Paraneoplastic conditions

Paraneoplastic dermatoses are a group of skin conditions that have strong associations with internal malignancies. They often precede, but can follow the diagnosis of malignancy. Cutaneous findings resulting from the entry of tumour cells into the skin are not considered paraneoplastic dermatoses.

This chapter is set out as follows:

The criteria for paraneoplastic conditions are:

• The tumour and cutaneous changes develop over a similar period of time and follow a parallel course
• A specific type of neoplasia occurs with the paraneoplasia
• The dermatosis is rare in the general population, and may be recalcitrant to treatment
• There is a high frequency of association between skin reaction and tumour

For the purpose of this website, this chapter is divided as follows:

• Conditions (and signs) strongly associated with malignancy 
• Conditions with variable malignant association - mainly haematological
• Conditions with variable malignant association - others

Conditions (and signs) strongly associated with malignancy

Malignant acanthosis nigricans

• Differs to typical acanthosis nigricans (AN) in that lesions arise more suddenly, are more extensive and severe. The mucosa, palms and soles are much more frequently involved, and papillomatous thickenings around the lips and eyes may be the presenting feature

• The vast majority of cases of malignant AN are secondary to adenocarinoma of the stomach, but other malignancies sometimes found include other GI tract tumours, lung, uterus, ovaries, and urinary tract

Tripe palms (syn. acanthosis palmaris, acquired pachydermatoglyphia)

• ​Presents with yellowish, velvety, diffuse palmar hyperkeratosis, with accentuated dermatoglyphic patterns, leading to a rough appearance that resembles the intestinal villosities, which explains the term tripe palms

• Neoplastic processes have been reported in 90% of cases, with gastric and lung cancer accounting for 50% of tumours. Less commonly associated malignancies include head and neck tumours, and tumours of the genitourinary tract and breast

Basex's acrokeratosis paraneoplastica

• ​Features similar to psoriasis. Three stages have been described:
• Stage 1: characterised by poorly defined psoriasiform plaques involving the ears (helices), nose, fingers, and toes. A painful paronychia develops with no evidence of bacterial or fungal infection. Nail changes include dystrophy, horizontal and vertical ridging (75%), subungual hyperkeratosis, and nail plate atrophy 

• Stage 2: characterised by involvement of larger and more proximal cutaneous regions; a palmoplantar keratoderma with central clearing; and there may be involvement of the cheeks

• Stage 3: characterised by involvement of the legs, knees, thighs, and arms

• Associated with squamous cell carcinoma of the upper aerodigestive tract (oral cavity, pharynx, larynx, oesophagus) 

Erythema gyratum repens

• Presents as a widespread, serpiginous, polycyclic and pruriginous erythema, which is desquamative around the edges and fast-growing, about 1 cm per day, producing concentric figures that resemble a wood surface

• 80% of cases are associated with internal malignancy, most commonly the lung. 20% of cases appear to have no cause 

Necrolytic migratory erythema

• Necrolytic migratory erythema (NME) is, in most cases, associated with a glucagonoma, which is a slow growing malignant tumour predominantly arising in the α‐cells of the pancreas. The triad of an unusual dermatosis, recent‐onset diabetes and weight loss should trigger consideration of NME, although cutaneous manifestations may precede the diagnosis of glucagonoma by several years

• The lesions of NME wax and wane in a cycle of about 10 days, beginning with an erythematous patch that blisters centrally, erodes, and then crusts over and heals with hyperpigmentation. The lesions are typically annular or polycyclic and may become confluent 

Paraneoplastic pemphigus

• The pemphigus family is a rare group of immunobullous conditions affecting skin and/or mucous membranes

• Paraneoplastic pemphigus (PNP) occurs in association with malignancy, and is characterised by painful blisters and denuded areas of the mouth, lips, oesophagus and skin

• PNP has been described most commonly in association with B-cell lymphoproliferative disorders, but also thymoma, sarcoma and various other carcinomas

Carcinoid syndrome

• This syndrome describes the manifestations of some carcinoid tumours - flushing, bronchoconstriction, gastrointestinal hypermotility, and cardiac disease. Carcinoid tumours are neuroendocrine tumours derived from a primitive stem cell that may differentiate in to any of various adult endocrine-secreting cells, producing peptides, hormones, and neurotransmitters

• Paroxysmal flushing is present in virtually all cases; episodes typically last a few minutes and may be more widespread than other causes of flushing, sometimes involving the whole body. Nearly 75% of carcinoid tumours are gastrointestinal (especially involving the appendix and ileum), 25% are bronchial, and a small number arise at other sites including the larynx, pancreas, gallbladder and ovary. Flushing is described as varying according to the site of the neoplasm. The most common midgut tumours (appendix and ileum) are associated with a gradual development of fixed cyanotic erythema in the flushing distribution, whereas foregut tumours (stomach, pancreas, lung) are associated with a brighter pink flush

Florid cutaneous papillomatosis (FCP)

• Is characterised by the rapid onset of numerous warty papules on the trunk and the extremities that are clinically indistinguishable from viral warts. A skin biopsy is required to make the diagnosis

• It is usually associated with gastric adenocarcinoma

The Leser-Trélat sign

• ​Is characterised by the abrupt appearance of large numbers of seborrhoeic keratoses, often with an inflammatory base, that rapidly increase in size and number

• The association with malignancy, usually of the stomach or colon, remains controversial

Conditions with variable malignant association - mainly haematological

Numerous conditions are associated with the Myelodysplastic syndrome (MDS), monoclonal gammopathy of undetermined significance (MGUS), and haematological malignancies. Patients in these groups require monitoring (twice yearly) of FBC, immunoglobulins & plasma electrophoresis looking for abnormalities and also trends, with a low threshold for haematological referral and bone marrow biopsy. 

Neutophilic dermatoses 

There are many types of neutrophilic dermatoses. Two of the best described are:

• Sweet's syndrome 
• A neutrophilic dermatosis, characterised by fever, peripheral neutrophil leucocytosis and the acute onset of painful, erythematous papules, nodules or plaques 
• 25% of cases are associated with malignancy, which is more likely if the rash affects the face
• Most tumours are haematological, especially AML, however a few are solid tumours, especially genitourinary, breast or gastrointestinal. Sweet's syndrome may be the initial manifestation of malignancy or may precede the diagnosis by months or years. Additional episodes of Sweet’s may also be an indication of cancer recurrence

• Pyoderma gangrenosum
  
  • A neutrophilic dermatosis that manifests initially as a papule, pustule or nodule, but this soon develops in to a painful ulcer (or ulcers), which enlarges rapidly (normally > 1 cm per day), with an irregular, undermined, purple-blue edge
    
  • 50-70% of cases have an underlying cause, approximately equally divided between three groups:
    • Inflammatory bowel disease (IBD), especially ulcerative colitis
    • Haematological conditions, especially myeloid leukaemia's. Also myelodysplasia and monoclonal gammopathy. Lesions on the trunk have a greater association with malignancy
    • Inflammatory arthritis such as rheumatoid arthritis

Eosinophilic dermatoses 

• The main clinical pattern of eosinophilic dermatoses associated with haematological malignancies are a bullous pemphigoid-like pattern, an insect bite-like pattern, and an eosinophilic cellulitis-like pattern

Primary, and myeloma-associated, systemic amyloidosis

• This group of amyloidosis originates in the bone marrow and is sometimes referred to as amyloid L chain type (AL) amyloidosis

• The signs and symptoms are generally non-specific and include itch, fatigue, weight-loss, shortness of breath, a hoarse voice, numbness and tingling

• Petechiae, purpura and ecchymoses are the most common skin findings. The face, especially around the eyelids and the periorbital skin (pinch purpura or raccoon eyes sign), and flexural regions are the most commonly affected sites. Haemorrhagic blisters may form following skin trauma such as pinching

• The most characteristic skin lesions consist of waxy papules, nodules, or plaques. Flexural sites such as the eyelids, retroauricular region, neck, axilla, inguinal and anogenital region are the predominant sites. Plaques may coalesce to form large tumefactive lesions

• The majority of cases are of unknown cause (primary systemic amyloidosis), although it can be secondary to myeloma

Scleromyxoedema

• A form of lichen myxoedematosus characterised by a generalised papular eruption on a sclerodermoid background

• Lesions are very numerous, presenting as 2–3 mm, firm, waxy, closely spaced, dome-shaped or flat‐topped papules, often arranged in a strikingly linear pattern. The skin is shiny and thick (ie sclerodermoid) and may be red-brown in colour. The glabella typically is involved with deep longitudinal folding. Deep furrowing can also be evident on the trunk, shoulders and limbs

• Scleromyxoedema is nearly always associated with haematological disease, especially monoclonal gammopathy, and also myeloma, lymphoma and leukaemia

Conditions with variable malignant association - others

 Palmoplantar keratoderma

• This is a term used to define a marked thickening of the skin on the palms and soles, either as a focal entity, or diffuse

• Keratoderma can be inherited, acquired, and rarely, paraneoplastic:
  • The Howell-Evans' syndrome - this is inherited and should be suspected from a family history of oesophageal carcinoma 
  • Acquired diffuse palmoplantar keratoderma has occasionally been associated with carcinoma of the bronchus 

Acquired ichthyosis

• The ichthyoses are a group of skin conditions characterised by a diffuse, generally uniform and persistent pattern of scaling. Most are inherited

• Acquired ichthyosis arises in adult life, and is rare. It is occasionally associated with malignancy, of which Hodgkin lymphoma account for 70-80%  

Dermatomyositis

• A rare, multisystem disorder mainly affecting the skin, muscle and blood vessels in which characteristic erythematous and oedematous changes in the skin are usually associated with muscle weakness and inflammation

• Clinical features include:
• A purple-red ‘heliotrope’ facial rash, affecting the eyelids, upper cheeks, forehead and temples, frequently associated with oedema of the eyelids and periorbital skin
• Gottron's papules - these are small red-purple, flat-topped papules, found on the extensor surfaces of the metacarpophalangeal and interphalangeal joints and around the nailfolds (they can also affect the feet and other extensor surfaces)

• Dermatomyositis in adults has been linked with an increased likelihood of developing cancer, particularly of the cervix, lungs, pancreas, breasts, ovaries and gastrointestinal tract, and non-Hodgkin’s lymphoma

• The relative risk of malignancy is 2.2 at diagnosis increasing to 4.8 five years later. The risk appears to higher in males, with increasing age, and with positive Jo-1, TIF1 or MDA5 antibodies. One study demonstrated a 17-fold increased risk of ovarian cancer 5 years after presentation

Pityriasis rotunda

• ​Characterised by multiple, well-defined, circular, hyper or hypopigmented, scaly macules that are typically found on the trunk, buttocks and thighs. It is rare in North America and Europe, and more common among Japanese, S. African Bantu, and West Indian black individuals 

• One-third of patients have an underlying disease, including tuberculosis, leprosy, liver and lung diseases. 5% of cases are paraneoplastic, the neoplasms include hepatocellular, gastric and oesophageal carcinoma, prostate cancer, chronic lymphocytic leukaemia and multiple myeloma

Multicentric reticulohistiocytosis

• A rare histiocytic proliferative disorder, first described in 1954 by Goltz and Laymon, in which joints, skin and mucous membranes are affected

• Lesions are non-tender, firm, brown-yellow papules, varying in size from 1-10 mm and can coalesce to form plaques with a cobblestone surface - this may give a characteristic “coral-bead” appearance, which is considered pathognomonic. The nodules grow slowly, and rarely ulcerate

• Other organs may be involved and 20% of patients have an internal malignancy. The most common tumours are gastric, ovarian, breast and uterine carcinomas, myeloma, melanoma and lymphoma

Extramammary Paget's disease (EMPD)

• EMPD is an uncommon intraepithelial adenocarcinoma composed of neoplastic cells showing glandular differentiation

• EMPD affects the perianal, and genital/groin sites

• Lesions of EMPD are characterised by a well-defined and slightly elevated edge, which encloses a pink-red area of skin. The surface can have erosions, crusts and scale

• Approximately 25% of cases of EMPD are a secondary phenomena with the primary tumour arising in deeper appendageal structures of the dermis or from organs with a contiguous epithelial lining eg perianal EMPD is associated with adenocarcinoma of the gastrointestinal tract, and genital-groin EMPD is associated with genitourinary malignancy 

Appendageal tumours

• Certain appendageal tumours are associated with malignancy - Muir-Torre syndrome, Birt-Hogg-Dube syndrome, Brooke-Spiegler syndrome, Cowden syndrome (syn. multiple hamartoma syndrome), Gardner syndrome

A number of other conditions, including a group of genodermatoses, and occasionally some cases of panniculitis, vasculitis, erythroderma, and secondary erythromelalgia can be associated with paraneoplastic syndromes.