Cancer of unknown primary origin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2], Maria Fernanda Villarreal, M.D. [3]

Synonyms and Keywords: Occult cancer; CUP; Metastases of unknown primary origin; Unknown primary origin neoplasm; Cancers of unknown primary site; Neoplasms of unknown primary site; Carcinoma of unknown primary; Cancer of unknown origin; Cancer of unknown primary; Unknown primary tumors; UPT; Metastatic malignant neoplasms

Overview

Cancer of unknown primary origin or CUP is the diagnosis of metastatic cancer when the anatomic site of origin remains unidentified. Cancer of unknown primary origin is common, and it accounts for 2–5% of all cancers. Cancer of unknown primary origin may be classified according to pathology findings into 4 groups: adenocarcinomas, poorly differentiated carcinomas, squamous cell carcinomas, and carcinomas with neuroendocrine differentiation. The majority of patients with cancer of unknown primary origin may be initially asymptomatic. Early clinical features include fatigue, weight-loss, and loss of appetite. If left untreated, the majority of patients with cancer of unknown primary origin may progress to develop multiple organ failure, heart failure, and death. The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status. The 5-year survival of patients with cancer of unknown primary origin is less than 2%.

Historical Perspective

  • Cancer of unknown primary origin was first described in 1980.
  • From 1980 to 1990, the definition of unknown primary cancer was based on imaging results.[1]

Classification

Pathophysiology

  • The exact pathogenesis of cancer of unknown primary origin is not fully understood.
  • Cancer of unknown primary, like other cancers, arises from one cell that has managed to escape regulation and produces a tumor at a certain site (the site of origin) and consequently metastasizes to other parts of the body.
  • It is thought that the site of origin of CUP remains unknown due to one of the following theories:[2]
    • Remaining small and undetectable clinically
    • Disappearing after metastasizing
    • Elimination by body's defense

Causes

  • The cause of CUP has not been identified.
  • Several studies have evaluated the chromosomal and molecular anomalies found in cancers of unknown primary; however, they could not identify unique causes of metastasis of unknown primaries relative to those with known primary origins.
  • Overexpression of several genes has been noted in patients with cancer of unknown primary including Ras, p53, Bcl-2, and Her-2.[3][4]

Differentiating Cancer of Unknown Primary Origin from Other Diseases

  • Cancer of unknown primary is a diagnosis of exclusion; hence, all other differentials in addition to primary tumor location must be ruled out prior to diagnosis.
  • Cancer of unknown primary origin must be differentiated from other diseases that cause sudden weight-loss, fatigue, and loss of appetite, such as:[2]

Epidemiology and Demographics

  • The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide.[5][6]
  • Cancer of unknown primary origin is common, and it accounts for 3–5% of all malignant epithelial tumors.[7]
  • Cancer of unknown primary origin is the fourth most common cause of cancer-related death.[5]

Age

  • Patients of all age groups may develop cancer of unknown primary origin.
  • Cancer of unknown primary origin is more commonly observed among adults and elderly patients with a mean age of 59 upon presentation.[8]

Gender

  • Cancer of unknown primary origin affects men and women equally except for squamous cell carcinomas where males are affected twice as frequently as females.[9]

Race

  • There is no racial predilection to cancer of unknown primary origin.

Risk Factors

  • There are no established risk factors for cancer of unknown primary origin.

Natural History, Complications and Prognosis

  • Early clinical features include fatigue, weight-loss, and loss of appetite.
  • Cancers of unknown primary origin are characterized by their aggressiveness, early dissemination, and unpredictable metastasis.
  • Upon presentation, around 60% of patients with cancer of unknown primary have two or more affected sites.[8]
  • The most common sites of metastasis in cancer of unknown origin are lymph nodes, lungs, liver, bones, and pleura.[10]
  • If left untreated, the majority of patients with cancer of unknown primary origin may progress to develop multiple organ failure, heart failure, and death.
  • Common complications of cancer of unknown primary origin, may include: hypercalcemia, adrenal insufficiency, and inappropriate antidiuretic syndrome, hematologic disorders, and malignant effusions.
  • Prognosis is generally poor, and the average survival time of patients with cancer of unknown primary origin is approximately 6-12 months after diagnosis.[11][12]
  • Sites of metastasis and prognosis differ with the types of CUPs:[3][13][14][15]
Type Common sites of metastasis Characteristics 5-year survival rates
Adenocarcinoma Liver, lungs, bones, axillary lymph nodes, and peritnoneum Most common type of CUP 5%
Squamous cell carcinoma Cervical lymph nodes More common in males 30%
Neuroendocrine carcinoma Bone marrow, bone lesions, lymph nodes, and lungs Predominating type in children 17%
Undifferntiated Lungs and lymph nodes Rapid tumor growth 13-16%

Diagnosis

Diagnostic Criteria

Symptoms

  • Cancer of unknown primary origin may be asymptomatic.
  • Symptoms of cancer of unknown primary origin may include the following:[2]

Physical Examination

  • Patients with cancer of unknown primary origin usually appear cachexic.
  • There are no remarkable findings in the physical examination of these patients; the presentation is variable and depends on many factors including the primary tumor's origin and extent of organs involved.[2]

Laboratory Findings

  • There are no specific diagnostic laboratory findings associated with cancer on unknown primary origin; however, certain abnormal laboratory findings may help in locating the primary origin of the tumor.

Electrocardiogram

  • There are no ECG findings associated with cancer of unknown primary origin.

X-ray

  • A chest x-ray is a prerequisite in the diagnosis of cancer of unknown primary; however, it's value is of less significance when it comes to locating the primary tumor or differentiating it from a metastatic lesion.[19]
  • A mammography may be helpful in the identification of the primary origin of the tumor in women presenting with metastatic adenocarcinoma.[20]

Echocardiography or Ultrasound

  • There are no specific echocardiography or ultrasound findings associated with cancer of unknown primary origin. However, a testicular or breast ultrasound may be helpful in the localization of the primary origin of the tumor in certain cases.[18]

CT scan

  • CT scan may be helpful in the diagnosis of cancer of unknown primary origin. It is considered one of the most valuable diagnostic tools in the search for the primary origin of the tumor.
  • CT scanning has provided a 20% increase in diagnostic accuracy relative to other imaging modalities.[21]

MRI

  • There are no MRI findings associated with cancer of unknown primary origin. However, a breast MRI may be helpful in the detection of the tumor's primary origin in females with isolated axillary lymphadenopathy and suspected primary breast carcinoma.[22]

Other Imaging Findings

  • There are no other imaging findings associated with cancer of unknown primary origin.

Other Diagnostic Studies


 
 
 
 
 
 
 
 
 
 
Tumor of unknown primary origin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Full medical history and physical exam
• Basic blood and biochemical analysis
• CT scan of chest, abdomen, and pelvis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Histopathologic examination
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Squamous cell carcinoma
 
 
 
Neuroendocrine carcinoma
 
 
 
Adenocarcinoma and poorly differntiated carcinoma
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Octreoscan
• Plasma chromogranin A
 
 
 
 
 
 
 
 
 
 
 
Additional tests specific to location of metastasis
 
 
 
 
 
 
 
 
 
Additional tests speciifc to gender
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cervical lymphadenopathy
 
Inguinal lymphadenopathy
 
Bone metastasis
 
 
 
Men
 
Women
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Panendoscopy
• CT scan of head and neck
• Diagnostic bilateral tonsillectomy
 
• Complete clinical examination of external genital organs
• Pelvic CT scan or ultrasound
 
• Anoscopy
• Colposcopy (if female)
• Complete clinical examination of head and neck
• Panendoscopy
• Bone scintigraphy
• Xrays of painful areas
 
 
 
• PSA
• αFP
• βHCG
 
• Mammography
• Pelvic ultrasound or CT scan
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional tests specific to location of metastasis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Midline and/or mediastinal lymphadenopathy
 
Cervical and/or supraclavicular lymphadenopathy
 
Axillary lymphadenopathy
 
Liver metastasis
 
Lung metastasis
 
Bone metastasis
 
Single metastasis
 
Pleural effusion
 
Periotneal effusion
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Testicular ultrasound
• Chest and abdominal CT scan
 
• Testicular ultrasound
• Head and neck CT scan
• Panendoscopy
• EBV testing (to rule out undifferentiated nasopharyngeal carcinoma)
 
Women:
• Breast ultrasound
• Breast MRI
 
Women:
• αFP assay (if undifferntiated carcinoma)
• Colposcopy
 
Women:
• βHCG
Men:
• Testicular ultrasound
• Chest and abdominal CT scan
 
• Bone scintigraphy
• Xrays of painful areas
 
• Full body CT scan
• Bone scintigraphy
 
• Chest CT scan
 
Women:
• Abdominal and pelvic CT scan

Treatment

Medical Therapy

  • There is no treatment for cancer of unknown primary origin; the mainstay of therapy is supportive care.[28]
  • The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status.
  • Medical therapy for cancer of unknown primary origin should be adjusted on an individual basis and according to well-defined clinicopathologic subsets.[28]
  • The table below summarizes different types of medical therapy strategies for cancer of unknown primary origin.
Treatment for cancer of unknown primary origin

Adapted from the European Society of Medical Oncology[28]

Sub-type Proposed treatment

Poorly differentiated carcinoma, predominately nodal disease

Platinum based combination chemotherapy

Peritoneal carcinomatosis in female

Platinum based chemotherapy

Isolated axillary nodal metastases in female

Identical to breast cancer with similar nodal involvement

Squamous carcinoma of cervical lymph nodes

Irradiation for N1-N2 disease.
For higher stages induction chemotherapy with platinum-based combination is suggested

Liver, bone, or multiple-site metastases of adenocarcinoma

Low toxicity chemotherapy of palliative orientation or best supportive care are acceptable

Surgery

Prevention

  • There are no primary preventive measures available for cancer of unknown primary origin.[28]
  • There is no evidence that follow-up of asymptomatic patients is needed.[28]

References

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  2. 2.0 2.1 2.2 2.3 2.4 2.5 Varadhachary GR (2007). "Carcinoma of unknown primary origin". Gastrointest Cancer Res. 1 (6): 229–35. PMC 2631214Freely accessible. PMID 19262901. 
  3. 3.0 3.1 Hainsworth JD, Lennington WJ, Greco FA (2000). "Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site.". J Clin Oncol. 18 (3): 632–5. PMID 10653878. doi:10.1200/JCO.2000.18.3.632. 
  4. Briasoulis E, Tsokos M, Fountzilas G, Bafaloukos D, Kosmidis P, Samantas E; et al. (1998). "Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study.". Anticancer Res. 18 (3B): 1907–14. PMID 9677443. 
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  6. Fong T, Govindan R, Morgensztern D. Cancer of unknown primary. J Clin Oncol 2008 ASCO Ann Meet Proc. 2008;26 (15S:22159.
  7. Pavlidis N, Pentheroudakis G (2012). "Cancer of unknown primary site.". Lancet. 379 (9824): 1428–35. PMID 22414598. doi:10.1016/S0140-6736(11)61178-1. 
  8. 8.0 8.1 Abbruzzese JL, Abbruzzese MC, Hess KR, Raber MN, Lenzi R, Frost P (1994). "Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.". J Clin Oncol. 12 (6): 1272–80. PMID 8201389. doi:10.1200/JCO.1994.12.6.1272. 
  9. Muir C (1995). "Cancer of unknown primary site.". Cancer. 75 (1 Suppl): 353–6. PMID 8001006. 
  10. 10.0 10.1 Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M; et al. (1988). "Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients.". Arch Intern Med. 148 (9): 2035–9. PMID 3046543. 
  11. Nelson KA, Walsh D, Abdullah O, McDonnell F, Homsi J, Komurcu S, LeGrand SB, Zhukovsky DS (2000). "Common complications of advanced cancer". Semin. Oncol. 27 (1): 34–44. PMID 10697020. 
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  13. Hainsworth JD, Dial TW, Greco FA (1988). "Curative combination chemotherapy for patients with advanced poorly differentiated carcinoma of unknown primary site.". Am J Clin Oncol. 11 (2): 138–45. PMID 2451881. 
  14. Nguyen C, Shenouda G, Black MJ, Vuong T, Donath D, Yassa M (1994). "Metastatic squamous cell carcinoma to cervical lymph nodes from unknown primary mucosal sites.". Head Neck. 16 (1): 58–63. PMID 8125789. 
  15. Kuttesch JF, Parham DM, Kaste SC, Rao BN, Douglass EC, Pratt CB (1995). "Embryonal malignancies of unknown primary origin in children.". Cancer. 75 (1): 115–21. PMID 7804965. 
  16. Briasoulis E, Pavlidis N (1997). "Cancer of Unknown Primary Origin.". Oncologist. 2 (3): 142–152. PMID 10388044. 
  17. Collado Martín R, García Palomo A, de la Cruz Merino L, Borrega García P, Barón Duarte FJ, Spanish Society for Medical Oncology (2014). "Clinical guideline SEOM: cancer of unknown primary site.". Clin Transl Oncol. 16 (12): 1091–7. PMC 4239766Freely accessible. PMID 25392080. doi:10.1007/s12094-014-1244-0. 
  18. 18.0 18.1 18.2 Bugat R, Bataillard A, Lesimple T, Voigt JJ, Culine S, Lortholary A, Merrouche Y, Ganem G, Kaminsky MC, Negrier S, Perol M, Laforêt C, Bedossa P, Bertrand G, Coindre JM, Fizazi K (2003). "Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002)". Br. J. Cancer. 89 Suppl 1: S59–66. PMC 2753014Freely accessible. PMID 12915904. doi:10.1038/sj.bjc.6601085. 
  19. Nystrom JS, Weiner JM, Wolf RM, Bateman JR, Viola MV (1979). "Identifying the primary site in metastatic cancer of unknown origin. Inadequacy of roentgenographic procedures.". JAMA. 241 (4): 381–3. PMID 758556. 
  20. Abbruzzese JL, Abbruzzese MC, Lenzi R, Hess KR, Raber MN (1995). "Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin.". J Clin Oncol. 13 (8): 2094–103. PMID 7636553. doi:10.1200/JCO.1995.13.8.2094. 
  21. Karsell PR, Sheedy PF, O'Connell MJ (1982). "Computed tomography in search of cancer of unknown origin.". JAMA. 248 (3): 340–3. PMID 7087129. 
  22. Olson JA, Morris EA, Van Zee KJ, Linehan DC, Borgen PI (2000). "Magnetic resonance imaging facilitates breast conservation for occult breast cancer.". Ann Surg Oncol. 7 (6): 411–5. PMID 10894136. 
  23. Molina R, Bosch X, Auge JM, Filella X, Escudero JM, Molina V; et al. (2012). "Utility of serum tumor markers as an aid in the differential diagnosis of patients with clinical suspicion of cancer and in patients with cancer of unknown primary site.". Tumour Biol. 33 (2): 463–74. PMID 22161237. doi:10.1007/s13277-011-0275-1. 
  24. Tytor M, Olofsson J (1986). "Cervical lymph node metastases with occult primary.". Clin Otolaryngol Allied Sci. 11 (6): 463–7. PMID 3815873. 
  25. Mousseau M, Schaerer R, Lutz JM, Ménégoz F, Faure H, Swiercz P (1991). "[Hepatic metastasis of unknown primary site].". Bull Cancer. 78 (8): 725–36. PMID 1932839. 
  26. Lefebvre JL, Coche-Dequeant B, Van JT, Buisset E, Adenis A (1990). "Cervical lymph nodes from an unknown primary tumor in 190 patients.". Am J Surg. 160 (4): 443–6. PMID 2221252. 
  27. Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Pentheroudakis G; et al. (2015). "Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.". Ann Oncol. 26 Suppl 5: v133–8. PMID 26314775. doi:10.1093/annonc/mdv305. 
  28. 28.0 28.1 28.2 28.3 28.4 Briasoulis E, Tolis C, Bergh J, Pavlidis N (2005). "ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP)". Ann. Oncol. 16 Suppl 1: i75–6. PMID 15888766. doi:10.1093/annonc/mdi804. 

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