Bethesda Handbook of Clinical Oncology, 2nd Edition
Carcinoma of Unknown Primary
Hung T. Khong
Departments of Medicine and Pharmacology, USA Cancer Research Institute, University of South Alabama, Mobile, Alabama
Carcinoma of unknown primary (CUP) is defined as the detection of one or more metastatic tumors for which routine evaluation, including history and physical examination, routine blood work, urinalysis, chest x-ray (CXR), and histologic evaluation, fails to identify the primary site.
- Incidence: 3% of all diagnosed oncologic cases are CUP.
- Gender: male-to-female ratio is approximately 1:1.
- Age: highest incidence is in the sixth decade of life.
CLINICAL FEATURES AND PROGNOSIS
- At presentation, most patients (97%) complain of symptoms at metastatic site(s). Common presenting sites and common metastatic sites are listed in Tables 32.1 and 32.2.
- Nonspecific constitutional symptoms also are common: anorexia, weight loss, and fatigue.
- At diagnosis, more than 50% of patients (59%) have multiple sites (more than two) of metastatic involvement.
TABLE 32.1. Common Presenting Sites
TABLE 32.2. Common Metastatic Sites
- In general, the median survival time of patients with CUP is 3 to 4 months; however, some recent studies have reported a median survival duration of 5 to 12 months.
- Most patients (55% to 85%) die within 1 year; 5% to 10% survive at 5 years (see Fig. 32.1).
FIG. 32.1. Kaplan–Meier survival curve of 1,000 consecutive patients with cancer of unknown primary (CUP). Median survival is 11 months (95% confidence interval [CI], 10 to 12 months).
Poor Prognostic Factors
- Male gender
- Adenocarcinoma histology
- Increasing number of involved organ sites
- Hepatic involvement
- Supraclavicular lymphadenopathy.
Advantageous Prognostic Factors
- Nonsupraclavicular lymphadenopathy
- Neuroendocrine histology
- A recent study of 1,000 patients (from M.D. Anderson) revealed several prognostic subgroups. Some subgroups are shown in Table 32.3.
TABLE 32.3. Median Survival in Some Prognostic Subgroups
- The recommended initial evaluation is listed in Table 32.4.
- Generous tissue samples should be obtained at the first biopsy.
- Accurate pathologic evaluation is critical.
- Light microscopic examination: four major histologic subtypes can be identified by the initial light microscopic examination (see Fig. 32.2).
- Immunoperoxidase staining (IPS) should be performed in all CUP cases of poorly differentiated carcinomas (PDCs). Table 32.5 lists some immunoperoxidase stains that are most useful.
- Electron microscopy should be considered if the tumor cannot be identified by IPS.
- Most common primary sites are listed in Table 32.6.
TABLE 32.4. Initial Evaluation
FIG. 32.2. Relative sizes of various clinical and histologic subgroups of patients with cancer of an unknown primary (CUP) site as determined by optimal clinical and pathologic evaluation. Potentially treatable subgroups are indicated in italics and comprise approximately 40% of patients. PDC, poorly differentiated carcinoma; PDA, poorly differentiated adenocarcinoma; PDMN, poorly differentiated malignant neoplasm. (From Hainsworth JD, Greco FA. Treatment of patients with cancer of an unknown primary site. N Engl J Med 1993;329:257–263, with permission.
TABLE 32.5. Immunoperoxidase Staining in the Differential Diagnosis of Carcinoma of Unknown Primary Site
TABLE 32.6. Primary Sites (Diagnosed During Life or at Autopsy)
WELL-DIFFERENTIATED OR MODERATELY DIFFERENTIATED ADENOCARCINOMA OF UNKNOWN PRIMARY
- Typically elderly patients
- Metastatic tumors at multiple sites
- Poor performance status (PS) at diagnosis
- Common metastatic sites: lymph nodes, liver, lung, and bone
- Most common primary sites identified: the lung and pancreas (45%) (Table 32.6)
- Poor prognosis (median survival of 3 to 4 months)
- Primary site is rarely found (<15% before death); an exhaustive search is not indicated.
Additional studies that should be performed include prostate-specific antigen (PSA) serum level and/or IPS for men and mammography, serum CA 15-3, serum CA 125, and estrogen receptor/progesterone receptor (ER/PR) (IPS) for women. Computerized tomography (CT) scan of the abdomen can identify a primary site in approximately 30% of cases. In patients with CUP who have metastatic adenocarcinoma to the axillary lymph nodes and a negative mammogram, breast magnetic resonance imaging (MRI) detected a primary breast cancer in 9 (75%) of 12 patients in one study and in 19 (86%) of 22 patients in another study.
- Most cases (90%) of well-differentiated or moderately differentiated adenocarcinoma of unknown primary show low response rates (RRs) and few complete responses with systemic chemotherapy.
- Patients in this group have a poor prognosis.
- The empiric chemotherapy for CUP has been discussed in Table 32.7.
- The various subsets of patients with different types of CUPs who can be treated are discussed in the following sections.
TABLE 32.7. Empiric Chemotherapy for Carcinoma of Unknown Primary
Peritoneal Carcinomatosis in Women
- Typical of ovarian cancer
- Occasionally associated with cancers from the gastrointestinal (GI) tract or breast
- Serum CA125 level is often elevated.
- Treatment is the same as for stage III ovarian cancer (laparotomy with surgical cytoreduction, followed by taxane or platinum-based combination chemotherapy) (see Chapter 17). It should be noted that about 20% of patients have complete remission (CR) and 16% have prolonged disease-free survival.
Women with Axillary Lymph Node Metastases
- Suggests breast cancer.
- ER/PR should be checked
- Occult breast primary is found in 55% to 75% of cases.
- Axillary node metastases should be treated in the same manner as stage II breast cancer.
- Modified radical mastectomy has been recommended.
- Alternatively, radiation therapy (XRT) to the breast can be performed after axillary node dissection.
- Adjuvant systemic chemotherapy should also be considered (see Chapter 17).
- Patients with metastatic sites in addition to axillary nodes should be treated for metastatic breast cancer (see Chapter 12).
Men with Elevated Prostate-specific Antigen or Osteoblastic Bone Metastasis
- If the PSA serum level or tumor staining is positive, a regimen of hormonal therapy similar to that used for metastatic prostate cancer (Chapter 14) should be started.
- If osteoblastic bone metastases are present, empiric hormonal therapy should be started regardless of the PSA levels.
Patients with a Single Metastatic Site
- Surgical excision and/or XRT is performed.
POORLY DIFFERENTIATED CARCINOMA/ADENOCARCINOMA OF UNKNOWN PRIMARY
- Poorly differentiated carcinoma and poorly differentiated adenocarcinoma (PDA) account for 30% of CUP (PDC accounts for two thirds of CUP and PDA accounts for one third of CUP).
- Patients with PDC and PDA show poor response to fluorouracil-based chemotherapy and exhibit a short survival.
- Some patients have neoplasms that are highly responsive to platinating agent–based combination chemotherapeutic treatments. Some long-term survivors and cures have been described for both PDC and PDA.
- Younger median age (about 40 years)
- Rapid progression of symptoms
- Evidence of rapid tumor growth
- Most common sites of metastatic involvement (50% of cases): lymph nodes, mediastinum, and retroperitoneum.
- IPS is useful in the pathologic evaluation of PDC and PDA.
- Electron microscopic evaluation should be performed if tumor cannot be identified by IPS.
- Genetic analysis may be useful [e.g., i(12p), del(12p), or multiple copies of (12p) are diagnostic of germ cell tumor].
- Additional workup should include CT scan of chest and abdomen, and serum β-human chorionic gonadotropin (β-HCG) and α-fetoprotein (AFP).
- Extragonadal germ cell cancer syndrome
- This syndrome is commonly found in young men.
- These are predominantly midline tumors (mediastinum or retroperitoneum).
- The syndrome is characterized by elevated levels of β-HCG, AFP, or both.
- Genetic analysis may be diagnostic (e.g., abnormalities in chromosome 12).
- This syndrome should be treated in the same manner as a germ cell tumor (Chapter 16).
- Poorly differentiated neuroendocrine carcinoma
- These carcinomas are high-grade tumors.
- It is characterized by multiple metastatic sites.
- The carcinomas are highly responsive to cisplatin-based chemotherapy.
- The overall RR for combination chemotherapy was 71% (33 of 46 patients), with a complete response (CR) in 28% (13 of 46 patients); 17% of patients (8 of 46 patients) showed durable disease-free survival.
- Patients in this group should be treated with a regimen of combination chemotherapy including a platinating agent and etoposide (Table 32.7). It should be noted that other patients with PDC or PDA should receive an empiric therapy of platinating agent–based chemotherapy (Table 32.7). (In a prospective study of 220 patients, the overall RR was 62%, with a complete RR of 26%. Thirteen percent of patients were considered cured.)
POORLY DIFFERENTIATED MALIGNANT NEOPLASMS OF UNKNOWN PRIMARY
- Poorly differentiated malignant neoplasms of unknown primary are found in 5% of all patients with CUP.
- Specialized pathologic study found 35% to 65% of the malignant neoplasms to be lymphomas; carcinomas accounted for most of the remaining cases. Less than 15% of the neoplasms are melanoma and sarcoma.
SQUAMOUS CELL CARCINOMA OF UNKNOWN PRIMARY
Cervical Node Involvement
High Cervical Node(s)
- Workup and treatment of squamous cell carcinoma of unknown primary in the high cervical nodes is the same as that for primary head and neck cancer (see Chapter 1).
- High long-term survival rates (30% to 70%) have been reported after local treatment.
- The role of chemotherapy is undetermined.
Low Cervical or Supraclavicular Node(s)
- Histology can be either squamous, adenocarcinoma, or poorly differentiated tumors.
- Poorer prognosis (particularly for adenocarcinoma histology) is because lung and GI tract are frequent primary sites.
- If no other sites of disease are found, a few patients (10% to 15%) will have a long-term disease-free survival with aggressive local therapy (surgery and/or XRT).
- The role of chemotherapy is undetermined.
Inguinal Lymph Node(s)
- A primary site in the genital or anorectal areas is often identified in most patients.
- Curative therapy is available for some of these patients.
- If no primary is found, surgical node dissection (with or without XRT) can offer long-term survival.
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