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.[1]
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 [2]
Up to 1992, there were only 49 cases in the literature, 41 of which (84%) were associated with a neoplasm.[3]
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 [4]
Classification
There is no established system for the classification of EGR. However, we can classify EGR as:
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 [5]
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: [6]
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
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: [6]
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:
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
migratory circinate erythema/plaques 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,
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
Pathogenesis
Not fully known but theories relate it to immunologic mechanisms.
Not fully clarified but attributed to zinc deficiency and hypoaminoacedemia as Increased glucagon increases gluconeogesis.
Although NME can be the first symptom of glucagonoma, high glucagon levels cant explain the skin manifestations.
Clinical manifestation/symptoms
Skin lesions, weight loss, fatigue, fever, and anorexia
Weight loss, anemia, diabetes, diarrhea, and stomatitis.
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
Prognosis
Skin manifestations can be improved within 48 hours of the resection of the underlying tumor
The improvement sometimes can temporary with recurrence of the skin lesions specially in cases of metastasis
Death can occur any time dending on the type and location of tumoe rnd the timingg f its discovery
Lesions disaapears after the underlying etiology is managed (allergy, infection, malignancy)
if no underlying cause, lesions can recur after discontinuation of the supportive treatment.
Due to the difficulty of NME recognition, and its association with glucagonoma, diagnosis is usually delayed(3)
NME usually resolved after the resection and treatment of the pancreatic tumor, eg 10 days after tumor resection
Early recognition is crucial for better diagnosis
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 [6]
If the underlying malignancy left untreated, the debilitating pruritus could persist until the patient dies [6]
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 [6]
Laboratory Findings
There are no diagnostic laboratory findings associated with EGR.
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 [6]
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].
References
↑Rothman, Stephan (1925). "Über Hauterscheinungen bei bösartigen Geschwülsten innerer Organe". Archiv für Dermatologie und Syphilis. 149 (1): 99–123. doi:10.1007/BF02297811. ISSN0340-3696.