Paraneoplastic syndrome

Paraneoplastic syndrome refers to any sign or symptom which occurs due to hormone or cytokine production by tumour cells, or by the immune response to the malignancy. Generally, it's defined as any syndrome due to non-metastatic effects of the malignancy. Paraneoplastic syndromes are rare, occuring in somewhere from 2-20% of malignancies. They often develop before the cancer diagnosis.

It’s important to recognise these diseases because they can give earlier diagnosis of the tumour and because their prognosis is better the earlier the treatment is initiated.

Pathomechanism

There may be many underlying mechanisms. Tumour cells may produce hormones or cytokines which cause systemic or distant effects. Another mechanism is molecular mimicry, where the immune system T cells or antibodies directed against the tumour cells may mistakenly attack healthy cells.

"B symptoms" - fever, night sweats, and weight loss

Three constitutional symptoms for malignancy are especially well known. These are the so-called "B symptoms":

• Fever (38°C at least)
• Drenching night sweats (the clothes and bed sheets are soaked through by sweat)
• Unintentional weight loss >10% of weight in the last 6 months

These symptoms are called B symptoms because in the Ann-Arbor staging for Hodgkin lymphoma, the presence of these symptoms confer a worse prognosis and the tumour stage is denoted "B" if present (and "A" if absent). Despite originally being used in lymphomas, B symptoms may be present in any malignancy. The presence of B symptoms is a sign of systemic inflammation and a poor prognostic sign.

Cachexia, a severe catabolic state which leads to extreme weight loss and muscle wastage, may occur due to malignancy. It occurs due to production of TNF alpha and other cytokines by the tumour. Loss of appetite may also occur and contribue to the weight loss.

Endocrinology

Ectopic hormone production, where tumours produce hormones that are not characteristic for the tissue the tumour originates from, is one of the more common forms of paraneoplastic syndrome. The most common example is how some small cell lung cancers produce ACTH. Some hepatocellular or pancreatic carcinomas produce serotonin and bradykinin, leading to carcinoid syndrome.

Hypercalcaemia is another paraneoplastic syndrome. Normal tissues produce parathyroid hormone-related protein (PTHrP) in small amounts. Squamous cell carcinomas of the lung may produce large enough amounts of PTHrP to cause hypercalcaemia.

Hypertrophic osteoarthropathy is a condition where there is new bone formation on the distal ends of long tube-like bones like the phalanges. Arthritis and digital clubbing are also common. It occurs in non-small cell lung cancers.

Neurology

Main article: Paraneoplastic neurological syndromes

Neurological paraneoplastic syndromes are among the least common but among the most severe. They are mostly mediated by antibodies targeting healthy antigens.

Anti-NMDA encephalitis is a form of encephalitis caused by antibodies against the NMDA receptor. There is almost always an underlying ovarian teratoma or another malignancy. It mostly affects young women and is rare, affecting only 1,5 per million per year. It causes psychiatric and neurological symptoms.

Paraneoplastic cerebellar degeneration refers to subacute degeneration of the cerebellum. It has a poor response to therapy.

Dermatology

Many dermatological paraneoplastic syndromes exist, but they are rare.

Acanthosis nigricans is normally a genetic disorder characterized by formation of grey-black patches on the skin, an asymmetric velvety thickening and hyperpigmentation of skin folds. Pruritus may also occur. In may occur often before the malignancy itself becomes symptomatic. It's most common in elderly

Leser-Trélat sign refers to the sudden appearance of many seborrheic keratoses, a form of common benign skin tumour. This is associated with solid cancers, especially GI malignancies.

Other possible dermatological paraneoplastic syndromes include:

• Dermatological disorders only seen as paraneoplastic syndromes (obligate paraneoplastic disorders)
  • Erythema gyratum repens
    • Adenocarcinoma
  • Acrodermatitis psoriasiformis
    • Upper airway cancer
  • Hypertrichosis acquisita
  • Acrokeratosis bazex/acrokeratosis paraneoplastica
    • Psoriasiform lesions
    • Upper airway or GI cancer
  • Paraneoplastic pemphigus
• Dermatological orders also seen without malignancies (facultative paraneoplastic disorders)
  • Pyoderma gangrenosum
    • Painful, rapidly progressive ulcerated lesions
    • Also in Crohn disease
  • Bullous pemphigoid
  • Dermatomyositis
  • Sweet syndrome
    • Painful erythematous papules, plaques, nodules
  • Generalised herpes zoster (due to immune system depression)
  • Generalized acquired ichthyosis

Haematology

Anaemia is a common feature of malignancy. This may be due to bleeding in ulcerated tumours or due to hormones and cytokines which act on the bone marrow.

• Migratory thrombophlebitis is a condition where blood clots move around in the body and cause symptoms. It occurs in carcinomas of pancreas and lung.
• Disseminated intravascular coagulation may occur in acute promyelocytic leukaemia and prostatic adenocarcinoma
• Deep vein thrombosis

Cardiology

Nonbacterial thrombotic endocarditis, called marantic endocarditis, may occur in mucin-secreting adenocarcinomas