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ANEMIA TABLE EXAMPLE

Types of Anemia	Clinical manifestation	Signs/Symptoms	Hemolysis
Iron deficiency anemia	Menorrhagia GI loss Surgery Pregnancy Diet	Glossitis Cheilosis Dysphagia Pica Koilonchia	No
Anemia due to chronic disease	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	Headache Shortness of breath Palpitations	No
Vitamin B12 deficiency anemia	Pernicious anemia Crohn`s disease Gastrectomy veganism	Neurological deficit Memory loss Nystagmus	No

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

Disease	Erythema Characteristics	Signs and Symptoms	Associated Conditions	Histopathology	Lab finding & Other evaluation	prognosis
Erythema gyratum repens (EGR)	Migratory annular and configurate erythematous bands that form concentric rings Wood grain scaly appearance scales follows the leading edge of the bands Eruption migrates more rapidly, 1cm/d	Skin eruptions severe Generalized itching (pruritus) scaly erythematous patches over trunk and proximal extremities, sparing the hands, feet, and face. Can eventually involve the face    weight loss Malaise and fatigue fever anorexia Lymphadenopathy Headache and convulsion (intracranial metastasis) Shortness of breath (bronchogenic carcinoma)	Dermatologic conditions: ichthyosis palmar/plantar hyperkeratosis Less frequently EGR copresent with: pityriusis rubru piluris, bullous pemphigoid, pemphigus vulgaris, discoid lupus eythemutosus, psoriusiform lesions, and nonspecific vesicles and bullae. Tuberculosis CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia).	The epidermis: Acanthosis Focal parakeratotosis and spongiosis The dermis: Mild focal spongiosis and parakeratosis Moderate perivascular mononuclear, lymphocytic, and histiocytic infiltrate Eosinophils and melanophages have also been reported in the infiltrate Diffuse to moderate edema of the connective tissue can be seen	No specific laboratory changes Eosinophilia has been reported Decreased T lymphocytes and increased B lymphocytes 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 Extensive evaluation for possible cancer CBC,CMP, imaging as CT chest or abdomen	Skin manifestations can be improved within 48 hours of the resection of the underlying tumor The improvement sometimes can be temporary with recurrence of the skin lesions specially in cases of metastasis Death can occur any time depending on the type and location of tumor and the timing of its discovery
Erythema annulare centrifugum (EAC)	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	annular or polycyclic lesions which may begin as urticaria-like papules Eventually old lesions can spontaneously resolve in several days to a few weeks while new eruptions develop. The deep form of EAC has a firm, indurated border, is rarely pruritic, and has no scale. The superficial type of EAC has an indistinct scaly border and is usually pruritic	Infections Allergic reactions to drugs	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 presen 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	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    Evaluation for possible infection or drug reaction (prescribed and non-prescribed) complete blood count, urinalysis, and routine serum liver and kidney function tests.	Lesions disappears after the underlying etiology is managed (allergy, infection, malignancy) if no underlying cause, lesions can recur after discontinuation of the supportive treatment.
Necrolytic migratory erythema (NME)	Migratory circinate erythema/plaques with areas of necrosis and sloughing (3) Crusted  Erythematous scaly plaques with centrifugal growth	Red erythematous scaly plaques over Perineum, distal extremities, lower abdomen, and face Spontaneous exacerbation and remission periods without knowing what the trigger is Weight loss anemia diabetes diarrhea stomatitis.	No other association can be misdiagnosed as contact dermatitis or intertrigo, inverse psoriasis, zinc deficiency, and other nutritional deficiencies	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	Increased glucagon level (3) Evaluation of the associated tumor: CT or MRI abdomen Selective visceral angiography to localize the tumor Positron Emission tomography (PET) Octreotide scintigraphy	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 and prognosis

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].

Class I

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Class III: Harm

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Class IIa/IIb

"1. (Level of Evidence: A)"

"2. (Level of Evidence: B)"