Paraneoplastic syndrome - when cancer is not the only problem

Introduction

Cancer is not always just a "local" problem, at the site where it initially arose or at the site where it has spread. Sometimes a malignant disease sets off a chain of events in the body that go beyond the tumor itself and its metastases. Paraneoplastic syndromes are one of the most intriguing and complex examples of such an effect – a manifestation where a tumor, from a distance, triggers an autoimmune reaction or produces substances that disrupt the normal function of various organs and systems in the body. Although relatively rare, their timely recognition can save lives, help in the earlier detection of tumors or improve the quality of life in advanced disease.

What exactly is a paraneoplastic syndrome?

Paraneoplastic syndromes are a set of symptoms and clinical signs that arise as an indirect consequence of a malignant tumor, and not due to its local presence, pressure, growth or metastases.

The most common consequences are:

·         so-called Ectopic (we could translate as not occurring in the usual or “normal” place in the body) production of hormones and other active substances by tumor cells (meaning that the tumor produces substances that are normally produced by completely different tissues)

·         Autoimmune response, where the defense system mistakenly attacks its own tissues, thinking that they are foreign tissues or tumor cells

·        Cytokine dysregulation – imbalances of substances that normally regulate inflammation and the immune system’s response

These syndromes can affect almost every organ system: neurological (nerve), endocrine (hormonal), muscular, bone, blood, skin and others.

When do they occur?

Paraneoplastic syndromes can occur at all stages of a malignant disease:

·          Before cancer is diagnosed (sometimes as the first sign)

·          During the course of the disease, even when the tumor appears stable

·          After treatment, and even when the tumor cannot be found by conventional diagnostic methods such as radiological imaging

·         As a sign of disease recurrence (relapse)

Interestingly, some of these syndromes may disappear after treatment of the tumor, confirming their association with the underlying disease. Although successful treatment of the underlying cancer is the primary goal, paraneoplastic syndromes, which are a set of symptoms caused by the cancer, can sometimes persist due to the long-term effects of the immune response or other mechanisms. In such cases, a detailed workup is necessary so that the condition is not mistakenly characterized as disease activity.

How common are they?

The exact frequency is difficult to estimate because it is believed that many cases of paraneoplastic syndromes go unrecognized (often the symptoms are considered symptoms of the disease itself, the treatment, or something else). It is estimated that about 7–15% of all oncology patients develop some form of paraneoplastic syndrome over time. They most often occur with small cell lung cancer (a very aggressive form of lung cancer that accounts for about 15–20% of lung cancer cases). They can also be seen with breast cancer, ovarian cancer, and hematological diseases - lymphoma (cancer of the lymph nodes), leukemia, and myeloma

Main types of paraneoplastic syndromes

1. Hormonal (endocrinological) syndromes

·         Hypercalcemia (increased calcium in the blood)

Tumors can secrete PTHrP (parathyroid hormone-related peptide), a substance similar to a hormone that normally regulates calcium levels. This causes elevated calcium in the blood, which can lead to fatigue, nausea, constipation, confusion, and in severe cases, coma. Common causes are: lung cancer (squamous cell type), breast cancer, kidney cancer, myeloma.

·         Cushing's syndrome

Tumor cells can produce ACTH (adrenocorticotropic hormone), which normally stimulates the adrenal glands to produce the hormone cortisol. Of course, in this case, excessive amounts of cortisol are produced, which causes weight gain, muscle weakness, high blood pressure, high blood sugar and mood swings. Most common in: small cell lung cancer.

·         SIADH – syndrome of inappropriate ADH secretion

The tumor produces too much ADH (antidiuretic hormone, which regulates water retention in the body). The result is water retention and a decrease in sodium in the blood (hyponatremia), which can cause weakness, headache, confusion and seizures. Again most common in: small cell lung cancer.

·          Hypoglycemia

The tumor can secrete IGF-2 (insulin-like growth factor), which causes a drop in blood sugar – especially between meals. This sometimes occurs with liver tumors, pancreatic tumors, or large sarcomas.

2. Neurological and muscular syndromes

·         Lambert-Eaton syndrome

The immune system produces antibodies against calcium channels, which reduce the transmission of signals between nerves and muscles. The result is weakness, especially in the legs. Most often in: small cell lung cancer.

·         Paraneoplastic cerebellar degeneration

A rare neurological disorder caused by an abnormal immune response to cancer. It is characterized by a malfunction of the immune system that attacks the cerebellum, and often occurs before the diagnosis of cancer is made. Damage to the cerebellum causes dizziness, unsteady gait, and difficulty with speech and coordination. Antibodies such as anti-Yo, anti-Hu, or anti-Tr, which attack the nervous system, can be found in the blood. It can occur with: breast and ovarian cancer, lymphoma.

·         Limbic encephalitis

Inflammation of a part of the brain caused by the immune system attacking its own tissues – in this case the limbic system, crucial for emotions and memory. Symptoms include forgetfulness, behavioral changes, epileptic seizures. Associated with: testicular, breast, lung tumors.

·         Sensory neuropathy

Symmetrical loss of sensation, sometimes pain, tingling or burning. Anti-Hu antibodies, which attack sensory nerve cells, are often detected.

3. Skin manifestations

·         Acanthosis nigricans

Dark, velvety skin changes, usually on the neck and armpits. In adults, this can be a sign of stomach or pancreatic cancer.

·          Dermatomyositis

Rash around the eyes (so-called heliotrope rash), red changes in the joints and muscle weakness. Can be a sign of lung, ovarian, breast cancer.

·         Leser–Trélat sign

Sudden appearance of a large number of seborrheic keratoses (dark, thickened patches on the skin). It is a possible sign of digestive system cancer.

4. Hematological syndromes (related to blood)

·         Thrombophilia and Trousseau syndrome

Trousseau syndrome, also known as Trousseau's sign of malignancy or migratory thrombophlebitis, is a medical condition characterized by the development of blood clots (thrombi) that appear in various places in the body over time, often in connection with an underlying cancer, especially adenocarcinoma (glandular cell tumor). Often the first sign of pancreatic or stomach cancer.

·         Anemia, leukemoid reactions

They occur due to the tumor's effect on the bone marrow or through inflammatory substances (cytokines). The blood count may look as if the patient has an infection, although the cause is the tumor.

5. Renal and rheumatological syndromes

·         Glomerulonephritis

Damage to the glomeruli, the parts of the kidney that filter blood and produce urine, leads to protein loss in the urine, edema (swelling due to fluid accumulation), and high blood pressure. It can occur with lung cancer, breast cancer, and lymphoma.

·         Paraneoplastic arthritis and vasculitis

Joint pain, edema, and inflammation of the blood vessels are sometimes the first signs of a tumor – they are often confused with rheumatoid arthritis.

Diagnosis – when should you suspect a paraneoplastic syndrome?

Paraneoplastic syndrome should be suspected in patients with unusual symptoms that cannot be explained by known or common diseases. Particular caution is required in patients known to have a malignant disease predisposing to the development of paraneoplastic syndrome, primarily small cell lung cancer. Suspicion also applies to patients with unusual skin changes, neurological disorders without a clear cause, the appearance of multiple thrombosis sites, or sudden weakness

The work-up includes tests such as PET/CT, brain MRI, paraneoplastic antibody testing, and laboratory tests of hormone and electrolyte levels, all depending on the individual patient, symptoms, and other present diseases (especially malignant).

Treatment

Since paraneoplastic syndrome is an indirect consequence of the effects of the tumor, the most important step is to treat the malignant disease itself. Paraneoplastic syndrome symptoms often resolve after tumor surgery or successful oncological treatment such as chemotherapy, immunotherapy, or radiotherapy. If the symptoms are due to autoimmune mechanisms, corticosteroids (anti-inflammatory drugs), intravenous immunoglobulins (purified antibodies from the blood of healthy donors), plasmapheresis (cleansing the blood of harmful antibodies), and immunosuppressants (drugs that suppress the immune response, e.g. rituximab or cyclophosphamide) are used. In some patients, it is not possible to directly act on the cause of the problem, and we focus on suppressing the symptoms. For this purpose, for example, depending on the situation, calcium-lowering drugs (e.g. bisphosphonates), physical therapy, drugs for epilepsy, pain, dizziness, etc. can be used.

Conclusion

Paraneoplastic syndromes are a challenge and an opportunity - they can help in the early detection of cancer, but they can also significantly worsen the patient's quality of life if ignored. In their approach and treatment, collaboration between different specialists is crucial – oncologists, neurologists, endocrinologists, dermatologists, nephrologists...

For patients, it is important to know that a strange symptom does not necessarily mean "another disease" – sometimes it is a message from the body that something is changing and that the underlying diagnosis needs to be reassessed. It is certainly important to report any changes you notice to your doctor so that the severity of the change can be assessed and any further treatment may be needed.

The article was published in the magazine Doktor u kući.

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