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: Maria Fernanda Villarreal, M.D. [2]

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

Overview

Cancer of unknown primary origin 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 3–5% 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, and 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.[1]
  • From 1980 to 1990, the definition of unknown primary cancer was based on imaging results.[1]

Classification

  • Cancer of unknown primary origin may be classified according to pathology findings into 5 groups:[3]
  • Well and moderately differentiated adenocarcinomas
  • Poorly differentiated carcinomas
  • Squamous cell carcinomas
  • Undifferentiated neoplasms
  • Carcinomas with neuroendocrine differentiation

Pathophysiology

  • The pathogenesis of cancer of unknown primary origin is characterized by the migration of stem cells.[3]
  • Stem cells play a key role in cancer development, it has been proposed that a cancer of unknown primary site may form when deregulated, premalignant or cancerous stem cells migrate away from their natural tissue and give rise to a cancer in the new site before or without generating a tumor in their original tissue.[1]
  • Genetic mutations associated with the development of cancer of unknown primary origin, include: EGFR, KRAS, HER2, BRAF, ROS-1, ALK, AKT1, P53, and NRAS.
  • There are no characteristic findings on gross pathology of cancer of unknown primary origin.[4]
  • On microscopic histopathological analysis findings will depend on tumor histology.[3]

Causes

  • Common causes of cancer of unknown primary origin, may include:[3]
  • Squamous cell carcinomas
  • Adenocarcinomas
  • Neuroendocrine tumors
  • Mixed tumors (such as sarcomatoid, basaloid, or adenosquamous carcinomas)

Differentiating Cancer of Unknown Primary Origin from Other Diseases

  • Cancer of unknown primary origin must be differentiated from other diseases that cause sudden weight-loss, fatigue, and loss of appetite, such as:[3]

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 cancers.
  • Cancer of unknown primary origin is the fourth most common cause of cancer-related death.[5]
  • In 2009, age-adjusted incidence of cancer of unknown primary origin was estimated to be 9.5 cases per 100,000 individuals in the United States.[5]
  • In 2009, age-adjusted incidence of cancer of unknown primary origin was estimated to be 18 cases per 100,000 individuals in Australia.[5]
  • In 2009, age-adjusted incidence of cancer of unknown primary origin was estimated to be 5.3-6.7 cases per 100,000 individuals in the Netherlands.[5]

Age

  • Patients of all age groups may develop cancer of unknown primary origin.[5]
  • Cancer of unknown primary origin is more commonly observed among adults and elderly patients.

Gender

  • Cancer of unknown primary origin affects men and women equally.

Race

  • African American individuals are more likely to develop cancer of unknown primary origin.

Risk Factors

  • The most important risk factor in the development of cancer of unknown primary origin is the presence of primary cancer.[1]

Natural History, Complications and Prognosis

  • 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, and inappropriate antidiuretic syndrome, hematologic disorders, and malignant effusions.[2]
  • 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]
  • 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 there is a biopsy-proven malignancy for which the anatomic origin is unknown.[3]
  • The initial approach for cancer of unknown primary origin should include : medical history, detailed physical examination, liver and kidney function tests, complete blood count, chest radiography, abdomen and pelvis computed tomography (CT), and mammography or a prostate-specific antigen (PSA).[3]

Symptoms

  • Cancer of unknown primary origin may be asymptomatic.
  • Symptoms of cancer of unknown primary origin may include the following:[3]

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

Treatment

Medical Therapy

  • There is no treatment for cancer of unknown primary origin; the mainstay of therapy is supportive care.[7]
  • 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.[7]
  • 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[7]

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

  • 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.[7]
  • There is no evidence that follow-up of asymptomatic patients is needed.[7]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Wikipedia. https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin Accessed on April 4, 2016
  2. 2.0 2.1 2.2 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. 
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Varadhachary GR (2007). "Carcinoma of unknown primary origin". Gastrointest Cancer Res. 1 (6): 229–35. PMC 2631214Freely accessible. PMID 19262901. 
  4. 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. 
  5. 5.0 5.1 5.2 5.3 5.4 5.5 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. PMC 3778275Freely accessible. PMID 23860528. doi:10.1038/bjc.2013.386. 
  6. Fong T, Govindan R, Morgensztern D. Cancer of unknown primary. J Clin Oncol 2008 ASCO Ann Meet Proc. 2008;26 (15S:22159.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 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. PMID 15888766. doi:10.1093/annonc/mdi804. 

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