Chapter 77: Cancer of Unknown Primary Site
INTRODUCTION
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.
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 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).
LIKELY PRIMARY PROFILE | COMMONLY CONSIDERED IHC TO ASSIST IN DIFFERENTIAL DIAGNOSIS OF CUPSa |
---|---|
Breast | ER, GCDFP-15, mammaglobin, Her-2/neu, GATA3 |
Ovarian/mullerian | ER, WT1 gene, CK7, PAX8, PAX2 |
Lung adenocarcinoma | TTF-1; nuclear staining, napsin A, SP-A1 |
Germ cell | β-HCG, AFP, OCT3/4, CKIT, CD30 (embryonal), SALL4 |
Prostate | PSA, α-methylacyl CoA racemase/P504S (AMACR/P504S), P501S (prostein), and PSMA, NKX3-1 |
Intestinal | CK7, CK20, CDX-2, CEA |
Neuroendocrine | Chromogranin, synaptophysin, CD56 |
Sarcoma | Desmin (desmoid tumors), factor VIII (angiosarcomas), CD31, smooth muscle actin (leiomyosarcoma), MyoD1 (rhabdomyosarcoma) |
Renal | RCC, CD10, PAX8, CD10 |
Hepatocellular carcinoma | Hep Par-1, Arg-1, glypican-3 |
Melanoma | S100, SOX-10, vimentin, HMB-45, tyrosinase and melan-A |
Urothelial | CK7, CK20, thrombomodulin, uroplakin III |
Mesothelioma | Calretinin, WT1, D2-40, mesothelin |
Lymphoma | LCA, CD3, CD4, CD5, CD20, CD45 |
SCC | p63, 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).
FIGURE 77-1
DIAGNOSIS
An approach to assessing unknown primary cancers with adenocarcinoma histology is shown in Fig. 77-2.
FIGURE 77-2
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.
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Citation
Kasper, Dennis L., et al., editors. "Chapter 77: Cancer of Unknown Primary Site." Harrison's Manual of Medicine, 20th ed., McGraw Hill Inc., 2020. harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623217/all/Chapter_77:_Cancer_of_Unknown_Primary_Site.
Chapter 77: Cancer of Unknown Primary Site. In: Kasper DLD, Fauci ASA, Hauser SLS, et al, eds. Harrison's Manual of Medicine. McGraw Hill Inc.; 2020. https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623217/all/Chapter_77:_Cancer_of_Unknown_Primary_Site. Accessed December 9, 2024.
Chapter 77: Cancer of Unknown Primary Site. (2020). In Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., & Loscalzo, J. (Eds.), Harrison's Manual of Medicine (20th ed.). McGraw Hill Inc.. https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623217/all/Chapter_77:_Cancer_of_Unknown_Primary_Site
Chapter 77: Cancer of Unknown Primary Site [Internet]. In: Kasper DLD, Fauci ASA, Hauser SLS, Longo DLD, Jameson JLJ, Loscalzo JJ, editors. Harrison's Manual of Medicine. McGraw Hill Inc.; 2020. [cited 2024 December 09]. Available from: https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623217/all/Chapter_77:_Cancer_of_Unknown_Primary_Site.
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