Kaposi Sarcoma
Although Kaposi sarcoma is a vascular lesion, its distinct etiology and sensitivity both to radiation and to a wide variety of chemotherapeutic agents distinguish it from other soft tissue sarcomas. Four variants of KS have been identified: classic, transplant associated, lymphadenopathic, and AIDS-KS.
Classification The classic variant presents as multiple blue-red flat skin lesions that indolently progress to nodules and plaques on the lower legs. This variant presents most commonly in elderly men, particularly those of Mediterranean origin. A second variant occurs in patients who receive organ transplants. KS develops an average of 16 months after transplantation. Transplant-associated KS develops most commonly in men, particularly if either the recipient or the organ donor is of Mediterranean extraction. A third aggressive variant is a lym-phadenopathic KS that occurs in young children and is endemic to some areas of Africa.
The fourth variant is an aggressive epidemic KS that occurs in AIDS patients. This variant is 20 times more common in men who acquire HIV by sexual contact with men than in those who acquire it by parenteral means.The percentage of AIDS patients with KS ranges from 1% in men with hemophilia to 21% in men who have sex with men.66 The incidence of KS in men with AIDS in the United States decreased from 40% in 1981 to less than 20% in 1992,3,67,68 and it is expected to continue to decline with more effective antiretroviral combination therapy.67
In 1993, Chang and colleagues identified in an AIDS-KS skin lesion DNA fragments of a previously unrecognized her-pesvirus that has alternatively been called Kaposi sarcoma-associated herpesvirus (KSHV) and human herpesvirus type 8 (HHV-8).33 Over 95% of KS lesions, regardless of source or clinical subtype, have been found to be KSHV-associated. Immuno-suppression of the host appears to be an important cofactor in the clinical expression of KS.3
KSHV, together with Epstein-Barr virus (EBV), belongs to the gamma herpesviruses.3 Gamma herpesviruses cause tumors, particularly lymphoproliferative disorders and lym-phomas, in humans and animals [see Table 4]. KSHV infection rates parallel the global incidence of KS, with low rates in the United States, Europe, and Asia; intermediate rates in Mediterranean countries; and high rates (> 50%) in some locations in Central Africa (e.g., Uganda, Zambia, and South Africa).69
Independent of their HIV serostatus, men who have sex with men have a higher rate of KS than the general male population and can have antibodies associated with KS in rates approaching 40%.7071
Diagnosis Clinical manifestations of KS may differ with the variants of the disease. In classic KS, faint reddish-purple macules or patches appear on the feet. HIV-associated KS presents most commonly as cutaneous lesions but also may appear in the oral mucosa or lymph nodes. In contrast to classic KS lesions, HIV-associated KS lesions often begin on the upper body (i.e., face, trunk, or arms). Skin biopsy should be obtained in patients with suspected KS. The histopathologies of all KS variants are similar: spindle-shaped cells in the dermis, with extravasat-ed red blood cells present in slits between irregular vascular spaces [see 2:XMalignant Cutaneous Tumors].
Table 4 Herpesviruses Found in Human and Nonhuman Hosts
|
Gamma herpesviruses |
Rhadinovirus |
|
Epstein-Barr virus |
|
|
Equine herpesvirus type 2 |
|
|
Herpesvirus saimiri |
|
|
Kaposi sarcoma-associated herpesvirus |
|
|
Lymphocryptovirus |
|
|
Alpha herpesviruses |
Herpes simplex virus type 1 |
|
Herpes simplex virus type 2 |
|
|
Equine herpesvirus type 1 |
|
|
Pseudorabies virus |
|
|
Varicella-zoster virus |
|
|
Beta herpesviruses |
Human cytomegalovirus |
|
Human herpesvirus type 6 |
|
|
Human herpesvirus type 7 |
Peripheral Neuroectodermal Tumors and Extraosseus Ewing
Sarcoma
Peripheral neuroectodermal tumors (PNETs) and Ewing sarcoma of bone and soft tissue have similar cytogenetic mutations [see Translocations Diagnostic of Sarcomas, above]. PNETs and extraosseus Ewing sarcomas present as masses most commonly in soft tissue of the chest wall and extremities. They are generally treated with resection, radiation, and chemotherapy in regimens used for Ewing sarcoma of bone [see Sarcomas of Bone and Cartilage, Ewing Sarcoma, below].
Gastrointestinal Stromal Tumors
GISTs occur predominantly in middle-aged patients but may rarely occur in younger individuals. Approximately 70% of GISTs occur in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. Survival correlates with tumor location (i.e., patients with GISTs located in the esophagus and stomach survive longer than those with tumors located in the small bowel). Age, mitotic index, and size less than 5 cm are also independent prognostic factors.
Classification Until 1990, most gastrointestinal sarcomas were thought to be leiomyosarcomas because they histological-ly resembled smooth muscle. However, clinical oncologists observed that GI leiomyosarcomas had a distinctly lower response rate to standard doxorubicin-based chemotherapy than did leiomyosarcomas of the uterus, trunk, and extremities. Subsequent immunocytochemical studies showed that GI sarcomas frequently lacked muscle markers that were typical of leiomyo-sarcomas found at other anatomic sites. The subset without muscle or Schwann cell (S-100) markers were eventually termed GISTs. These tumors almost universally expressed CD117 (c-kit) and often CD34, which are also expressed on hematopoietic progenitor cells.
Genetic factors Most GISTs express c-kit, a growth factor receptor with tyrosine kinase activity. c-kit is a proto-oncogene located on the long arm of chromosome 4 (4q11-q12) that encodes a transmembrane tyrosine kinase receptor. Its ligand is a stem cell factor. c-kit regulates normal hematopoiesis, as well as migration of germ cells, and is also expressed in normal human mast cells, immature myeloid cells, melanocytes, epithelial breast cells, and interstitial cells of Cajal (the gastrointestinal pacemaker cells). Interstitial cells of Cajal have immunohisto-chemical profiles similar to those of GISTs (i.e., c-kit and CD34 positive; desmin and S-100 negative) and thus are currently thought to be the cell of origin of GISTs.
c-kit mutations72 in the juxtamembrane domain of GISTs include in-frame deletions and point mutations in exon 11 in approximately 60% of cases.73 Mutations in most of the remaining cases involve exon 13 and exon 9. The mutated receptor is activated constitutively without its ligand, driving neoplastic transformation.
Diagnosis The most common symptoms of GIST at initial presentation are abdominal pain and gastrointestinal bleeding. CT and MRI scans may suggest the diagnosis and define the extent of the lesion. Diagnosis is typically confirmed histologically. The Carney triad includes the diagnosis of gastric stromal tumors (formerly called epithelioid leiomyosarcoma), functioning extra-adrenal paragangliomas, and pulmonary hamartomas (chondromas).74-76 Patients with one or two components of the triad should be evaluated for the other components. Pulmonary lesions detected on radiographs may be either metastases or benign hamartomas; biopsy must be performed before chemotherapy is administered for presumed metastatic disease.
Mesothelioma
The annual incidence of mesothelioma is not known with certainty. Mesotheliomas are difficult to diagnose, even by expert pathologists. Because cancer deaths are coded by primary site of the neoplasm (primary neoplasms of pleura and peritoneum) and not by histologic diagnosis (mesothelioma), data from death certificates are unreliable for estimating disease frequency despite the rapid progression to fatal outcome that is typical of malignant mesothelioma. A reasonable estimate is that about 2,000 new cases of mesothelioma occur annually in the United States (range, 1,000 to > 3,000 cases).77 Reported rates have increased in the past decade, perhaps by as much as 50%.78 In the United States, mesothelioma is approximately threefold to fivefold more common in men than in women.78-80
Etiology Persons at high risk for mesothelioma are those exposed to the processing and commercial uses of asbestos. The mineral is mined, milled, and used in a wide range of industrial and commercial products, including insulation, textiles, heat protectors, filters, and construction materials (e.g., spackling, roofing, siding, and floor and ceiling tiles).80 Workers who are exposed to high levels of asbestos include miners, millers, producers of asbestos products, and laborers who install plumbing, boilers, and heating equipment. Workers who may not handle asbestos directly but are in proximity to others working with the material (e.g., carpenters, electricians, and welders) are also at risk.
Malignant mesothelioma is rarely curable; therefore, screening of asbestos workers for mesothelioma is inappropriate.81 However, smoking greatly increases the risk of lung cancer (but not mesothelioma) in asbestos workers, and smoking cessation efforts are needed in this high-risk group.81,82 A detailed exposure history should emphasize the period 20 to 50 years before diagnosis and should include possible household-contact exposure. Brief exposures may be long forgotten, and asbestos exposure can be documented in about 30% to 70% of patients with mesothelioma.77
Malignant pleural mesothelioma most commonly develops in the fifth to seventh decades of life (median age, 60 years). A significant proportion of patients with mesothelioma in whom the diagnosis was made between 20 and 40 years of age report household or neighborhood asbestos exposure during childhood. Children who present with the disease generally have no apparent asbestos exposure.
Diagnosis Dyspnea, chest pain, or both prompt patients to seek medical attention. Physical examination is remarkable for dullness at one lung base, and chest x-rays typically reveal a large, freely movable unilateral pleural effusion. Occasionally, patients are asymptomatic, and the pleural effusion is found incidentally on chest x-ray. Sixty percent of patients have right-sided lesions, and fewer than 5% have bilateral involvement at the time of diagnosis.
A CT or MRI scan of the chest to assess the extent of disease is indicated if any treatment is contemplated. Loss of lung volume is evident early on CT. In advanced disease, scoliosis with con-tracture of the ipsilateral hemithorax is visible even on chest x-ray. Despite a history of asbestos contact in 50% to 70% of patients, pleural plaques or interstitial fibrosis is apparent on chest x-ray in only about 20% of patients; however, pleural calcifications are evident on CT scan in nearly 50% of patients and at autopsy in 87%.
Initial misdiagnosis is common, and pathologic opinion appears particularly diverse in cases in which litigation is involved. Special immunoperoxidase staining has made the diagnosis of mesothelioma more reliable. Because a substantial percentage of mesotheliomas develop in patients with no known asbestos exposure and because other malignancies are common in asbestos workers, asbestos exposure alone should not influence the diagnosis of mesothelioma.
Treatment of soft tissue sarcomas
Patients with possible sarcoma should be referred to an institution with an experienced sarcoma service. If preoperative evaluation reveals no evidence of metastasis on chest CT, the goal of treatment is the control of local disease. Primary therapy for most relatively small localized soft tissue sarcomas (except for rhabdomyosarcoma and Kaposi sarcoma) is surgery. Wide excision (3 to 6 cm of pathologically documented normal tissue) is optimal to avoid the need for radiotherapy, particularly for abdominal or low-grade lesions. Careful pathologic examination of the margins is essential to document adequate resection and identify any involved margins that require further resection. If lesions are deep or adjacent to a major nerve, visceral organ, or bone, surgical margins may be necessarily narrow (e.g., 1 mm or less) or even involved in tumor. When pathologic margins are small (< 3 to 6 cm), radiation may be used to decrease the risk of local failure. Adequate radiotherapy (6,600 cGy or more) can usually be delivered to lesions located in the extremities; however, the risk of radiation damage to visceral organs generally precludes these doses for treatment of tumors located in the retroperitoneum or abdomen. Low-grade lesions, if adequately resected, are generally curable; thus, wide surgical margins are especially important to ensure local control. Very large lesions are often initially treated with radiation and chemotherapy to facilitate ultimate resection.
Table 5 Meta-analysis of Doxorubicin-Based Adjuvant Chemotherapy for Localized Resectable Soft Tissue Sarcoma*
|
Hazard Rate |
P-Value |
Absolute Benefit at 10 Years (%) |
|
|
Local recurrence-free intervals |
0.73 |
0.016 |
6 (from 75 to 81) |
|
Distant recurrence-free intervals |
0.70 |
0.0003 |
10 (from 60 to 70) |
|
Overall survival |
0.89 |
0.12 |
4 (from 50 to 54) |
Superficial trunk lesions are frequently resectable with wide margins. For extremity lesions, a combined modality of conservative (often limb-sparing) surgery and radiotherapy may achieve local control without increasing the risk of locoregional recurrence.83-85 The current standard of limb-sparing surgery combined with radiotherapy or radical resection (often amputation), as practiced at experienced centers, has improved local control from approximately 20% in 1950 to 90% or higher to-day.83 Local control rates remain 50% to 75% for trunk lesions but only 30% to 50% for primary retroperitoneal lesions.86-91 Many primary retroperitoneal and head and neck lesions involve vital structures and are unresectable at presentation.
Adjuvant Chemotherapy
Adjuvant chemotherapy is standard practice for the treatment of rhabdomyosarcomas, osteosarcomas, and Ewing sarcomas, but it remains controversial for other adult soft tissue sarcomas. Nevertheless, most experts agree that the risks of adjuvant chemotherapy are not warranted for low-grade lesions (given their low probability of metastatic spread) and for lesions less than 5 cm, even if high grade, because of their excellent prognosis.
Initial pilot studies investigating the effectiveness of adjuvant chemotherapy in adult soft tissue sarcomas reported significant survival benefit compared to survival reported in historical control subjects. However, subsequent randomized studies found that survival with no adjuvant chemotherapy to be higher than previously reported. Because surgical resection of recurrent local disease and even pulmonary metastases is sometimes curative, disease-free survival may be a less meaningful end point than overall survival.
A meta-analysis of individual patient data from all randomized doxorubicin-based adjuvant trials in patients with sarcoma included data from 1,568 patients [see Table 5]. Adjuvant chemotherapy improved the time to local and distant recurrence-free survival (hazard ratios, 0.73 and 0.70; P = 0.016 and 0.0003, respectively). However, overall survival in the group receiving chemotherapy showed only a 4% advantage and a hazard ratio of 0.89 (P = 0.12).92 Adjuvant trials of doxorubicin and ifosfamide regimens have produced mixed results.
Therapy for Advanced Soft Tissue Sarcomas
Resection Resection of subpleural metastases in carefully selected patients results in disease-free survival in about 20% of patients.95-97 Patients with a disease-free interval longer than 12 months, fewer than five nodules, and a tumor doubling time of more than 20 days have the best prognosis. In one large study, the median disease-free survival for all patients undergoing repeat resections was 42.8 months, with an estimated 5-year survival of 36%.96 Prolonged survival was associated with fewer than three nodules at the time of the second resection. A combined-modality approach (chemotherapy before resection) has yet to be evaluated in a randomized trial.
Single-agent chemotherapy Single-agent chemotherapy is generally chosen for palliation, particularly in older patients and in those with low-grade lesions. Doxorubicin is the most active single agent in soft tissue sarcomas, with a response rate of 15% to 35% in various studies.
A dose-response relationship has been observed for doxoru-bicin in randomized trials.101-103 Dose rates of 60 to 70 mg/m2 every 3 weeks are generally superior to dose rates of 50 mg/m2 or less.
Dacarbazine has a single-agent response rate of about 16% for most sarcomas and response rates of up to 44% when used in combination with doxorubicin in the treatment of leiomyo-sarcomas.104,105 Nausea, which is a common side effect, may be improved by continuous infusion administration.106
Ifosfamide, an analogue of cyclophosphamide, is effective against sarcoma alone or in combination with doxorubicin.107,108 Mesna must be administered in conjunction with ifosfamide to prevent bladder injury.
Combination chemotherapy Combination chemotherapy is generally used (1) for patients for whom a response would facilitate curative resection of a primary lesion and (2) for patients with unresectable or metastatic sarcoma. Combination chemotherapy is also used as palliation, particularly in patients younger than 50 years who have high-grade lesions. A combination of doxorubicin and ifosfamide produces response rates of 17% to 25%.98,109,110 The median survival for patients with unresectable or metastatic sarcoma is 12 months, with no significant differences in survival.
