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In August 1997, a 74-year-old man was referred to a urologist for further evaluation of a urinary tract infection (UTI) that had not resolved despite a 2-month course of various enteral antibiotics and phenazopyridine hydrochloride. Upon presentation, the patient reported a 2-month duration of urinary difficulties, including dysuria, polyuria, nocturia, and increased urge sensation. He also reported a recent 5-lb weight loss and loose, ribbon-like stools during the previous 2 months. There was no hematuria, fever, or flank or abdominal pain.

The patient had an extensive medical history. In 1988, he was diagnosed with stage B2, moderately differentiated adenocarcinoma of the prostate (Gleason score, 4). His treatment consisted of radiation therapy to the prostate and pelvis, with a total tumor dose of 6,600 centigrays (cGy). Treatment was completed in May 1988. His history also included diverticulosis in 1990, a kidney stone in 1991, and deep vein thrombosis in the left leg twice in the preceding 9 years.

His social history was unremarkable. He was married with four adult children--all alive and well. There was no family history of neoplasms. Although he was a retired chemical engineer, he denied any exposure to chemicals or environmental radiation. He did not use tobacco, but he consumed one beer and 1.5 oz of vodka each evening. Until his recent medical problems, he was very healthy and active.

At the time the patient presented to the urologist, the physical examination was unremarkable and vital signs were within normal ranges. Initial laboratory data were significant for a prostate-specific antigen of 11 ng/mL; magnesium, 1.5 mg/dL; albumin, 2.6 g/dL; and international normalized ratio, 1.6 (normal range for a patient not receiving anticoagulant therapy, 0.9-1.1).

A computed tomography (CT) scan of the abdomen and pelvis performed in early September revealed a 3-cm necrotic mass in the dome of the bladder with extension into the sigmoid colon, as well as thickening of the sigmoid colon wall (see Figure, page 106). Colonoscopy was performed, and two benign polyps were removed. Again, no neoplastic changes were noted. Later in September, cystoscopy was performed and a biopsy specimen was obtained from the bladder mass. The specimen contained atypical cells that were consistent with chronic radiation cystitis. No neoplastic changes were noted at that time.

Later in October, the patient underwent an exploratory laparotomy, which revealed a large purplish mass located on the dome of the bladder and extending into the sigmoid colon. Three small purplish implants were discovered in the mesentery and omentum. A partial sigmoid resection was done.

Initial frozen sections showed neoplastic changes consistent with an unspecified sarcoma. Final pathology revealed angiosarcoma. The patient tolerated the procedure extremely well and had an uneventful recovery.

In November, bilateral ureteral calculi were detected, requiring treatment with lithotripsy and stents.

The patient was generally in good health, so in December he was started on chemotherapy with doxorubicin, liposomal doxorubicin, and ifosfamide to reduce the residual tumor tissue in the bladder. Because of a subsequent decline in his condition, however, he completed only half of the 6-month course of chemotherapy.

Despite treatment, the patient's urinary difficulties persisted. In February 1998, he presented to the urologist with persistent hematuria and increasing polyuria. An ileal loop diversion was performed.

During the procedure, numerous tumor implants were noted on the mesentery and omentum and throughout the bowel. The initial tumor in the dome of the bladder had grown dramatically and extended into the pelvis, completely surrounding both ureters. Findings from pathologic examination of the mass were consistent with angiosarcoma.

Despite aggressive medical care, the patient deteriorated rapidly. On May 2, 1998, he was admitted to the hospital for pneumonia and dehydration. Six days later, he was transferred to hospice care because of his continued rapid decline. The patient died on May 15--7 months after the initial diagnosis.

DISCUSSION

Sarcomas are rare connective tissue neo-plasms that account for only 1% of all malignancies. [1] Angiosarcomas are rarer still, accounting for only 1% to 2% of all soft tissue sarcomas. [2] Although they can occur in any tissue, more than half of all angiosarcomas are found in skin and soft tissue. Other frequent sites include the breast, liver, spleen, and bone. [13]

Emanating from vascular endothelial cells, angiosarcomas are highly aggressive, malignant neoplasms. Morbidity and mortality associated with angiosarcoma are high because of frequent local recurrence. Another contributing factor is early distant metastases, which most commonly affect the liver, spleen, and gastrointestinal tract. [1,2]

For many years, the only identified risk factors for angiosarcoma were chemical exposures, specifically thorium dioxide, polyvinyl chloride, arsenic, and insecticides. Lymphedema (eg, chronic lymphedematous extremity, congenital lymphedema [Milroy's disease], or filarial lymphedema), is also now associated with the development of angiosarcoma. Rare cases have been attributed to pyothorax, retained foreign bodies (eg, surgical sponges), and visceral metastases of Kaposi's sarcoma. [2-4]

The most rapidly emerging link to induction of angiosarcoma, however, is exposure to external beam therapeutic radiation. [2] The risk for developing postirradiation secondary neoplasms is increasing as survival among patients undergoing radiation therapy increases. [5] In the United States, 7% to 10% of all new cancers (140,000 cases per year) are a secondary malignancy. [6] A patient with one primary malignancy has a 31% increased risk of developing a second cancer, [6] and radiation therapy increases the risk by an additional 5% [6,7] For a tumor to be considered a secondary neoplasm induced by the radiation, certain criteria must be met (see Table [3,8,9]).

The mean survival for angiosarcoma of the skin and soft tissue is 20 months; intestine, 1 to 3 months; and other sites, less than 1 year. The long-term survival at 2 years and 5 years is 32% and 12%, respectively. Factors influencing survival include the tumor's size, stage (T1, 32% survival; T2, 13% survival), and grade (low grade, 44% survival; high grade, 20% survival). [1-3]

DIAGNOSIS

Angiosarcoma is often diagnosed after it has already progressed significantly. This is generally because of the location of the tumors and their rapid growth. Their tendency to metastasize early is another contributing factor. [1]

On gross appearance, angiosarcomas typically present as sharply demarcated red or purple nodules. As they enlarge, the tumors undergo central necrosis with hemorrhage. The mass then takes on a tan or gray appearance. Cutaneous tumors vary from bluish discolorations to nonresolving hematomas to soft-tissue ulcerations. [5,8]

Histologically, angiosarcoma can be very diverse, which complicates identification. However, three general patterns occur: (1) the cells are closely packed and round or spindle-shaped, with an undifferentiated morphology; (2) they align themselves in sheets; or 3) they form vascular sinuses. [8]

Immunohistochemistry findings are more consistent. The tumor cells express factor VIII-related antigen, CD34, vimentin, ulex europaeus lectin 1, and BMA-120 monoclonal antibodies. [2,5,8,10] Of these, factor VIII-related antigen and ulex europaeus lectin 1 are most commonly used as diagnostic markers.

The case presented in this article meets the standards for diagnosis of radiation-induced neoplasms. The tumor arose within the area irradiated during the prostate cancer treatment, and a total dose of 6,600 cGy had been administered. The tumor developed more than 6 years after the radiation therapy-- within the parameters of the latency period. Chronic lymphedema was absent, and the secondary angiosarcoma was histologically distinct from the initial adenocarcinoma of the prostate. Chronic radiation cystitis was evidence of the cellular radiation injury. [3,5,9]

TREATMENT

Angiosarcomas generally respond poorly to conventional surgical and medical treatment, but surgical resection is the treatment of choice. However, approximately 80% of the tumors recur within 12 to 24 months of resection. In one study, no clear margins were found during surgical resection in more than 50% of first excisions. Thus, wide-margin resection during surgery might help improve the long-term prognosis. [14,5]

Adjuvant irradiation and chemotherapy may also be indicated. [3] Specific treatment regimens are individualized to meet each patient's needs.

CONCLUSION

Despite the potential for such secondary neoplasms as angiosarcoma, the high curative rates associated with radiation therapy far outweigh its risks. However, clinicians can minimize this risk by taking specific protective measures during radiation therapy. For example, bystander tissue should be shielded to minimize the amount of exposure, beam alignment should be optimized and field size minimized, and adjuvant therapy should be judiciously employed.

When secondary neoplasms develop, early detection may help improve prognosis. Therefore, patients who have previously undergone radiation therapy must be diligently screened for secondary neoplasms.

Stephanie Vamos is a physician assistant in cardiothoracic surgery at Lahey Clinic in Burlington, Mass.

REFERENCES

(1.) Mark RJ, Poen JC, Tran LM, et al. Angiosarcoma. A report of 67 patients and a review of the literature. Cancer. 1996;77:2400-2406.

(2.) Chami TN, Ratner LE, Henneberry J, at al. Angiosarcoma of the small intestine: a case report and literature review. Am J Gastroenterol. 1994;89:797-800.

(3.) Cafiero F, Gipponi M, Peressini A, et al, Radiation-associated angiosarcoma: diagnostic and therapeutic Implications--two case reports and a review of the literature. Cancer. 1996;77:2496-2502.

(4.) Navon JD, Rahimzadeh M, Wong AK, of al. Angiosarcoma of the bladder after therapeutic irradiation for prostate cancer. J Urol. 1997;157:1359-1360.

(5.) Hansen SH, Holck S, Flyger H, Tange UB. Radiation-associated angiosarcoma of the small bowel. A case of multiploidy and a fulminant clinical course. APMIS. 1996;104:891-894,

(6.) Nelson NJ. Solutions bring new problems: secondary cancers are a risk for some survivors. J Natl Cancer Inst. 1997;89:1483-1485,

(7.) Epstein R, Hanham I, Dale R. Radiotherapy-induced second cancers: are we doing enough to protect young patients? Eur J Cancer. 1997;33:526-530,

(8.) Stroup RM, Chang YC. Angiosarcoma of the bladder: a case report. J Urol. 1987;37:984-985.

(9.) Tsumoda A, Shibusawa M, Kawamura M, et at. Colorectal cancer after pelvic irradiation: case reports, Anticancer Res. 1997;17:729-732.

(10.) Perin T, Massarut S, Roncadin M, Canzonieri V. Radiation-associated angiosarcoma: diagnostic and therapeutic implications--two case reports and a review of the literature [letter, comment]. Cancer. 1997;80:519-521.

CRITERIA FOR RADIATION-INDUCED TUMORS [3,8,9]

* The tumor must arise within the field of irradiation.

* More than 2,000 cGy must have been administered.

* Five or more years must have passed between exposure to the radiation and development of the secondary tumor.

* Chronic lymphedema cannot be concurrently present.

* Confirmation of a distinct second neoplasm must be made by histology.

* Evidence of cellular radiation damage must exist.

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