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]

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%.

Cancer of unknown primary origin was first discovered in the 1980s and was based solely on imaging studies.

Cancer of unknown primary origin may be classified based on light microscopy of the tissue biopsy into 4 groups including adenocarcinomas, squamous cell carcinomas, poorly differentiated tumors, and carcinomas with neuroendocrine differentiation.

The exact pathogenesis of cancer of unknown primary origin is not fully understood. Several studies noted consistency between metastatic cancer of unknown primary and metastases with known primary origins based on chromosomal abnormalities and over expression of several genes.

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.

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.

The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide. Patients of all age groups may develop cancer of unknown primary origin. In most cases cancer of unknown primary origin affects men and women equally. There is no racial predilection to cancer of unknown primary origin.

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

There is insufficient evidence to recommend routine screening for cancer of unknown primary origin.

Early clinical features include fatigue, weight-loss, and loss of appetite. 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.

The diagnosis of cancer of unknown primary origin is made when the following diagnostic criteria are met: tissue biopsy indicating malignancy and all known primary origins of cancer are ruled out. The initial approach may vary on a case-by-case basis; however, the diagnosis is made after histopathological and clinical testing.

The majority of patients with cancer of unknown primary origin are asymptomatic.

There are no remarkable findings in the physical examination of CUP patients; the presentation is variable and depends on many factors including the primary tumor’s origin and extent of organs involved.

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.

A chest x-ray is a prerequisite in the diagnosis of cancer of unknown primary; however, its value is of less significance when it comes to locating the primary tumor or differentiating it from a metastatic lesion.

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.

CT scan may be helpful in the diagnosis of cancer of unknown primary origin.

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

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

Other diagnostic studies for cancer of unknown primary that may help establish the origin of the tumor include tumor markers, diagnostic tonsillectomy, and gastrointestinal endoscopy.

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 clinical and pathological subsets.

Surgical intervention is not recommended for the management of cancer of unknown primary origin.

There are no primary preventive measures available for 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]

Cancer of unknown primary origin was first discovered in the 1980s and was based solely on imaging studies.

• Cancer of unknown primary origin was discovered in the 1980s.
• In the beginning, cancer of unknown primary was defined based on imaging results and only few empirical therapy options were available.^[1]

• Between 1980 and 1990, the definition of cancer of unknown primary origin was based solely on imaging and treatment was limited to few empirical therapies.
• From 1990 to 2000, improvement in imaging techniques and immunohistochemical testing aided in the diagnosis of CUP. This time range also saw the rise of empirical therapy in treating CUP.
• In 2000, the emergence of tissue-of-origin molecular profiling, provided a more successful site-directed therapy especially when used with immunohistochemical testing
  • Hence, the years 2000-2010 realized an increase in tailored therapy models.^[2]

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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]

The exact pathogenesis of cancer of unknown primary origin is not fully understood. Several studies noted consistency between metastatic cancer of unknown primary and metastases with known primary origins based on chromosomal abnormalities and overexpression of several genes.

• 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 or more of the following theories:^[1]
  • 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.^[1]

The factors that keep the primary site of CUP hidden have not yet been identified.

Several studies noted consistency between metastatic cancer of unknown primary and metastases with known primary origins based on chromosomal abnormalities and overexpression of several genes including:

• Bcl2^[2]
  • Bcl-2 expression was seen in 65% of tumors
  • It was found to be overexpressed in 40% of tumors
• p53^[2]
  • Expression of p53 was detected in 70.2% of tumors
  • It was found to be overexpressed in 53% of tumors
• C-myc^[3]
  • 96% of the tumors studied showed positive immunoreactivity for c-myc
• Ras^[3]
  • 92% of the tumors studied showed positive immunoreactivity for Ras
• C-erbB-2^[3]
  • 65% of the tumors studied showed positive immunoreactivity for c-erbB-2

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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]

The cause of cancer of unknown primary origin has not been identified.

• The cause of cancer of unknown primary origin 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.^[1][2]

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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]

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 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:^[1]

• Incidentaloma
• Anemia
• Tuberculosis
• Multiple myeloma

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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]

The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide. Patients of all age groups may develop cancer of unknown primary origin. In most cases cancer of unknown primary origin affects men and women equally. There is no racial predilection to cancer of unknown primary origin.

• The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide.^[1][2]
• Cancer of unknown primary origin is common, and it accounts for 3–5% of all malignant epithelial tumors.^[3]
• Cancer of unknown primary origin is the fourth most common cause of cancer-related death.^[1]

• 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.^[4]

• Cancer of unknown primary origin affects men and women equally except for squamous cell carcinomas where males are affected twice as frequently as females.^[5]

• There is no racial predilection to 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]

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

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

• The risk factors are based on the primary origin of the tumor.

For more information on risk factors of colorectal cancer, click here.

For more information on risk factors of ovarian cancer, click here.

For more information on risk factors of prostate cancer, click here.

For more information on risk factors of breast cancer, click here.

For more information on risk factors of pancreatic cancer, click here.

For more information on risk factors of gastric cancer, click here.

For more information on risk factors of lung cancer, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

There is insufficient evidence to recommend routine screening for cancer of unknown primary origin.

There is insufficient evidence to recommend routine screening for cancer of unknown primary origin.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Early clinical features include fatigue, weight-loss, and loss of appetite.

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.

Cancer of unknown primary presents differently depending on the organs affected by the metastatic spread of the tumor; however, there are certain common characteristics that patients with CUP present with:^[1]

• Brief medical history without specific complaints
• Advanced metastases at time of diagnosis
• Irregular pattern of metastatic spread
• Usually with poor prognosis

Upon presentation, around 60% of patients with cancer of unknown primary have two or more affected sites.^[2]

The most common sites of metastasis in cancer of unknown origin are lymph nodes, lungs, liver, bones, and pleura.^[3]

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.^[4][5]

Sites of metastasis and prognosis differ with the types of CUPs:^[6][7][8][9]

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%

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