Pocket Oncology (Pocket Notebook Series), 1st Ed.

CANCER OF UNKNOWN PRIMARY (CUP)

Jean K. Lee and Lewis J. Kampel

Overview & Epidemiology

• CUP, or occult 1° tumors: Histologically proven malignant tumors w/o an identified 1° site. Pts w/CUP have a wide variety of presentations w/usu poor prognosis; median survival of 6–9 mos (Eur J Cancer2003;39:1990)

• 31000 cases of CUP diagnosed yearly in US; 4–5% of all CA

• Genetic basis: 2.8% cases of occult 1° found to be familial, w/occurrence of lung, kidney, & CRC in families

• 1° tumor site found in <30% of pts w/CUP

Clinical Presentation

• Pts may p/w sx related to site of mets. Multiple sites involved in >50% pts often including liver, lungs, bones, & LNs. Patterns of met sites unreliable to determine 1° site

• Favorable features include mets limited to LN, poorly differentiated carcinoma w/midline distribution, & resectable tumors. Unfavorable features include male gender, pathological dx of adenocarcinoma w/mets involving multiple organs, nonpapillary malignant ascites, cerebral mets, adenocarcinoma w/lung, pleural, or bone lesions

Pathology

• Classified into 5 major subtypes: Well- or moderately differentiated adenocarcinoma (60%), poorly differentiated adenocarcinoma, or undifferentiated carcinoma (29%), SCC (5%), poorly differentiated malignant neoplasm (cannot be further classified by light microscopy, 5%), & well- or poorly differentiated NETs (1%)

• Multiple chromosomal abnormalities & overexpression implicated: Ras, BCL2 (40% CUP cases), HER2, p53 (53%)

Immunohistochemistry (IHC)

• IHC useful in characterization of poorly differentiated or undifferentiated tumors for pathologic dx but large marker panels not recommended

• Key screening markers for CUPs summarized below

Initial Diagnostic Workup

• Initial w/u includes thorough hx & PEx including breast, genitourinary, pelvic, & rectal exams

• Lab studies: CBC, electrolytes, LFTs, U/A, occult blood stool testing. In men, consider serum PSA. Common tumor markers (CEA, CA19-9, CA 15-3, CA-125) generally not useful for dx

• Imaging: Chest CT, & CT or MRI of the abdomen & pelvis used to determine extent of disease: Localized vs. disseminated. In women, consider mammography & pelvic imaging. Role of PET/CT scans remains unclear & not recommended for routine screening

• Tissue bx: Core-needle bx preferred over FNA. Detailed review of pathology findings & review of past biopsies or malignancies

• <30% of cases w/occult mets will have 1° site identified

Management

• Consider surgery or RT for localized disease & systemic therapies for adv stage disease

• No specific chemotherapy regimen considered standard of care. Empiric chemotherapy considered for pts w/unclassified tumors w/disseminated disease who are sx w/PS of 1–2, or aymptomatic pts w/PS of 0 & aggressive disease

• Choice of chemotherapy regimen based on histologic type of CA. Often use a combination of platinum & newer cytotoxic agent (taxanes, GEM, irinotecan) or offer clinical trials. Median survival of 7–10 mos; 2-y survival rates of 20–25% (Semin Oncol 2009;36:65)

• Specific chemotherapy regimens based on phase II/III trials include

1.Adenocarcinoma of unknown 1°: Paclitaxel & carboplatin ± etoposide, carboplatin & docetaxel, CIS & GEM, GEM & docetaxel, Cap w/OX & 5-FU/leucovorin & OX

2.SCC: Platinum based regimens, including CIS/carboplatin in combination w/5-FU, paclitaxel, docetaxel, GEM

3.NET: Well-differentiated NETs treated as carcinoid tumors; while high-grade or small cell subtypes treated as SCLC w/platinum plus etoposide combination Rx

• Important role of psychosocial support & symptomatic mgmt, including palliative & hospice care