Erythema gyratum repens

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Gammel's disease.

Historical Perspective

• In 1925 Rothman wrote a comprehensive review on the subject of cutaneous manifestations in patients with malignant tumors and since then cases were added to proof for the relationship between internal neoplasm and some skin lesions.
• In 1953, the dermatologist, Dr. John A Gammel who was trained to link bizarre or recalcitrant dermatoses to internal diseases was the first one who described and labeled Erythema Granulatum Repens in a 55-year-old patient who had been complaining of pruritic scaly skin eruption and found few months later to have poorly differentiated adenocarcinoma
• Up to 1992, there were only 49 cases in the literature, 41 of which (84%) were associated with a neoplasm
• EGR is associated with internal malignancy in 82% of cases. However, between 1990 and 2010, data was collected from the medical records of patients form dermatology department in University of Genoa and from databases as pubmed and medline, the conclusion of this literature review was that EGR is no longer considered as an obligate paraneoplastic syndrome. More than expected cases of EGR were found with no neoplasm association

Classification

• There is no established system for the classification of EGR. However, we can classify EGR as:
  • Paraneoplastic EGR
  • Non-paraneoplastic EGR could be:
    • Idiopathic EGR
    • EGR-like eruptions (different dermatologic lesions that mimic EGR)
    • EGR with concomittant skin disease as:
      • pityriasis rubra pilaris, psoriasis, ichthyosis, CREST, rheumatoid arthritis, tuberculosis, bullous pemphigoid, linear IgA disease, and hypereosinophilic syndrome
    • Drug-induced EGR examples are:
      • Azathioprine with type I autoimmune hepatitis
      • Interferon given for hepatitis C virus–related chronic hepatitis

Pathophysiology

• The cause of EGR has not been identified.
• Many theories suggest that EGR is due to immunologic mechanisms. The immunologic mechanism theory is evidenced by the observed immunofluorescence patterns of IgG, C3, and C4 at the basement membrane:
  • Theory 1 the tumor induces antibodies that cross-react with the basement membrane of skin
  • Theory 2 the tumor produces polypeptides that bind skin antigens and render them immunogenic 
  • Theory 3 deposition of tumor antigen-antibody complexes onto the basement membrane causes reactive dermatitis seen in EGR

Causes

• The cause of erythema gyratum repens has not been identified.
• Different theories suggest that EGR etiology is stemmed from an immunologic reaction.
• There is strong evidence of the association of EGR and systemic neoplasm proofed by the improvement of the skin lesions after the neoplasm treatment. However, that association doesn't mean causation.

Differentiating Erythema Gyratum Repens from Other Diseases

• EGR has a narrow differential diagnosis. It has to be differentiated from Reactive gyrate erythematous eruptions, such as:
  • Reactive (figurate or gyrate) erythemas that are associated with malignancy include:
    • Erythema annulare centrifugum (EAC)
    • Necrolytic migratory erythema (NME)
  • Reactive (figurate or gyrate) erythemas that are not associated with malignancy include:
    • Erythema marginatum rheumaticum
    • Erythema chronicum migrans   
    • Familial annular erythema
    • The carrier state of chronic granulomatous disease
    • Subacute cutaneous lupus erythematosus
    • Neonatal lupus erythematosus

Reactive (figurate or gyrate) erythemas that are associated with malignancy
	EGR	EAC	NME
Reactive erythema (figurate or Gyrate)	Yes	Yes	Yes
Associated malignancy?	More closely associated (84%) Not obligatory paraneoplastic syndrome	Only a minority of patients	Can be the first presenting symptom in 70% of patients with glucagonoma syndrome (2) NME is the hallmark of gluconoma (3) Obligatory paraneoplastic syndrome (2)
Commonly associated neoplasm	Lung cancer     Esophageal cancer    Breast cancer Metastatic cancer with an unknown origin Cervical, stomach, and pharyngeal cancer (less common)	No particular type of cancer appears to predominate    Mutinous ovarian carcinoma    Bronchial carcinoma    Myeloma	Mainly pancreatic neuroendocrine tumors (PNETs) (glucagonoma)
Other association	Tuberculosis CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia).	Infections Allergic reactions to drugs	No other association but it can be misdiagnosed as contact dermatitis or intertrigo, inverse psoriasis, zinc deficiency, and other nutritional deficiencies
Skin lesion description	Migratory annular and configurate erythematous bands that form concentric rings   Wood grain scaly appearance scale follows the leading edge of the bands Eruption migrates more rapidly, 1cm/d    Cover the trunk and proximal extremities, sparing the hands, feet, and face. Can eventually involve the face	Migratory annular and configurate erythematous or polycyclic lesions Urticarial in appearance," ringed, arcuate figures" Eruption migrate at a slower rate (2 -3 mm/d) reaching up to 10 cm in diameter with central clearing. Cover only a small percentage of the total body surface	Circinate erythema with areas of necrosis and sloughing (3) Crusted  Erythematous scaly plaques with centrifugal growth Spontaneous exacerbation and remission periods without knowing what the trigger is Perineum, distal extremities, lower abdomen, and face are the most commonly affected sites.
First named/described by	Gammel in 1952	Darier 1916	Becker et al. in 1942 was the first to describe the association Wilkinson in 1973 was the first who named it.
Incidence	Very rare	Uncommon but not rare	Rare paraneoplastic dermatosis Studies in the US showed only 2,705 cases of pancreatic neuroendocrine tumors in a period of 28 years, with glucagonomas in only 1.3% of these neoplasms Combined with glucagonoma syndrome, has an estimated global incidence of 1 case per 20 million people (3)
Demographics	Caucasian Male: female ratio is 2: 1 Average age was 62 years.	No tendency for EAC to favor any age, race, or sex.
Subgroups		Deep: Firm border, rarely pruritic, no scales Superficial: indistinct scaly border , usually pruritic,
Histopathology	Nonspecific moderate perivascular lymphohistiocytic infiltrate    Mild focal spongiosis parakeratosis    Eosinophils and melanophages have also been reported in the dermal infiltrate	Deep form: Mononuclear, perivascular infiltrate in the middle and lower portions of the dermis (coat sleeve-like configuration) Infiltrate is primarily of lymphocytes, but eosinophils are occasionally present Extravasation of erythrocytes is associated with endothelial swelling    No epidermal changes    Superficial: more non-specific slight superficial perivascular lymphohistiocytic infiltrate    Focal parakeratosis and mild spongiosis with microvesiculation	Paleness and spongiosis of the upper layer of the epidermis. A perivascular lymphocytic and histiocytic infiltrate Necrotic keratinocytes are common and can lead to erosions, crusting and scaling
Lab finding	No specific laboratory changes Eosinophilia has been reported Decreased T lymphocytes and increased B lymphocytes were observed in an EGR patient with increased luteinizing hormone and follicle-stimulating hormone as well as decreased serum levels of C3    Normal percentages of B and T lymphocytes and normal T-cell function were reported in an EGR patient without cancer.	No specific laboratory changes Eosinophilia of the peripheral blood, as well as tissue, can be observed in EAC associated with a drug reaction or parasitic infection    Decreased T lymphocytes and increased B lymphocytes	increased glucagon level (3)
Other evaluation	Extensive evaluation for possible cancer CBC,CMP, imaging as CT chest or abdomen EGR patients with underlying malignancies had cancers associated with tobacco abuse.	Evaluation for possible infection or drug reaction (prescribed and non-prescribed) complete blood count, urinalysis, and routine serum liver and kidney function tests.	Evaluation of the associated tumor: CT or MRI abdomen Selective visceral angiography to localize the tumor Positron Emission tomography (PET) Octreotide scintigraphy
Treatment	Identification and treatment of the underlying condition (eg. resection of the tumor)	Identification and treatment of the underlying condition (eg. resection of the tumor)	Identification and treatment of the underlying condition (eg. resection of the tumor)
	Symptomatic therapy as antihistamine and corticosteroids (Not very effective)	Systemic corticosteroids for the deep form and topical corticosteroids for the superficial form Lesions of EAC, however, frequently recur following discontinuation of such treatment
Pathogenesis			Not fully clarified but attributed to zinc deficiency and hypoaminoacedemia Increased glucagon increases gluconeogesis
clinical manifistation/symptoms			weight loss, anemia, diabetes, diarrhea, and stomatitis.
Prognosis			due to the difficulty of NME recognition, and its association with glaconoma, diagnosis is usually delayed(3) NME usually resolved after the resection and treatment of the pancreatic tumor

Epidemiology and Demographics

• EGR is a rare dermatologic disease, usually associated with paraneoplastic neoplasm

Age

• The average age of onset of EGR is in the seventh decade of life (65 years old)

Gender

• The male to female ratio is 2:1

Race

• EGR commonly affects Caucasians

Risk Factors

• There are no established risk factors for EGR

Screening

• There are no screening tests for EGR.
• Screening for internal malignancy should be done immediately after EGR is diagnosed.

Natural History, Complications, and Prognosis

• The majority of patients with EGR presents with severely pruritic erythematous skin lesions that appear several months prior to the malignancy diagnosis
• If the underlying malignancy left untreated, the debilitating pruritus could persist until the patient dies
• Prognosis depends on the type of the underlying tumor and the probability of its treatment. It depends on the time of the EGR onset and the neoplasm discovery. The course and prognosis of EGR can be one of the following:
  • Complete cure of the skin eruption and pruritus after removal and treatment of the internal neoplasm
  • Temporary improvement then recurrence of the eruption (specially in cases of metastasis)
  • No effect of the tumor treatment on the course of EGR
  • Death can occur few weeks after the discovery of the malignancy, few months, or four years as in Gammel's patient.

Diagnosis

Diagnostic Study of Choice

• EGR is mainly diagnosed clinically by its characteristic skin lesions.
• It is considered as a cutaneous marker of malignancy with high specificity so physicians shouldn't miss its unique clinical skin presentation.

History and Symptoms

• The universal symptoms of EGR are:
  • Skin eruptions
  • Intense pruritus
• Other symptoms related to the associated internal malignancy are:
  • Weight loss
  • Anorexia
  • Fatigue
  • Fever
  • Many patients with EGR and malignancy had a history of tobacco smoking
  • some patients with EGR and malignancy have a family history of neoplasm

Physical Examination

• Patients with EGR can be ill-appearing and lethargic
• Thorough physical exam should be done to look for signs of malignancy as lymph node enlargements, mass, abdominal distension, shortness of breath, pleural effusion,or papilloedema.
• The rash consisting of wavy erythematous concentric bands that can be figurate, gyrate, or annular.
• The bands are arranged in parallel rings and lined by a fine trailing edge of scale, a pattern often described as “wood grained.
• The rash typically involves large areas of the body but tends to spare the face, hands, and feet and it can expand as fast as a cm a day.
• Bullae can also form from within the areas of erythema

Laboratory Findings

• There are no diagnostic laboratory findings associated with EGR.
• Eosinophilia is observed in 60% of cases
• Evaluation to exclude systemic involvement:
  • CBC, CMP, urine analysis, LFT, guaiac stool test, serum protein electrophoresis

Imaging Findings

• There are no imaging findings associated with EGR.
• Imaging of the chest and abdomen could show malignancy findings.

Other Diagnostic Studies

• Direct immunofluorescence in some cases shows patterns of IgG, C3, and C4 at the basement membrane
• The histopathologic features of EGR is non-specific.
• Biopsy specimens show the following:
  • Acanthosis, mild hyperkeratosis, focal parakeratosis, and spongiosis confined to the epidermis and superficial dermis.
  • Mononuclear, lymphocytic, and histiocytic perivascular infiltrate in the superficial plexus can also be seen
• Thorough paraneoplastic workup includes:
  • Computed tomography of thorax, abdomen, and pelvis
  • Positron emission tomography/computed tomography
  • Upper and lower gastrointestinal endoscopy
  • Tumor markers
  • Blood tests including lactate dehydrogenase and QuantiFERON to exclude tuberculosis.

Treatment

Medical Therapy

• There is no treatment for EGR; the mainstay of therapy is supportive care and treating the underlying condition
• Various dermatologic and immunosuppressive therapies have been used to treat EGR.
• Systemic steroids are frequently ineffective.
• Topical steroids, vitamin A, and azathioprine have also failed to relieve skin manifestations.
• Improvement of EGR, and its associated intense pruritus depends on recognition and treatment of the underlying malignancy.
• Chemotherapy can be used to treat the internal malignancy.

Surgery

• Surgical resection of the internal tumor could be recommended as part of the management of EGR.

Prevention

• There are no primary preventive measures available for [disease name].