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metastatic cancer of unknown primary

Epidemiology: - 5-10% of cancers presenting to oncologist Pathology: 1) 60% have adenocarcinoma 2) 35% have poorly differentiated carcinoma Immunohistochemistry: 1) adrenal carcinoma: - CEA -, CAM5.2 -, AE1/AE3 -, CK7 -, CK17 -, CK20 - 2) breast adenocarcinoma: - CEA +, AE1/AE3 +, CK7 +, GCDFP-15 +/- 3) cholangiocarcinoma, primary: - CEA +, AE1/AE3 +, CAM5.2 +, CK7 +, CK20 + 4) colorectal adenocarcinoma: - CEA +, AE1/AE3 +, CK20 +, CK7 -/rare + 5) endocervical carcinoma: CEA +, AE1/AE3 +, 6) endometrial carcinoma: CEA -, 7) epithelioid hemangioendothelioma: - CD31 +, CD34 +, factor VIII +, CAM5.2 -/+, CEA - 8) hepatocellular carcinoma (except fibrolamellar): - CK7 -, CK20 -, CD34 + sinusoids 9) lung squamous cell carcinoma: 34betaE12 +, CK7 -, CK20 - 10) lung adenocarcinoma: - CEA +, CEAD-14 -, AE1/AE3 +, CK7 +, TTF1 +/-, ber-EP4 + 11) lung small cell carcinoma: CAM5.2 +, AE1/AE3 +, TTF1 + 12) mesothelioma: CEA -, CK7 +, ber-EP4 - 13) pancreatic adenocarcinoma: CEA +, AE1/AE3 +, CK20 +, CK7 + 14) prostate adenocarcinoma: CEA -, 15) renal adenocarcinoma: - CEA -, CAM5.2 +, AE1/AE3 +, CK7 -, CK17 -, CK20 -, vimentin +, CD10+ (clear cell variant) 16) thyroid follicular carcinoma: - thyroglobulin +, TTF1 +, vimentin + 17) rare CD45 membrane staining may be seen in undifferentiated & neuroendocrine carcinomas History: 1) smoking 2) asbestos exposure 3) abdominal pain 4) family history of breast cancer, ovarian cancer, colon cancer 5) inflammatory bowel disease (colon carcinoma) 6) hepatitis or cirrhosis (hepatocellular carcinoma) 7) removal of skin lesions (melanoma) Physical examination: 1) lymph nodes 2) thyroid 3) skin 4) prostate (men) 5) breasts, pelvic examination (women) 6) rectum Laboratory: 1) stool evaluation for occult blood 2) urinalysis 3) complete blood count (CBC) 4) liver function tests 5) serum prostate-specific antigen (men) 6) presence of tumor markers is rarely diagnostic a) serum beta chorionic gonadotropin (beta-hCG) b) serum alpha-fetoprotein (AFP) c) serum carcinoembryonic antigen (CEA) d) serum CA-125 (women) 1] not useful for diagnosis or prognosis [4] 2] may be useful in montoring response to therapy e) CA-19-9, CA-15-3 rarely useful 7) multigene expression profiles not recommended [4] 8) biopsy (see biopsy of metastatic cancer of unknown primary) Radiology: 1) chest X-ray 2) abdominal & pelvic computed tomography (CT) 3) mammography (women) 4) magnetic resonance imaging (MRI) of breast - women with cancer in axillary lymph nodes but non-diagnostic mammogram 5) CT of head & neck - enlarged cervical lymph nodes 6) PET scan (positron-emission tomography) a) has not been shown to impyyrove outcomes b) not recommended [4] 7) contrast radiography of GI tract not routine Differential diagnosis: - axillary lymphadenopathy in women* - obtain MRI of breast - if positive, treat according to breast cancer stage - if negative, treat as stage 2 breast cancer - isolated cervical lymphadenopathy - obtain upper endoscopy, bronchoscopy, laryngoscopy - if negative, treat with chemotherapy & radiation as for head & neck cancer - isolated inguinal lymphadenopathy - anorectal, genital & perirectal examination - if negative, lymph node resection of local radiation therapy - peritoneal carcinomatosis & ascites - treat as ovarian cancer - cytoreductive surgery & chemotherapy - midline non-adenocarcinoma of the mediastinum or retroperitoneum - obtain serum alpha-fetoprotein & serum beta-chorionic gonadotropin - testicular exam & testicular ultrasound - treat with platinum-based chemotherapy for germ cell tumors * NEJM knowledge+ seems to endorse fine needle aspiration followed by a core biopsy Management: 1) establish diagnosis with sufficient histologic specimen a) biopsy most accessible site b) open biopsy preferred to fine needle aspiration (FNA) c) FNA unsatisfactory for lymph node biopsy 2) special consideration is given to treatable malignancies a) germ cell cancer b) choriocarcinoma c) head & neck carcinoma d) breast cancer e) ovarian cancer 3) exhaustive search for primary tumor has not been shown to improve outcomes [4] - treat tumor based on histology & prognostic factors [4] 4) special cases: presentations that dictate specific workups & therapies a) squamous cell carcinoma in a cervical node - suggests head & neck cancer - upper GI endoscopy, bronchoscopy, laryngoscopy [4] - treatment: - radical neck dissection - radiotherapy +/- chemotherapy b) carcinoma in axillary nodes (female) - suggests breast cancer - obtain MRI of breasts [4] - treatment - breast radiotherapy or mastectomy - adjuvant chemotherapy - axillary node dissection [4] c) peritoneal carcinomatosis & ascites (female) - suggests ovarian cancer - debulking surgery - cisplatin + paclitaxel chemotherapy d) poorly differentiated cancer, predoinantly midline - men age < 50, lung or retroperitoneal or mediastinal mass or lymph nodes, elevated serum beta-hCG or serum AFP - suggests germ cell tumor (extragonadal) - cisplatin/VP-16-based chemotherapy e) bony metastases (male) - suggests prostate cancer - digital rectal examination & serum prostate-specific antigen - tumor stained for prostate-specific antigen (PSA) expression - androgen blockade: leuprolide plus flutamide f) adenocarcinoma, liver metastases, elevated CEA - suggests gastrointestinal malignancy - upper endoscopy & colonoscopy if evidence of gastrointestinal bleeding - with resection of detected tumor(s) - 5-fluorouracil - regardless of serum CEA level, if localized to the abdomen, treat as gastrointestinal malignancy [4] g) isolated inguinal lymphadenopathy - anorectal, perineal & genital examination [4] h) unknown primary with disease mostly below the diaphragm, treat as gastrointestinal cancer i) unknown primary with disease mostly above the diaphragm, treat as lung cancer [4] j) disseminated adenocarcinoma of unknown primary has unfavorable prognosis regardless of degree of diffentiation - aggressive treatment with platinum-based chemotherapy [4] 5) some patients may benefit from radiation or chemotherapy 6) supportive care 7) prognosis: poor prognostic indicators a) failure to find treatable neoplasm b) older age c) adenocarcinoma d) multiple metastases e) multiple comorbidities f) low performance status 8) hospice/palliative care appropriate for poor prognosis

Related

biopsy of metastatic cancer of unknown primary metastasis

Specific

metastatic adenocarcinoma of unknown primary

General

cancer of unknown primary metastatic neoplasm (metastatic cancer)

References

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  3. Dabbs. Diagnostic Immunohistochemistry. Churchill-Livingstone, 2002. chapter 7; p171
  4. Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16. 17, 18, 19. American College of Physicians, Philadelphia 2006, 2009, 2012, 2015, 2018, 2021.
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  7. Hainsworth JD, Spigel DR, Litchy S, Greco FA. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol. 2006 Aug 1;24(22):3548-54. PMID: 16877720
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  11. Varadhachary GR Carcinoma of unknown primary: focused evaluation. J Natl Compr Canc Netw. 2011 Dec;9(12):1406-12. PMID: 22157558
  12. Fizazi K, Greco FA, Pavlidis N et al. ESMO Guidelines Committee. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v133-8. PMID: 26314775 - Fizazi K, Greco FA, Pavlidis N et al. ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011 Sep;22 Suppl 6:vi64-8. PMID: 21908507
  13. National Cancer Institute Carcinoma of Unknown Primary - Health Professional Version https://www.cancer.gov/types/unknown-primary/hp