Fuller Albright first proposed that tumors could inappropriately secrete hormones, thereby causing corresponding endocrine symptoms. In 1941, he discovered that hyperphosphatemia in kidney cancer was due to the secretion of PTH by the cancerous tissue. Later, Liddle (1969) introduced the term "ectopic hormone syndrome" to describe the endocrine symptoms caused by tumors. However, the term "ectopic" is actually quite inappropriate, because the hormones secreted by tumor cells are also secreted in small amounts by the same tissue under normal conditions. For example, when lung tissue cells, which normally secrete small amounts of ACTH, become cancerous, they produce more ACTH. True "ectopic secretion" is very rare, but this term has been widely accepted. On the other hand, some active substances secreted by tumors that cause endocrine symptoms do exhibit hormone-like effects but have no natural hormone counterparts (e.g., NSILA, discussed later). Therefore, such syndromes can more accurately be broadly referred to as "ectopic endocrine syndrome."

Ectopic endocrine syndrome is commonly seen in elderly patients. The endocrine manifestations may appear in the early stages of the tumor or even precede tumor symptoms, making them potential early indicators of certain tumors. The peptide hormones or hormone-like substances can serve as serological markers. Endocrine manifestations may also occur in the advanced stages of tumors, necessitating attention during diagnosis or differential diagnosis.

bubble_chart Etiology

The pathogenesis of this syndrome has not been fully elucidated, and the following hypotheses currently exist.

1. Loss or translocation of suppressor genes: In normal cells, DNA coding is regulated by suppressor genes, with only relevant DNA being normally activated to transcribe into mRNA and express normal gene products. However, when malignant cells form, suppressor genes may be lost or translocated during mutation, leading to the derepression of normally suppressed DNA coding and the expression of corresponding products (including hormones).
2. APUD cell theory: Tumors capable of secreting ectopic polypeptide hormones all originate from ectodermal neural crest stem cells. These cells possess the characteristic of amine and/or amine precursor uptake and decarboxylation (APUD), hence the name APUD cells. They inherently carry genes capable of expressing various peptide hormones and biologically active amines, but under normal conditions, these are present in minimal amounts, with the corresponding genes in a suppressed state. These non-endocrine cells can secrete trace amounts of hormones under normal conditions, which can be regarded as remnants of the autocrine or paracrine signaling systems of lower organisms. With biological evolution, endocrine glands have differentiated into distinct tissues with corresponding regulatory systems. Non-endocrine cells have also lost their hormone-secreting functions during differentiation, with the relevant genes remaining suppressed. Once cancerous cells form, they may revert to primitive autocrine characteristics, producing large quantities of corresponding peptide or amine active substances.

bubble_chart Diagnosis

With the advancement of laboratory methods, it is now possible to diagnose cases that do not yet exhibit clinical symptoms of ectopic endocrine syndromes. The following diagnostic criteria are suitable for application in clinical or research work:

1. Tumor patients present with a syndrome of excessive hormone secretion or elevated hormone levels in plasma and/or urine, with levels proportional to the tumor's blood supply. Hormone concentrations in venous blood are significantly increased when measured from the tumor's supplying artery or venous blood.
2. The abnormally secreted hormones are not regulated by internal factors and cannot be suppressed by supraphysiological doses of exogenous hormones (non-suppressible).
3. Hyperfunction of the corresponding normal endocrine gland can be ruled out.
4. After anticancer treatment (tumor resection, radiotherapy, or chemotherapy), the related endocrine syndromes and hormone levels decrease. If the tumor recurs or metastasizes, the associated syndromes and abnormalities in generation and transformation may reappear.
5. The tumor tissue is confirmed to contain the hormone or its corresponding mRNA and can express it.