Occult Cancers

Occult cancer or Cancer of unknown primary origin (CUP), is a cancer that is determined to be at the advanced metastatic stage at the time of diagnosis, but this determination is established without the detection of the primary tumor that usually goes along with its metastatic satellites. (Source)  The clinical definition of CUP is a histologically confirmed metastatic cancer for which a thorough medical history, careful clinical examination, and extensive diagnostic work-up failed to detect the primary tumor. (1) Statistically, these cancers of unknown primary site (CUP) have a poor prognosis. CUP is found in about 3 to 5% of all people diagnosed with invasive cancer and carries a poor conventional prognosis in most (80 to 85%) patients. (Source)  The other 15 to 20% of patients have a relatively longer survival rate, but most still die prematurely from recurrence. (Source) CUPs account for 2-10% of the 10 most common malignancies in both sexes (2). Adenocarcinomas represent the largest proportion of CUP. (3)

Biological Mystery

For conventional oncology, these CUP remain somewhat of a biological mystery.  Histologically, metastatic tumors have the same type of tissues as the primary one. But in CUPs, not only the primary is missing but the distant tumors are heterogeneous. (4). Moreover, these tumors tend to carry a unique natural history, which includes characteristics such as early dissemination, clinical absence of a primary tumor, unpredictable metastatic pattern, and aggressive biological and clinical behaviors. (5)


CUP is characterized by masses or swellings found somewhere in the body, either by physical examination or on medical imaging performed for another indication.The disease typically develops rapidly, and metastases may occur in places in the body that are otherwise unusual. (Source)

Comprehensive physical examination is part of the process to identify a possible primary source of cancer; this should include the breasts, lymph nodes, the skin, external genitals, as well as an internal examination of the rectum and of the pelvic organs.(Source)

The location of metastases may be a clue as to the underlying source, even if this cannot be found on investigations. For instance, a woman in whom there is axillary lymphadenopathy (swelling in the lymph nodes of the armpit) it is likely that the cancer originated in the breast, and men with lymph node deposits in the mediastinum of the chest and/or retroperitoneal space of the abdomen may have a germ cell tumor. (Source)


Cancer of unknown primary source is not a single type of cancer, although researchers have attempted to find a common characteristic that explains why a cancer might spread very early without causing symptoms at the site of origin. It is generally accepted that cancer of unknown primary site exists because the primary tumor is not identified due to clinical or technological inefficiencies, or because the primary tumor  stays dormant after spreading the cancer cells that generate the metastases. Another theory is that the immune system was able to detect the primary and either shrink it to undetectable size or eliminate it entirely.

The Migratory Nature of Cancer Stem Cells

Because stem cells have a natural ability to migrate and also 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.

Forming a tumor in a tissue is not a prerequisite for stem cells to move away from that tissue. Stem cells can migrate from their natural tissue and initiate a cancer in the new site before generating a detectable tumor in their natural tissue. In this case, the primary tumor could be identified after some time. However, stem cells can also migrate away from their natural tissue without generating a cancer there. In this case, the “primary tumor” would never exist.  Or the primary was destroyed by the immune system without leaving a trace. These are a few of the factors that help to explain why the primary site is not identified even on postmortem examination in many patients with these cancers. (6)

Some studies have shown molecular features shared by cancers of unknown primary origin. For example, a recent analysis of 1806 cases of cancer of unknown primary site has shown that TP53 is the most commonly mutated gene in these cancers (7).

However, the biological events that allow the primary site to remain occult after the development of metastases remain unknown. We still do not have hard evidence of this mechanism, be it the immune system

Embryogenesis & Metastases

Recent evidence suggests that the biological events occurring during the development of metastasis are similar to those occurring during embryonic development. During embryogenesis, stem cells invade tissues, move through the interior of the embryo, travel long distances, and establish in new places to participate in the formation of living organs and tissues (8) Similarly, during metastasis, cancer cells also invade tissues, move through the lymphatic and circulatory systems, travel long distances, and establish in new tissues to form death tumors. (9)

The activation of the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) seems to play a critical role in the migration ability of both embryonic stem cells and metastatic cells. The activation of these transition programs involves profound changes in cell morphology and behavior, including changes in cytoskeleton structure, cell polarity, cell-cell contact and extracellular matrix degradation.  In this perspective, recent data suggest that EMT activation is an early event in carcinogenesis, and that there is a crosstalk among EMT activation, the acquisition of molecular and functional traits of cancer stem cells, and the inactivation or mutation of p53. (10) Furthermore, while the migration ability of stem cells is repressed after embryonic development, the migration of cancer stem cells continues unabated.

Moreover, we also know that adult or tissue stem cells can increase their migratory activity when their microenvironment is altered. Adult stem cells may also increase their migratory potential after accumulating specific DNA alterations (11) This phenomenon would also partially explain why cancer stem cells tend to migrate out of the tumor that is being bombarded by chemo and radiation. Stem cells are vital for regeneation, they play a key role in tissue damage repair. When there’s tissue injury, this activates developmental programs that upregulate adult stem cell migration to the site of damage. (12) Interestingly, tissue injury may increase cancer risk . (13)

These premalignant stem cells may also acquire additional DNA alterations and become cancer stem cells (CSCs). These cancer cells seem to play a key role in tumor metastasis. (14) It has been proposed that CSCs can be both stationary (which establish tumor growth) and mobile (which lead to tumor metastasis). (15) Theser two populations of CSCs have been found in human cancer tissues. (16)


The view of CUP may provide relief to health professionals and patients. After a detailed imaging and pathologic analysis, oncologists can tell their patients with CUP that metastasis does not always involve the formation of a primary tumor, and that their diagnostic evaluation is complete. Furthermore, if the immune system is responsible for removing the primary, then it is even more established that cancer is more a metabolic and immune disease than a genetic one.  


(1). Pavlidis N, Pentheroudakis G. Cancer of unknown primary site: 20 questions to be answered. Ann Oncol. 2010;21(Suppl 7):vii303–7. DOI: 10.1093/annonc/mdq278. [PubMed]  Most cancers typically present as a single primary tumor. Over the course of time, particularly if the primary tumor is left untreated, smaller “satellite” tumors will appear at other places in the body, a phenomenon known as metastasis. Less commonly, a metastatic tumor is found first; but in most such cases, the primary tumor can then be located via examination and testing. Rarely (3-5% of the time), the primary tumor cannot be found because it is too small, or because it has regressed due to immune system activity or other factors. In such situations a diagnosis of cancer of unknown primary origin (CUP) is made
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