Chapter 095. Carcinoma of Unknown Primary (Part 1)

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Harrison's Internal Medicine Chapter 95. Carcinoma of Unknown Primary Carcinoma of Unknown Primary: Introduction Carcinoma of unknown primary (CUP) is a biopsy-proven (mainly epithelial) malignancy for which the anatomic site of origin remains unidentified after an intensive search. CUP is one of the 10 most frequently diagnosed cancers worldwide, accounting for approximately 3–5% of all cancer cases. Most investigators do not consider lymphomas, metastatic melanomas, and metastatic sarcomas that present without a known primary tumor to be CUP because these cancers have specific stage- and histology-based treatments that can guide management. A standard workup for CUP includes a medical history; physical...

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Chapter 095. Carcinoma of Unknown Primary (Part 1) Harrison's Internal Medicine > Chapter 95. Carcinoma of Unknown Primary Carcinoma of Unknown Primary: Introduction Carcinoma of unknown primary (CUP) is a biopsy-proven (mainly epithelial) malignancy for which the anatomic site of origin remains unidentified after an intensive search. CUP is one of the 10 most frequently diagnosed cancers worldwide, accounting for approximately 3–5% of all cancer cases. Most investigators do not consider lymphomas, metastatic melanomas, and metastatic sarcomas that present without a known primary tumor to be CUP because these
cancers have specific stage- and histology-based treatments that can guide management. A standard workup for CUP includes a medical history; physical examination; and laboratory studies, including liver and renal function tests, hemogram, chest x-ray, CT scan of the abdomen and pelvis, mammography in women, and prostate-specific antigen (PSA) test in men. With the increasing availability of additional sophisticated imaging techniques and the emergence of targeted therapies that have been shown to be effective in several cancers, oncologists must decide on the extent of workup that is warranted. Specifically, they must consider how additional diagnostic procedures may affect the choice of therapy and the patient's survival and quality of life. The reason tumors present as CUP remains unclear. One hypothesis is that the primary tumor either regresses after seeding the metastasis or remains so small that it is not detected. It is possible that CUP falls on the continuum of cancer presentation where the primary has been contained or eliminated by the natural body defenses. Alternatively, CUP may represent a specific malignant event that results in an increase in metastatic spread or survival relative to the primary. Whether the
CUP metastases truly define a clone that is genetically and phenotypically unique to this diagnosis remains to be determined. Introduction No characteristics that are unique to CUP relative to metastases from known primaries have been identified. Abnormalities in chromosomes 1 and 12 and other complex abnormalities have been found. Aneuploidy has been described in 70% of CUP patients with metastatic adenocarcinoma or undifferentiated carcinoma. The overexpression of various genes, including Ras, bcl-2 (40%), her-2 (11%), and p53 (26–53%), has been studied in CUP samples, but they seem to have no effect on response to therapy or survival. The extent of angiogenesis in CUP relative to that in metastases from known primaries has also been evaluated, but no consistent findings have emerged. Clinical Evaluation Obtaining a thorough medical history from CUP patients is essential, paying particular attention to previous surgeries, removed lesions, and family medical history to assess potential hereditary cancers. Physical examination, including a digital rectal examination in men and breast and pelvic examinations
in women, should be performed. Determining the patient's performance status, nutritional status, comorbid illnesses, and cancer-induced complications is essential since they may affect treatment planning. Role of Serum Tumor Markers and Cytogenetics Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific and not helpful in determining the primary tumor site. Men who present with adenocarcinoma and osteoblastic metastasis should undergo a PSA test. Patients with an elevated PSA should be treated as having prostate cancer. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated β-human chorionic gonadotropin (βhCG) and αfetoprotein (AFP) levels suggest the possibility of an extragonadal germ cell (testicular) tumor. Cytogenetic studies had a larger role in the past, although interpretation of these older studies can be challenging. In our opinion, with the availability of immunohistochemical stains, cytogenetic analyses are indicated only occasionally. We reserve them for undifferentiated neoplasms with inconclusive immunohistochemical stains and those for which a high suspicion of lymphoma exists.