Harrison’s Manual of Medicine



Syndrome of Unrecognized Extragonadal Germ Cell Cancer
Peritoneal Carcinomatosis in Women
Carcinoma in an Axillary Lymph Node in Women
Osteoblastic Bone Metastases in Men
Cervical Lymph Node Metastases

Cancer of unknown primary site (CUPS) is defined as follows: biopsy-proven malignancy; primary site unapparent after history, physical exam, CXR, abdominal and pelvic CT, CBC, chemistry survey, mammography (women), b-human chorionic gonadotropin (hCG) levels (men), a-fetoprotein (AFP) levels (men), and prostate-specific antigen (PSA) levels (men); and histologic evaluation not consistent with a primary tumor at the biopsy site. CUPS incidence is declining, probably because of better pathology diagnostic criteria; they account for about 3% of all cancers today, down from 10–15% 10 years ago. Most pts are over age 60. Cell lines derived from such tumors frequently have abnormalities in chromosome 1.
CLINICAL PRESENTATION   Pts may present with fatigue, weight loss, pain, bleeding, abdominal swelling, subcutaneous masses, and lymphadenopathy. Once metastatic malignancy is confirmed, diagnostic efforts should be confined to evaluating the presence of potentially curable tumors, such as lymphoma, Hodgkin’s disease, germ cell tumor, ovarian cancer, head and neck cancer, and primitive neuroectodermal tumor, or tumors for which therapy may be of significant palliative value such as breast cancer or prostate cancer. In general, efforts to evaluate the presence of these tumor types depends more on the pathologist than on expensive clinical diagnostic testing. Localizing symptoms, a history of carcinogen exposure, or a history of fulguration of skin lesion may direct some clinical testing; however, the careful light microscopic, ultrastructural, immunologic, karyotypic, and molecular biologic examination of adequate volumes of tumor tissue is the most important feature of the diagnostic workup in the absence of suspicious findings on history and physical exam (Table 73-1).

Table 73-1 Possible Pathologic Evaluation of Biopsy Specimens from Patients with Metastatic Cancer of Unknown Primary Site

HISTOLOGY   About 60% of CUPS tumors are adenocarcinomas, 10– 20% are squamous cell carcinomas, and 20–30% are poorly differentiated neoplasms not further classified on light microscopy.
PROGNOSIS   Pts with squamous cell carcinoma have a median survival of 9 months; those with adenocarcinoma or unclassifiable tumors have a median survival of 4–6 months. Pts in whom a primary site is identified usually have a better prognosis. Limited sites of involvement and neuroendocrine histology are favorable prognostic factors. Pts without a primary diagnosis should be treated palliatively with radiation therapy to symptomatic lesions. All-purpose chemotherapy regimens rarely produce responses but always produce toxicity. Certain clinical features may permit individualized therapy.
Syndrome of Unrecognized Extragonadal Germ Cell Cancer
In pts <50 years with tumor involving midline structures, lung parenchyma, or lymph nodes and evidence of rapid tumor growth, germ cell tumor is a possible diagnosis. Serum tumor markers may or may not be elevated. Cisplatin, etoposide, and bleomycin (Chap. 70) chemotherapy may induce complete responses in ³25%, and ~15% may be cured. A trial of such therapy should probably also be undertaken in pts whose tumors have abnormalities in chromosome 12.
Peritoneal Carcinomatosis in Women
Women who present with pelvic mass or pain and an adenocarcinoma diffusely throughout the peritoneal cavity, but without a clear site of origin, have primary peritoneal papillary serous carcinoma. The presence of psammoma bodies in the tumor or elevated CA-125 levels may favor ovarian origin. Such pts should undergo debulking surgery followed by paclitaxel plus cisplatin combination chemotherapy (Chap. 71). About 20% of pts will respond, and 10% will survive at least 2 years.
Carcinoma in an Axillary Lymph Node in Women
Such women should receive adjuvant breast cancer therapy appropriate for their menopausal status even in the absence of a breast mass on physical examination or mammography and undetermined or negative estrogen and progesterone receptors on the tumor (Chap. 68). Unless the ipsilateral breast is radiated, up to 50% of these pts will later develop a breast mass. Although this is a rare clinical situation, long-term survival similar to women with stage II breast cancer is possible.
Osteoblastic Bone Metastases in Men
The probability of prostate cancer is high; a trial of empirical hormonal therapy (leuprolide and flutamide) is warranted (Chap. 72).
Osteoblastic Bone Metastases in Men
Even if panendoscopy fails to reveal a head and neck primary, treatment of such pts with cisplatin and 5-fluorouracil chemotherapy may produce a response; some responses are long-lived (Chap. 66).

For a more detailed discussion, see Stone RM: Metastatic Cancer of Unknown Primary Site, Chap. 99, p. 628, in HPIM-15.



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