Chapter 77: Cancer of Unknown Primary Site


Cancer of unknown primary site (CUPS) is defined as follows: biopsy-proven malignancy; primary site unapparent after history, physical examination, chest x-ray, abdominal and pelvic CT, complete blood count, chemistry survey, mammography (women), β-human chorionic gonadotropin (hCG) levels (men), α-fetoprotein (AFP) levels (men), and prostate-specific antigen (PSA) levels (men); and histologic evaluation not consistent with a primary tumor at the biopsy site. About 90% of CUPS tumors are adenocarcinomas (60% well or moderately–well differentiated; 30% poorly differentiated), 5% squamous cell, 2% neuroendocrine, and 3% undifferentiated malignancy. CUPS incidence is declining, probably because of better pathology diagnostic criteria; it accounts for about 3% of all cancers today, down from 10–15% 15 years ago. Most pts are age >60. The tumors are often aneuploid. Cell lines derived from such tumors frequently have abnormalities in chromosome 1.


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 depend 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 examination. Immunohistochemical stains can be useful (Table 77-1).

TABLE 77-1: Select Immunohistochemical Stains Useful in the Diagnosis of CUPS
BreastER, GCDFP-15, mammaglobin, Her-2/neu, GATA3
Ovarian/mullerianER, WT1 gene, CK7, PAX8, PAX2
Lung adenocarcinomaTTF-1; nuclear staining, napsin A, SP-A1
Germ cellβ-HCG, AFP, OCT3/4, CKIT, CD30 (embryonal), SALL4
ProstatePSA, α-methylacyl CoA racemase/P504S (AMACR/P504S), P501S (prostein), and PSMA, NKX3-1
IntestinalCK7, CK20, CDX-2, CEA
NeuroendocrineChromogranin, synaptophysin, CD56
SarcomaDesmin (desmoid tumors), factor VIII (angiosarcomas), CD31, smooth muscle actin (leiomyosarcoma), MyoD1 (rhabdomyosarcoma)
RenalRCC, CD10, PAX8, CD10
Hepatocellular carcinomaHep Par-1, Arg-1, glypican-3
MelanomaS100, SOX-10, vimentin, HMB-45, tyrosinase and melan-A
UrothelialCK7, CK20, thrombomodulin, uroplakin III
MesotheliomaCalretinin, WT1, D2-40, mesothelin
LymphomaLCA, CD3, CD4, CD5, CD20, CD45
SCCp63, p40 (lung SCC), CK5/6
aPatterns emerging from coexpression of stains are better than individual stains to suggest putative primary site. Even with optimization, no IHC panel is 100% sensitive or specific (e.g., ovarian mucinous carcinoma can exhibit positivity with intestinal markers).
Abbreviations: AFP, α fetoprotein; Arg-1, arginase-1; β-hCG, β-human chorionic gonadotropin; CEA, carcinoembryonic antigen; CUPS, cancer of unknown primary site; ER, estrogen receptor; GCDFP-15, gross cystic disease fibrous protein-15; IHC, immunohistochemistry; LCA, leukocyte common antigen; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; SCC, squamous cell carcinoma; SP-A1, surfactant protein A precursor; TTF, thyroid transcription factor; WT, Wilms’ tumor.

Expression of cytokeratin subtypes may narrow the range of possible diagnoses (Fig. 77-1).

Approach to cytokeratin (CK7 and CK20) markers used in CUPS.


An approach to assessing unknown primary cancers with adenocarcinoma histology is shown in Fig. 77-2.

Algorithm for adenocarcinoma CUPS assessment. C, chemotherapy; CT, computed tomography; CUPS, cancer of unknown primary site; PET, positron emission tomography; RT, radiation therapy.


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.

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