Cancer of Unknown Primary

Ritesh Rathore, M.D.

Basic Information

Definition

Carcinoma of unknown primary (CUP) refers to a diverse group of malignancies for which the anatomic site of origin cannot be determined despite extensive investigations.

Synonyms

Cancer NOS
Cancer unspecified site
Malignancy unspecified site
CUP

ICD-10CM CODES
C80.1	Malignant (primary) neoplasm, unspecified

Epidemiology & Demographics

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CUP accounts for about 5% of all cancers, and the annual incidence in the United States is 7-12 cases per 100,000 persons.
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It is the seventh most frequent common cause of cancer and the fourth most common cause of cancer death. It predominantly occurs in adults and is more common in males.
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In the United States, an estimated 33,770 new cases are expected in 2017.
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Most cases of CUP are carcinomas, which are divided into adenocarcinomas (90%), squamous cell carcinomas (5%), and undifferentiated carcinomas (5%).
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There is a variable rate of mutations detected in CUP (18%-30%). The tumor suppressor gene p-53 has overexpression rates (40%-50%) or mutation rates (25%-40%) that are comparable to that seen in other solid tumors. The evaluation of VEGF-A (vascular endothelial growth factor-A, angiogenesis factor) and matrix metalloproteinases (enzymes that degrade stroma) showed that these are universally expressed and active angiogenesis is present in CUP.

Physical Findings & Clinical Presentation

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Physical findings can be variable and include generalized and organ-specific findings.
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General findings can include cachexia, pallor, edema, icterus, edema, skin rash, muscle wasting among others.
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Organ-specific findings are related to the dysfunction of the underlying organ(s) involved with CUP.
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The clinical course is often highlighted by a short presentation history, with symptoms and signs associated with metastatic sites, early dissemination, aggressive clinical course, and occasionally an unpredictable metastatic pattern.
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Multiple organs are involved at diagnosis in up to half of patients.

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The clinicopathologic subsets comprising CUP are shown in Table 1.

TABLE1 Clinicopathologic Subsets of Patients with CUPFrom Pavlidis N, Pentheroudakis G: Cancer of unknown primary site, Lancet 379(9824):1428-1435, 2012.

	Median Age (Years)	Sex of Patients (M/F)	Histopathology
Lymph nodes
Mediastinal retroperitoneal	<50	70%/30%	UDF or PDF
Axillary	52	0%/100%	Adenocarcinoma (WDF, MDF, or PDF)
Cervical	57-60	80%/20%	SCC
Inguinal	58	50%/50%	UDF, SCC, mixed SCC and adenocarcinoma
Peritoneal cavity
Primary peritoneal in women	55-65	0%/100%	Adenocarcinoma (serous papillary)
Ascites of other unknown origin	–	–	Adenocarcinoma (MDF or PDF; mucin; with or without signet ring cells)
Neuroendocrine tumors	63	60%/40%	PDF with neuroendocrine features; low-grade neuroendocrine cancers; small-cell anaplastic cancers
Liver (mainly) or other organs, or both	62	61%39%	Adenocarcinoma (MDF or PDF)
Lungs
Pulmonary metastases	–	–	Adenocarcinoma (WDF, MDF, or PDF)
Pleural effusions	–	–	Adenocarcinoma (MDF or PDF)
Bones (one or more)	–	–	Adenocarcinoma (WDF, MDF, or PDF)
Brain (one or more)	51-55	M>F	Adenocarcinoma (WDF, UDF, or PDF); SCC
F, women; M, men; MDF, moderately differentiated; PDF, poorly differentiated; SCC, squamous cell carcinoma; UDF, undifferentiated; WDF, well differentiated.

Diagnosis

Workup

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Comprehensive medical history

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Complete physical examination with particular attention to skin, lymph node sites, organ enlargement, and testes; also rectal examination and pelvic examination (in women) (Table 2)

TABLE2 Recommended Evaluation Following Initial Light Microscopic DiagnosisFrom Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Diagnosis	Clinical Evaluation^∗	Special Pathologic Studies
Adenocarcinoma (or poorly differentiated adenocarcinoma)	PET CT of chest, abdomen Men: serum PSA Women: mammogram Additional directed radiologic or endoscopic studies to evaluate abnormal symptoms, signs, laboratory values	Men: PSA stain Women: estrogen and progesterone receptor stains (if clinical features suggest metastatic breast cancer)
Poorly differentiated carcinoma	PET CT of chest, abdomen Serum hCG, AFP Additional directed radiologic or endoscopic studies to evaluate abnormal symptoms, signs, laboratory values	Immunoperoxidase staining Electron microscopy (if immunoperoxidase stains indeterminate)
Squamous carcinoma, cervical nodes	PET Direct laryngoscopy with visualization; biopsy of nasopharynx, pharynx, hypopharynx, larynx Fiberoptic bronchoscopy (if laryngoscopy is negative)	—
Squamous carcinoma, inguinal nodes	PET Complete examination of perineal area (including pelvic examination) Anoscopy Cystoscopy	—
AFP, α-fetoprotein; CT, computed tomography; hCG, human chorionic gonadotropin; PET, positron emission tomography; PSA, prostate-specific antigen.

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Histopathology review of biopsy specimens

Laboratory Tests

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Complete blood count
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Comprehensive chemistry panel
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Urine analysis
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Stool for occult blood
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Tumor markers (in selected cases): prostate-specific antigen (PSA), β-human chorionic gonadotrophin, α-fetoprotein.
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Adequate tissue biopsy with immunohistochemical (IHC) staining is done to guide broad diagnostic category assignments—carcinoma, melanoma, sarcoma, or lymphoma.
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Subtyping with IHC panels helps further classifying into adenocarcinoma, squamous carcinoma, germ cell tumor, neuroendocrine, thyroid, hepatocellular, or renal origin.

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Step-wise approach for IHC derived diagnosis of likely site of origin are depicted in Table 3.

TABLE3 Immunohistochemical Approaches for Diagnosis of CUPFrom Pavlidis N, Pentheroudakis G: Cancer of unknown primary site, Lancet 379(9824):1428-1435, 2012.

	Diagnosis
Step One
AE1 or AE3 pan-cytokeratin	Carcinoma
Common leukocyte antigen	Lymphoma
S100; HMB-45	Melanoma
S100; vimentin	Sarcoma
Step Two
CK7 or CK20; PSA	Adenocarcinoma
PLAP; OCT4; AFP; human chorionic gonadotropin	Germ cell tumors
Hepatocyte paraffin1; canalicular pCEA, CD10, or CD13	Hepatocellular carcinoma
RCC; CD10	Renal cell carcinoma
TTF1; thyroglobulin	Thyroid carcinoma
Chromogranin; synaptophysin, PGP9.5; CD56	Neuroendocrine carcinoma
CK5 or CK6; p63	Squamous cell carcinoma
Step Three
PSA; PAP	Prostate
TTF1	Lung
GCDFP-15; mammaglobin; ER	Breast
CDX2; CK20	Colon
CDX2 (intestinal epithelium); CK20; CK7	Pancreas or biliary
ER; CA-125; mesothelin; WT1	Ovary
Step one detects broad type of cancer. Step two detects subtype. Step three detects origin of adenocarcinoma. Positive results with any of these stains indicates a tumor is present, but without absolute certainty. AFP, α-fetoprotein; ER, estrogen receptor; OCT4, octamer-binding transcription factor 4; PAP, prostatic acid phosphatase; pCEA, polyclonal carcinoembryonic antigen; PLAP, placental alkaline phosphatase; PSA, prostate-specific antigen; RCC, renal cell carcinoma antigen.

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In up to 25% cases, a single site of origin can be narrowed down by IHC staining (e.g., TTF-1 positive and CK-1 positive lung cancer profile).
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Molecular diagnosis is carried out by commercially available multi-gene assays that utilize micro-array or polymerase chain reaction assays and can assist in finalizing diagnosis in up to 80% to 90% of cases in which initial IHC staining has been inconclusive.

Imaging Studies

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CT scans of the chest, abdomen, and pelvis; also CT of the neck in case of neck lymphadenopathy
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For selected cases
1. •
  
  PET scan
2. •
  
  Mammography and/or breast MRI
3. •
  
  Testicular ultrasonography

Treatment

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CUP patients often require early supportive care for their advanced cancer; also there is elevated psychosocial distress with the uncertainties of diagnosis and treatment options. Anxiety and depression are more common in CUP patients compared to patients with known primaries.
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Treatment is based according to the most likely site of origin for the cancer with systemic chemotherapy typically being the mainstay of therapy.
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Next-generation gene sequencing and in situ hybridization techniques in a large study of 1806 CUP cases were able to identify potential biomarkers predictive of therapeutic efficacy in 96% of cases. Additionally, biomarkers associated with a potential lack of benefit were identified in numerous cases, which could further refine the management of patients with CUP.

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Favorable and unfavorable CUP subsets are shown in Table 4.

TABLE4 Prognostic Classification of CUP PatientsFrom Pavlidis N, Pentheroudakis G: Cancer of unknown primary site, Lancet 379(9824):1428-1435, 2012.

Favorable Subset

Women with papillary adenocarcinoma of the peritoneal cavity

Women with adenocarcinoma involving the axillary lymph nodes

Poorly differentiated carcinoma with midline distribution

Poorly differentiated neuroendocrine carcinoma

Squamous cell carcinoma involving cervical lymph nodes

Adenocarcinoma with a colon-cancer profile (CK20+, CK7−, CDX2+)

Men with blastic bone metastases and elevated prostate-specific antigen (adenocarcinoma)

Isolated inguinal adenopathy (squamous carcinoma)

Patients with one small, potentially resectable tumor

Unfavorable Subset

Adenocarcinoma metastatic to the liver or other organs

Nonpapillary malignant ascites (adenocarcinoma)

Multiple cerebral metastases (adenocarcinoma or squamous carcinoma)

Several lung or pleural metastases (adenocarcinoma)

Multiple metastatic lytic bone disease (adenocarcinoma)

Squamous cell carcinoma of the abdominopelvic cavity

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Favorable CUP
1. ○
  
  Women with peritoneal adenocarcinoma when treated as advanced ovarian cancer with surgical cytoreduction and adjuvant systemic chemotherapy can have median survivals in the 36-month range.
2. ○
  
  Patients with a midline tumor characteristically treated as germ cell tumors have median survivals of 12 months.
3. ○
  
  Patients with poorly differentiated neuroendocrine cancers are treated with combination platinum-containing chemotherapy and median survivals are in the 15-month range.
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  Women with axillary nodal adenocarcinoma are approached as breast cancers with treatment plans incorporating axillary and breast surgery followed by adjuvant chemotherapy, hormone therapy and radiotherapy; survival rates are comparable to similarly staged breast cancers.
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  Patients with metastatic squamous neck nodal cancer are treated as head–neck cancers with chemoradiotherapy and/or neck dissection.
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  Patients with a colon adenocarcinoma profile are treated with systemic regimens as in metastatic colorectal cancers with median survivals in the 24-month range.
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  Men with blastic bone metastases and elevated prostate specific antigen are treated with initial androgen deprivation therapy and later on with systemic chemotherapy.
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Unfavorable CUP
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  Account for 75% to 80% of all CUP patients
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  The most common presentation is advanced visceral disease, often with liver metastases; median survivals with systemic platinum and taxane-containing chemotherapy are typically in the range of 6 to 7 months.