Cancer of unknown primary origin
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; Unknown primary tumors; UPT
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 5 groups: well and moderately differentiated adenocarcinomas, poorly differentiated carcinomas, squamous cell carcinomas, undifferentiated neoplasms, 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.[1] 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, inappropriate antidiuretic syndrome, hematologic disorders, and malignant effusions.[2] The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status.[1] The 5-year survival of patients with cancer of unknown primary origin is of 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.[3]
Classification
- Cancer of unknown primary origin may be classified into 4 groups initially according to light microscopy of the biopsy:[4]
- Adenocarcinomas
- Squamous cell carcinomas
- Poorly differentiated tumors
- Carcinomas with neuroendocrine differentiation
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:[4]
- Remaining small and undetectable clinically
- Disappearing after metastasizing
- Elimination by body's defense
- It remains unknown whether cancers of unknown primaries are genetically or phenotypically distinct from metastasis with known origins.[4]
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.[5][6]
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:[4]
Epidemiology and Demographics
- The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide.[7][8]
- Cancer of unknown primary origin is common, and it accounts for 3–5% of all malignant epithelial tumors.[9]
- Cancer of unknown primary origin is the fourth most common cause of cancer-related death.[7]
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.[10]
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.[11]
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 (lymph nodes are the most frequently involved in CUP).[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.[2][12]
- The 1-year survival rate of patients with cancer of unknown primary origin is less than 10%
- The 5-year survival of patients with cancer of unknown primary origin is of less than 2%
Diagnosis
Diagnostic Criteria
- The diagnosis of cancer of unknown primary origin is made when the biopsy indicates malignancy and after ruling out known primary origins of tumors.
- On microscopic histopathological analysis findings will depend on tumor histology.[4]
- The initial approach to exclude known origins of the tumor must include:[13]
- Detailed medical history
- Full physical examination
- Liver and kidney function tests
- Complete blood count
- Chest radiography
- Abdomen and pelvis computed tomography (CT)
- Mammography in females
- Prostate-specific antigen (PSA) in males
Symptoms
- Cancer of unknown primary origin may be asymptomatic.
- Symptoms of cancer of unknown primary origin may include the following:[4]
Physical Examination
- Patients with cancer of unknown primary origin usually appear cachectic.
- There are no remarkable findings in physical examination of patients with cancer of unknown primary origin.
Laboratory Findings
- Laboratory findings associated with cancer of unknown primary origin, may include:
- Elevated levels of carcinoembryonic antigen
- Elevated levels cancer antigen 125
- Elevated levels cancer antigen 19-9
- Elevated levels cancer antigen 27.29
- Elevated levels of lactate dehydrogenase
Imaging Findings
- CT scan is the imaging modality of choice for cancer of unknown primary origin.
Other Diagnostic Studies
- Cancer of unknown primary origin may also be diagnosed using immunohistochemical testing, FDG-PET, and biopsy (open and closed).[14]
Treatment
Medical Therapy
- There is no treatment for cancer of unknown primary origin; the mainstay of therapy is supportive care.[14]
- The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status.[1]
- Medical therapy for cancer of unknown primary origin should be adjusted on an individual basis and according to well-defined clinicopathologic subsets.[14]
- 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[14] | |
|---|---|
| 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. |
|
Liver, bone or multiple-site metastases of adenocarcinoma |
Low toxicity chemotherapy of palliative orientation or best supportive care are acceptable |
Surgery
- Surgical intervention is not recommended for the management of cancer of unknown primary origin.
Prevention
- There are no primary preventive measures available for cancer of unknown primary origin.[14]
- There is no evidence that follow-up of asymptomatic patients is needed.[14]
References
- ↑ 1.0 1.1 1.2 Wikipedia. https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin Accessed on April 4, 2016
- ↑ 2.0 2.1 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.
- ↑ Varadhachary GR, Raber MN (2014). "Cancer of unknown primary site". N Engl J Med. 371 (8): 757–65. doi:10.1056/NEJMra1303917. PMID 25140961.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Varadhachary GR (2007). "Carcinoma of unknown primary origin". Gastrointest Cancer Res. 1 (6): 229–35. PMC 2631214. PMID 19262901.
- ↑ 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. doi:10.1200/JCO.2000.18.3.632. PMID 10653878.
- ↑ 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.
- ↑ 7.0 7.1 Urban D, Rao A, Bressel M, Lawrence YR, Mileshkin L (2013). "Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities". Br. J. Cancer. 109 (5): 1318–24. doi:10.1038/bjc.2013.386. PMC 3778275. PMID 23860528.
- ↑ Fong T, Govindan R, Morgensztern D. Cancer of unknown primary. J Clin Oncol 2008 ASCO Ann Meet Proc. 2008;26 (15S:22159.
- ↑ Pavlidis N, Pentheroudakis G (2012). "Cancer of unknown primary site". Lancet. 379 (9824): 1428–35. doi:10.1016/S0140-6736(11)61178-1. PMID 22414598.
- ↑ 10.0 10.1 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. doi:10.1200/JCO.1994.12.6.1272. PMID 8201389.
- ↑ Muir C (1995). "Cancer of unknown primary site". Cancer. 75 (1 Suppl): 353–6. PMID 8001006.
- ↑ Altman E, Cadman E (1986). "An analysis of 1539 patients with cancer of unknown primary site". Cancer. 57 (1): 120–4. PMID 3940611.
- ↑ 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. doi:10.1038/sj.bjc.6601085. PMC 2753014. PMID 12915904.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 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. doi:10.1093/annonc/mdi804. PMID 15888766.