Hung T. Khong
DEFINITION
Carcinoma of unknown primary (CUP) is defined as the detection of one or more metastatic tumors for which standardized evaluation, including history and physical examination, routine blood work, urinalysis, chest x-ray, computed tomography (CT) scan, and histologic evaluation, fails to identify the primary site.
EPIDEMIOLOGY
■Incidence: 2% to 4% of all diagnosed oncologic cases in the United States 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
Clinical Features
■At presentation, most patients (97%) complain of symptoms at metastatic site(s). Common presenting sites and common metastatic sites are listed in Tables 31.1 and 31.2.
■Nonspecific constitutional symptoms also are common, such as anorexia, weight loss, and fatigue.
■At diagnosis, more than 50% of patients have multiple sites (more than two) of metastatic involvement.
Prognosis
■In general, the median survival time of patients with CUP is 6 to 9 months.
■Less than 20% of patients survive at 1 year and less than 10% at 5 years.
Poor prognostic factors include the following:
■Male gender
■Adenocarcinoma histology
■Increasing number of involved organ sites
■Hepatic or adrenal involvement
■Supraclavicular lymphadenopathy
Advantageous prognostic factors include the following:
■Nonsupraclavicular lymphadenopathy
■Neuroendocrine histology
■A study of 1,000 patients (from the M.D. Anderson Cancer Center) revealed several prognostic subgroups. Some of these are shown in Table 31.3.
DIAGNOSIS
■The recommended initial evaluation is listed in Table 31.4.
■Generous tissue samples should be obtained at the first biopsy.
■Accurate pathologic evaluation is critical.
■Light microscopic examination.
■Immunoperoxidase staining (IPS) should be performed in all CUP cases of poorly differentiated carcinomas (PDCs). Table 31.5 lists some immunoperoxidase stains that are most useful. In addition, some other useful markers are thyroid transcription factor (TTF-1) which is positive in lung and thyroid cancer; WT-1 which is positive in epithelioid mesothelioma, and serous ovarian cancer.
■Electron microscopy should be considered if the tumor cannot be identified by IPS.
■Most common primary sites are listed in Table 31.6.
■Gene and protein microarray technologies have emerged as valuable tools in the diagnosis of CUP. Three assays that are commercially available in the United States are the bioTheranostics CancerTYPE ID, a 92-gene RT-qPCR that provides a molecular classification of 39 tumor types in metastatic cancer with 85% sensitivity and more than 99% specificity; Pathwork Tissue of Origin Test, a 2000-gene microarray that identifies 15 origin sites, with 89% sensitivity and 99% specificity; and Rosetta miRview mets, a 48 microRNAs RT-qPCR, with 85% to 90% sensitivity and 99% specificity.
WELL-DIFFERENTIATED OR MODERATELY DIFFERENTIATED ADENOCARCINOMA OF UNKNOWN PRIMARY
Clinical Features
■Accounts for about 60% of CUP cases, typically affecting 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%) (see Table 31.6).
■Poor prognosis (median survival of 3 to 4 months).
■Primary site is rarely found (<15% before death); an exhaustive search is not indicated.
Further Workup
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. 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 of 12 (75%) patients in one study and in 19 (86%) of 22 patients in another study.
Treatment
■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 is discussed in Table 31.7.
■The various subsets of patients with different types of CUP who can be treated are discussed in the following sections.
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 platinum-based combination chemotherapy) (see Chapter 17). It should be noted that about 20% of patients have complete remission and 16% have prolonged disease-free survival.
Women with Axillary Lymph Node Metastases
■Suggests breast cancer.
■ER/PR and Her-2/neu should be checked.
■Occult breast primary is found in 55% to 75% of cases.
■Axillary node metastases in women should be treated in the same manner as stage II or III 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 should be performed.
POORLY DIFFERENTIATED CARCINOMA/ADENOCARCINOMA OF UNKNOWN PRIMARY
■PDC and poorly differentiated adenocarcinoma (PDA) account for 30% of CUP (PDC accounts for two-thirds of cases and PDA accounts for one-third).
■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.
Clinical Features
■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.
Pathologic Evaluation
■IPS is useful in the pathologic evaluation of PDC and PDA.
■Electron microscopic evaluation should be performed if tumor cannot be identified by IPS.
Further Workup
■Additional workup should include CT scan of chest, abdomen, and pelvis, and serum β-human chorionic gonadotropin (β-HCG), and α-fetoprotein (AFP).
Treatment
1.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.
•This syndrome should be treated in the same manner as a germ cell tumor (Chapter 16).
2.Poorly differentiated neuroendocrine carcinoma
•These carcinomas are high-grade tumors.
•They are 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 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 (see Table 31.7). It should be noted that other patients with PDC or PDA should receive an empiric therapy of platinating agent–based chemotherapy (see Table 31.7). (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
■Found in 5% of all patients with CUP.
■A 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
■Account for 5% of all patients with CUP.
Cervical Node Involvement
High Cervical Node(s)
■Workup and treatment of squamous cell CUP in the high cervical nodes are the same as those for primary head and neck cancer (see Chapter 1). PET scan may help identify the primary site in this setting.
■High long-term survival rates (30% to 70%) have been reported after local treatment.
■The role of chemotherapy is undetermined. However, concurrent chemoradiation is an option in patients with extracapsular spread or N2 or N3 disease.
Low Cervical or Supraclavicular Node(s)
■Histology can be 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.
REVIEW QUESTIONS
1.A 47-year-old man with chest pain is found to have mediastinal nodes. Biopsy of one of the enlarged nodes reveals adenocarcinoma. The most appropriate evaluation at this point is
A.CT chest, abdomen, and pelvis
B.β-hCG and AFP
C.PSA
D.C
E.A, B, and C
2.Further workups do not reveal the site of origin and PSA, β-hCG, and AFP were not elevated in the patient described in question 1. Which of the following choices BEST described the next approach:
A.Treat as poor-risk germ cell tumor
B.Testicular ultrasound
C.Treat as non–small cell lung cancer
D.A and C
E.A and B
3.A 54-year-old woman presents with an enlarged node in her left groin. Biopsy revealed squamous cell carcinoma. CT scans show no evidence of disease elsewhere. Which of the following is FALSE?
A.A primary site in the anogenital areas is most likely.
B.If there is no primary site found, surgical node dissection should be performed.
C.The patient has good prognosis.
D.The patient may be cured with locoregional therapy.
E.All of the above.
Suggested Readings
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7.Hainsworth JD, Rubin MS, Spigel DR, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon Research Institute. J Clin Oncol.2013;31:217-23.
8.HealthProfessional. 2012. http://www.nci.nih.gov/cancer/topics/pdq/treatment/unknownprimary/
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10.Le Chevalier T, Cvitkovic E, Caille P, et al. Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients. Arch Intern Med. 1988;148(9):2035-2039.
11.Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. 2003;39:1990-2005.
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13.Varadhachary GR, Greco FA. Overview of patient management and future directions in unknown primary carcinoma. Semin Oncol. 2009;36:75-80.