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Synonyms and keywords: Gammel's disease.
Erythema gyratum repens is a rare highly specific and characteristic paraneoplastic syndrome that usually affect older people. It is characterized by wood-grain scaly skin eruption with intense pruritus. The cause of erythema gyratum repens is unknown but many theories suggest immunologic etiology or toxicologic products that are released by the associated tumor. The first case of erythema gyratum repens was described by a dermatologist named Gammel in the year 1952. For many years after erythema gyratum repens original description, there was little progress in defining the pathogenesis of erythema gyratum repens. Erythema gyratum repens has no specific classification but we can classify it based on its association with an internal malignancy into para-neoplastic and non-para-neoplastic erythema gyratum repens. The most common malignancies associated with erythema gyratum repens are lung or bronchogenic cancer, esophageal cancer, and breast cancer. Erythema gyratum repens can also be associated with non-neoplastic diseases such as tuberculosis, autoimmune disorders, or CREST syndrome. Erythema gyratum repens is characterized by its pathogonomic figurate, gyrate, or annular erythematous skin eruptions. The intense pruritus can be debilitating and usually urges the patient to go to the emergency department. The microscopic histopathological features of erythema gyratum repens consist of acanthosis, focal parakeratotic, and spongiosis of the epidermis with perivascular mononuclear, lymphocytic, and histiocytic infiltrate in the superficial plexus of the dermis. Erythema gyratum repens is very rare and it mainly affects people in their seventieth decade, the male to female ratio is 2:1. Erythema gyratum repens is diagnosed clinically by its characteristic skin eruption and an urgent thorough paraneoplastic workup should be initiated to look for internal malignancies. Patients with erythema gyratum repens presents with intensely pruritic, gradually progressive, skin lesions that crawl rather than migrate from one body region to the other. It can start in the upper trunk or upper back and extends to involve the extremities sparing the face. The mainstay of the treatment of erythema gyratum repens is finding and treating the underlying malignancy. Symptomatic treatment is not very effective in relieving the pruritus and its associated pain. The management can be surgical removal of the tumor, chemotherapy, or palliative conservative management. The skin eruptions can improve completely after the removal of the underlying tumor, or can recur especially if the tumor recurred or metastasized. Patients can live a few weeks, months or up to five years depending on when and at what stage the malignancy was detected.
The association between cutaneous manifestations and systemic malignancies was first studied in 1925 by Rothman, the Hungarian investigative dermatologist, who wrote a comprehensive review on this subject and since then, cases were added to proof for the relationship between internal neoplasm and some skin lesions.
Erythema gyratum repens was first described by Dr. John A Gammel, the dermatologist, who was trained to link bizarre or recalcitrant dermatoses to internal malignancy, In 1952, in a 55-year-old patient who had been complaining of pruritic scaly skin eruption and diagnosed nine months later with poorly differentiated adenocarcinoma of the breast with metastasis to axillary lymph nodes.
In 1950, Dr. Gammel presented his case of Erythema gyratum repens before the Cleveland Dermatological Society as Erythema gyratum migrans then he changed the term to erythema gyratum repens because the eruption does not "migrate" from one place to another but "crawls" constantly in the areas involved, like "ants on an anthill".
In 1973, 45 year old man was diagnosed with erythema gyratum repens associated with metastatic, undifferentiated adenocarcinoma which was removed following a right- sided craniotomy. The patient was misdiagnosed with erythema perstans and the malignancy was discovered after 8 months of the skin manifestations.
Up to 1992, there were only 49 cases in the literature, 41 of which (84%) were associated with a neoplasm and that is why erythema gyratum repens has been considered as a paraneoplastic syndrome.
Between 1990 and 2010, a literature review was done by collecting data from the medical records of patients form dermatology department in University of Genoa and from databases as pubMed and medline, to conclude that erythema gyratum repens is no longer considered as an obligate paraneoplastic syndrome. More than expected cases of EGR were found with no neoplasm association.

# Pathophysiology
The pathogenesis of erythema gyratum repens is unclear
Many immunologic theories have been implicated in its pathogenesis.
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 erythema gyratum repens.
The gross appearance of the unique eruptions are:
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 scales, a pattern often described as wood grained.
The distinctive wood-grain appearance of the eruption is pathognomonic.
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 1 cm a day.
Bullae can also form from within the areas of erythema.
The microscopic histologic features of erythema gyratum repens are not characteristics but the following are the biopsy specimen findings that are compatible with the diagnosis:
The epidermis has thin atrophic patches with areas of acanthosis, focal parakeratotic horny layers, and spongiosis.
The dermis contains a moderate perivascular mononuclear, lymphocytic, and histiocytic infiltrate in the superficial plexus as well as mild focal spongiosis and parakeratosis.
Eosinophils and melanophages have also been reported in the dermal infiltrate.
Diffuse to moderate edema of the connective tissue can be seen.

# Historical Perspective
The association between cutaneous manifestations and systemic malignancies was first studied in 1925 by Rothman, the Hungarian investigative dermatologist, who wrote a comprehensive review on this subject and since then, cases were added to proof for the relationship between internal neoplasm and some skin lesions.
Erythema gyratum repens was first described by Dr. John A Gammel, the dermatologist, who was trained to link bizarre or recalcitrant dermatoses to internal malignancy, In 1952, in a 55-year-old patient who had been complaining of pruritic scaly skin eruption and diagnosed nine months later with poorly differentiated adenocarcinoma of the breast with metastasis to axillary lymph nodes.
In 1950, Dr. Gammel presented his case of Erythema gyratum repens before the Cleveland Dermatological Society as Erythema gyratum migrans then he changed the term to erythema gyratum repens because the eruption does not "migrate" from one place to another but "crawls" constantly in the areas involved, like "ants on an anthill".
In 1973, 45 year old man was diagnosed with erythema gyratum repens associated with metastatic, undifferentiated adenocarcinoma which was removed following a right- sided craniotomy. The patient was misdiagnosed with erythema perstans and the malignancy was discovered after 8 months of the skin manifestations.
Up to 1992, there were only 49 cases in the literature, 41 of which (84%) were associated with a neoplasm and that is why erythema gyratum repens has been considered as a paraneoplastic syndrome.
Between 1990 and 2010, a literature review was done by collecting data from the medical records of patients form dermatology department in University of Genoa and from databases as pubMed and medline, to conclude that erythema gyratum repens 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 concomitant skin disease as:
pityriasis rubra pilaris, psoriasis, ichthyosis, CREST, rheumatoid arthritis, tuberculosis, bullous pemphigoid, linear IgA disease, and hyper eosinophilic syndrome
Drug-induced EGR examples are:
Azathioprine with type I autoimmune hepatitis
Interferon given for hepatitis C virusrelated chronic hepatitis 
- Paraneoplastic EGR
- Non-paraneoplastic EGR could be: 
Idiopathic EGR
EGR-like eruptions (different dermatologic lesions that mimic EGR)
EGR with concomitant skin disease as:
pityriasis rubra pilaris, psoriasis, ichthyosis, CREST, rheumatoid arthritis, tuberculosis, bullous pemphigoid, linear IgA disease, and hyper eosinophilic syndrome
Drug-induced EGR examples are:
Azathioprine with type I autoimmune hepatitis
Interferon given for hepatitis C virusrelated chronic hepatitis 
- Idiopathic EGR
- EGR-like eruptions (different dermatologic lesions that mimic EGR)
- EGR with concomitant skin disease as:
pityriasis rubra pilaris, psoriasis, ichthyosis, CREST, rheumatoid arthritis, tuberculosis, bullous pemphigoid, linear IgA disease, and hyper eosinophilic syndrome
- pityriasis rubra pilaris, psoriasis, ichthyosis, CREST, rheumatoid arthritis, tuberculosis, bullous pemphigoid, linear IgA disease, and hyper eosinophilic syndrome
- Drug-induced EGR examples are:
Azathioprine with type I autoimmune hepatitis
Interferon given for hepatitis C virusrelated chronic hepatitis 
- Azathioprine with type I autoimmune hepatitis
- Interferon given for hepatitis C virusrelated 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
- 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 include:
Erythema annulare centrifugum (EAC)
Necrolytic migratory erythema (NME)
- 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
- Erythema marginatum rheumaticum 
- Erythema chronicum migrans
- Familial annular erythema
- The carrier state of chronic granulomatous disease
- Subacute cutaneous lupus erythematosus
- Neonatal lupus erythematosus

# 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.
- 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
- 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
- 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
- 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  
- 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.
- 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 .