction of figures provided the original source is properly cited.

The American Journal of Case Reports. For granting permission for reproduction of figures from their under Copy Right © Am J Case Rep. 2016 This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported LicenseUrol. Case Rep for granting permission for reproduction of figures from their journal provided the original source is properly cited; under copy right © 2016 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licences/by-nc-nd/4.0/)

Case Rep Oncol Med for granting permission for reproduction of figures from their journal provided the original work is properly cited.

References1. Cheng L, Nascimento A G, Neumann R M, et al. Hemangioma of urinary bladder. Cancer 1999; 86: 498 – 504.2. Jungano F. Sur un cas d’angiosarcome de la vessie. Annales des maladies des organs genitourinary 1907; 23: 1451 – 1461.3. Seethala R R, Gomez J A, Vakar-Lopez F. Primary angiosarcoma of bladder. Arch Pathol Lab Med 2006; 130 (10): 1543 – 1547.4. Al-Hussain T. Bladder Angiosarcoma – 2011; pathologyoutlines.com.5. Tavora F, Montgomery E, Epstein JI. A series of vascular tumours and tumourlike lesions of the bladder Am. J. Surg Pathol 2008; 32(8): 1213-9. 6. Pazonna J F, Gupta R, Wysock J, Schaeffer A J, Smith N D. Angiosarcoma of the bladder: Long-term survival after multimodal therapy. Urology 2007; 69(3): 575.e9- e10.7. Kulaga A, Ylimaz A, Wilkin R P, Tripkov K. Epitheliod Angiosarcoma of the of the bladder after irradiation for endometrioid adenocarcinoma. Virchows Arch 2007; 450(2): 245 – 246.8. Williams S K, Romaguera R L, Kava B. Angiosarcoma of the Bladder: Case Report and Review of the Literature

The Scientific World Journal 2008; 22; 8:508-11. 9. Engel, J.D., Kuzel, T.M., Moceanu, M.C., et al. Angiosarcoma of the bladder: a review. Urology 1998; 52(5): 778– 784.10. Mark R J, Poen J C, Tran LM, et al. Angiosarcoma. A report of 67 patients and a review of the literature. Cancer 1996; 77(11): 2400–2406.11. Nanus D M, Kelsen D, Clark D G Radiation-induced angiosarcoma. Cancer 1987; 60(4): 777–779.12. Morgan M A, Moutos D M, Pippitt C H Jr, Suda R R, Smith J J, et al. Vaginal and bladder angiosarcoma after therapeutic irradiation. South Med J. 1989; 82(11): 1434 – 1436.13. Navon J D, Rahimzadeh M, Wong A K, Carpenter P M, Ahlering T E. Angiosarcoma of the bladder after therapeutic irradiation for prostate cancer. J. Urol. 1997; 157(4): 1359–1360.14. Yap J, Chuba P J, Thomas R, Aref A, Lucas D, et al. Sarcoma as a second malignancy after treatment for breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 2002; 52(5), 1231–1237.15. Cahan W G, Woodard H Q, Higinbotham N L, et al. Sarcoma arsing in irradiated bone. Cancer 1948; 1: 3–29.16. Chen KT, Hoffman K D, Hendricks E J. Angiosarcoma following therapeutic irradiation. Cancer 1979; 44(6): 2044 – 2048.17. O’Sullivan B, Bell R, Bramwell V. Sarcoma of the soft tissues. In: Oxford Text Book of Oncology. 2nd edn. Oxford University Press, New York. 2002; pp. 2495–2523.18. Colville R J, Charlton F, Kelly CG, et al. Multidisciplinary management of head and neck sarcomas. Head Neck 2005; 27(9): 814–824.19. Warne R R, Ong J S L, Snowball B, Vivian J B. Primary angiosarcoma of the bladder in a young female. BMJ Case Reports 2011. pii: bcr1120103484.20. Ravi R. Primary angiosarcoma of the urinary bladder. Arch Esp Urol. 1993; 46(4): 351 – 353.21. Aragona F, Ostardo E, Prayer-Galetti T, Piazza R, Capitanio G. Angiosarcoma of the bladder: a case report with regard to histologic and immunohistochemical findings. Eur Urol. 1991; 20(2): 161 -163.22. Schindler S, De Frias D V S, Yu G H. Primary angiosarcoma of the bladder cytomorphology and differential diagnosis. Cytopathology 1999; 10: 137 – 143.

28Jacobs Publishers

http://creativecommons.org/licences/by-nc-nd/4.0/

http://creativecommons.org/licences/by-nc-nd/4.0/

https://www.ncbi.nlm.nih.gov/pubmed/10430259


https://doi.org/10.1097/PAS.0b013e31816293c5



https://doi.org/10.1016/j.urology.2007.01.021



https://doi.org/10.1007/s00428-006-0336-9

https://doi.org/10.1007/s00428-006-0336-9

https://doi.org/10.1007/s00428-006-0336-9

https://doi.org/10.1007/s00428-006-0336-9

https://doi.org/10.1100/tsw.2008.79





https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11%3C2400::AID-CNCR32%3E3.0.CO;2-Z


















https://doi.org/10.1002/hed.20232



https://doi.org/10.1136/bcr.11.2010.3484

https://doi.org/10.1136/bcr.11.2010.3484

https://doi.org/10.1136/bcr.11.2010.3484








23. Spiess P E, Kassouf W, Steinberg J R, Tuziak T, Hernandez M, et al. Review of the M.D. Anderson experience in the treatment of bladder sarcoma. Urol Oncol. 2007; 25(1): 38 - 45.24. Overholm E, Stripp D, Mamtani R, Arsdalen KV, Tripp P Angiosarcoma of the Bladder Following Prostate Radiotherapy. Am J Med. 2015; 128(5):e11-2. 25. Matoso A, Epstein J I. Epithelioid Angiosarcoma of the Bladder: A Series of 9 Cases. Am J. Surg Pathol 2015; 39(10): 1377 – 1382.26. Wang G, Black P C, Skinnider B F, Hayes M M, Jones E C. Post-radiation epithelioid angiosarcoma of the urinary bladder and prostate. Can Urol. Assoc J. 2016; 10(5-6): E197 – E200.27. Nizam A, Paquetta E L, Wang B G, Aragon-Ching J B. Epithelioid Angiosarcoma of the Bladder: A Case Report and Review of the Literature. 2018; 16(6):e1091-e1095.28. Gerbaud E, Ingels A, Ferlicot S, Irani J. Angiosarcoma of the Bladder: Review of the Literature and Discussion About a Clinical Case. Urol. Case Rep; 2017; 17: 13: 97 – 100. 29. Rallabandi H B, Swain M, Gowrishankar S, Sinha S. Postradiation angiosarcoma of bladder with extensive osseous metaplasia. Indian Journal of Pathology & Microbiology 2016; 59(1): 78 – 80. 30. Bahouth Z, Masarwa I, Halachmi S, Naliv O. Primary Angiosarcoma of Urinary Bladder: 13TH Reported Patient. Case Rep Oncol Med 2015; 2015: 652870. 31. Spina B, Pacella E, Introini C, Boccardo F, Lopez-Beltran A, et al. Primary bladder angiosarcoma with no apparent previous exposure to carcinogens: case report. Anat. Quant.

Cytopathol. Histopathol. 2013; 35(6): 349 – 352. 32. Beyazal M, Pirincci N, Yavuz A, Ozkacmaz S, Bulut G. Computed tomography and magnetic resonance imaging findings of primary bladder angiosarcoma: a case report. Clinical Imaging. 2014; 38(2): 212 – 214. 33. Abbasov B, Munguia G, Mazal P R, Haitel A, Koller A, et al. Epithelioid angiosarcoma of the bladder: report of a new case with immunohistochemical profile and review of the literature. Pathology 2011; 43(3): 290 – 293. 34. Stroup R M, Chang Y C. Angiosarcoma of the bladder: A case report. J Urol. 1987; 137: 984 – 985.35. Casal J, Singer E D, Monsarrat J M. Angiosarcoma of the bladder [In Spanish]. Rev Agent Urol. Nefrol. 1970; 39: 53 – 55.36. Otsubo S, Tanaka S, Kamiryo Y, Okumur K, Shimokama T, et al. A case of primary pleural angiosarcoma metastasising to the bladder. Nihon Hinyokika Gakkai Zasshi 2011; 102(5): 686 – 690. 37. Paner G P, Cox R M, Richards K, Akki A, Gokden N, et al. Pseudoangiosarcomatous urothelial carcinoma of the urinary bladder. Am J. Surg Pathol 2014; 38(9): 1251 – 1259. 38. Nawar N A, Olsen J, Jelic T M, He C. Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review Am J Case Rep. 2016; 17: 143–149. 39. Schwartz R A, Kardashian J F, McNutt N S, Crain W R, Welch K L, et al. Cutaneous angiosarcoma resembling anaplastic Kaposi;s sarcoma in a homosexual man. Cancer 1983; 51(4): 721 – 726.

29Jacobs Publishers

https://doi.org/10.1016/j.urolonc.2006.02.003




https://doi.org/10.1016/j.amjmed.2014.11.022



https://doi.org/10.1097/PAS.0000000000000444

https://doi.org/10.1097/PAS.0000000000000444

https://doi.org/10.1097/PAS.0000000000000444

https://dx.doi.org/10.5489%2Fcuaj.3220




https://doi.org/10.1016/j.clgc.2018.07.010



https://doi.org/10.1016/j.eucr.2016.12.007



https://doi.org/10.4103/0377-4929.178234

https://doi.org/10.4103/0377-4929.178234

https://doi.org/10.4103/0377-4929.178234

https://doi.org/10.4103/0377-4929.178234

https://doi.org/10.1155/2015/652870

https://doi.org/10.1155/2015/652870

https://doi.org/10.1155/2015/652870





https://doi.org/10.1016/j.clinimag.2013.10.003




https://doi.org/10.1097/PAT.0b013e328344e2fb













https://doi.org/10.1097/PAS.0000000000000241

https://doi.org/10.1097/PAS.0000000000000241

https://doi.org/10.1097/PAS.0000000000000241

https://dx.doi.org/10.12659%2FAJCR.896266




https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142%2819830215%2951%3A4%3C721%3A%3AAID-CNCR2820510428%3E3.0.CO%3B2-2




jacobs journal of nephrology and urology › uploads › article_pdf › 18 ›...

Documents