—  SHORT COURSE  —

INFLAMMATORY DISORDERS OF THE SKIN AND SUBCUTIS:
A PRACTICAL AND ANALYTICAL APPROACH



CASE #14: SWEET'S SYNDROME

Cynthia M. Magro, M.D., A.Neil Crowson, M.D., and Martin C. Mihm Jr., M.D.




Introduction/Pathogenesis
In 1964, Sweet described a process he termed acute febrile neutrophilic dermatosis characterized by the abrupt onset of fever with peripheral blood neutrophilia and tender erythematous plaques which showed heavy dermal neutrophilia at biopsy. He reported 8 patients all in whom a composite picture comprising painful cutaneous plaques with a site localization to the face, trunk, and extremities with accompanying fever and peripheral blood leukocytosis; he indicated a very good response to corticosteroids. Extra cutaneous manifestations include involvement of eyes, oral mucosa, joints and viscera. Ten percent of cases are associated with leukemia, generally myelomonocytic in type and or other forms of myeloid dyscrasia; there may be co-existing lesions of pyoderma gangrenosum. Other associated hematologic dyscrasia include polycythemia vera and myeloma. Some patients show lesions in association with chemotherapeutic-induced granulocytopenia, solid organ malignancies, Behcet's syndrome, various connective tissue diseases and infections such as with streptococcus or HIV, with drug ingestion, or with therapy with cytokines such as with G-CSF. It has also been described as a complication of all transretinoic acid therapy for treatment of acute promyelocytic leukemia.

A Sweet's like diathesis can occur at extracutaneous sites causing considerable morbidity and sometimes mortality. Specifically a patients with myelodysplastic syndrome developed intense infiltration of the myocardium which lead to conduction disturbances ultimately resulting her demise. Another case involved the bronchial mucosa .

In addition there is a distinctive variant of pyoderma gangrenosum which has overlap features with Sweet's syndrome. It is referred to as bullous pyoderma gangrenosum. The classic lesion is one characterized by vivid hues of an active blue-red elevated border and a bright erythematous halo. In contrast those lesions held to be diagnostic of pyoderma gangreosum in the setting of leukemia is one of a more superfiical lesion comprising concentric rings of necrotic tissue with subdued hues of blue-gray The lesions are characteristically painful.

Pathogenesis
Sweet's syndrome in the setting of hematologic dyscrasias occurs most commonly in AML with monocytic differentiation (I.e. AML type 4 and AML type 5). Neoplastic monocytes have been shown to produce IL1 and IL6 both of which are neutrophilic chemoattractants. In addition IL1 enhances the production of granulocyte colony stimulating factor from macrophages. As well neoplastic mononcytes are an important source of granulocyte colony stimulating factor. Granuocyte colony stimulating factor induces the proliferation and differentiation of neutrophils and also causes the mobilization of mature neutrophils from hematopoietic tissues. As well it enhances chemotaxis of neutrophils. Interleukin 1 induces the production of granulocyte colony stimulating factor from macrophages. The presumptive basis of the fever is due to the enhanced production of inflammatory cytokines. The question arises as to whether or not the various inflammatory cytokines are produced systemically or are they produced locally within the skin i.e. specifically are neoplastic monocytic cells within the dermis followed by secondary neutrophilic migration. Clonality of the granulocytes in lesions of Sweet's syndrome associated with myeloproliferative disease can be demsontrated in heterozygote females by the human androgen receptor (HUMARA) assay.

Not too suprisingly SS may occur in patients with AML who are receiving granulocyte colony stimulating factor. Hence the second setting is one related to exogenous administration of granulocyte colony stimulating factor. This case scenario appears applicable to this case. G-CSF and GM-CSF induces the differentiation of CD34+ cells resulting in FcgR1-positive neutrophils; in addition the maturation time in the marrow is shortened. Therefore SS in the setting of exogenous GCSF may closely parallel that the pathogenetic basis of SS in the setting of ATRA therapy. Specifically the neutrophils are clonal differentiated derivatives of the neoplastic myeloblasts.

Sweet's syndrome recently complicated all trans retinoic acid therapy for the treatment of acute promyelocytic leukemia. With all transretinoic acid therapy there is differentiation of the promyelocytes into mature neutrophilic forms. In APL there is a translocation of the 15 and 17 chromosomes which results in fusion of PML gene to the retinoic acid receptor gene. All-trans retinoic acid which exterts its effect via binding to the retinoic acid receptor has been shown to selectively differentate abnormal promyelocytes into mature granulocytes; complete remission occurs in 80 to 90% of newly diagnosed cases of APL. The onset of SS typically coincides with a rise in peripheral blood mature neutrophilic leukocytosis with a corresponding reduction in the number of peripheral blood blasts. At the onset of SS, the neutrophils within the dermis are largely immature and then manifest progressive maturation which mirrors the peripheral blood neutrophilic differentiation. This finding suggests that the neutrophils in lesions of ATRA associated SSS are mature clonal derivatives of the neoplastic promyelocytes. Presumably SS in the setting GCSF therapy and CCD34 + AML is also a clonal neutrophilic dermatosis.

The onset of SS during chemotherapy associated granulocytopenia has been described. The explanation is unclear by may relate to preferential sequestering of neutrophils to the skin. Finally SS in the setting of myelodysplasatic syndromes denote a poor prognosis whereby an accelerated course progressing to AML is described. Lesions of pyoderma gangrenosum may co-exist with Sweet's syndrome.

In patients with Sweet's syndrome serum levels of IL-1a, IL-1b, IL-2, and IFN-g were significantly elevated, whereas the IL-4 level was within the normal range. It would appear that Sweet's syndrome may be a Th1 mediated disorder.

Differential Diagnosis
A novel neutrophilic dermatosis has been described with some morphologic overlap features with Sweet's syndrome and the newly introduced entity of sterile neutrophilic folliculitis. Patients presented all with multiple acneiform papules and dome-shaped aseptic abscesses leaving scars. Histopathology disclosed a dense dermal polymorphonuclear neutrophil infiltrate and some mononuclear cells. Two of these patients had myelodysplastic syndromes while one had IgA myeloma. Hence abscess-forming neutrophilic dermatosis seems to be another type of neutrophilic dermatosis associated with hematological malignancies.

References

  1. Arun B, Berberian B, Azumi N, Frankel SR, Luksenburg H, Freter C. Sweet's syndrome during treatment with all-trans retinoic acid in a patient with acute promyelocytic leukemia. Leuk Lymphoma 1998;31:613-5
  2. Aubin F, Dufour MP, Angonin R, Misery L, Laurent R, Humbert P. Sweet's syndrome associated with cutaneous T cell lymphoma. Eur J Dermatol 1998;8:178-9.
  3. Chao SC, Lee JY, Tsao CJ. Sweet's syndrome in a severely neutropenic patient during therapy with recombinant human granulocyte colony-stimulating factor. J Formos Med Assoc 1997;96:276-9
  4. Choonhakarn C, Chetchotisakd P, Jirarattanapochai K, Mootsikapun P. Sweet's syndrome associated with non-tuberculous mycobacterial infection: a report of five cases. Br J Dermatol 1998;139:107-10
  5. Giasuddin AS, El-Orfi AH, Ziu MM, El-Barnawi NY. Sweet's syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines- J Am Acad Dermatol 1998;39:940-3
  6. Magro CM, De Moraes E, Burns F. Sweet's syndrome in the setting of CD34-postive acute myelogenous leukemia treated with granulocyte-colony stimulating factor: evidence for a clonal neutrophlic dermatosis. J Cutan Pathol 2001;28:90-6
  7. Probert C, Ehmann WC, al-Mondhiry H, Ballard J, Helm KF. Sweet's syndrome without granulocytosis. Int J Dermatol 1998;37:108-12
  8. Shimizu K. Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome. Am J Hematol 1998;58:337-8
  9. Thurnheer R, Stammberger U, Hailemariam S, Russi EW Bronchial manifestation of acute febrile neutrophilic dermatosis (Sweet's syndrome). Eur Respir J 1998;11:978-80.
  10. Urano Y, Miyaoka Y, Kosaka M, Kabe K, Uchida N, Arase S Sweet's syndrome associated with chronic myelogenous leukemia: demonstration of leukemic cells within a skin lesion. J Am Acad Dermatol 1999;40:275-9

Differential diagnosis
Other causes of neutrophilic dermal infiltrates include granuloma faciale, pustular vasculitic syndromes, pyoderma gangrenosum, rheumatoid neutrophilic dermatosis, the cutaneous manifestations of inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the pustulonecrotic lesions of cutaneous Wegener's granulomatosus. Finally, a dermatosis mimicking Sweet's syndrome clinically and histologically may be seen as an apparent id reaction to atypical mycobacterial infection.

References

  1. Prevost-Blank PL, Schwayder TA. Sweet's syndrome secondary to granulocyte colony-stimulating factor. J Am Acad Dermatol 1996;35:995-7.
  2. Choonhakarn C, Chetchotisakd P, Jirarattanapochai K, Mootsikapun P. Sweet's syndrome associated with non-tuberculous mycobacterial infection : a report of 5 cases. Br J Dermatol 1998;107-110.
  3. Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum : Classification and management. J Am Acad Dermatol 1996;34:395-409.
  4. Graham JA, Hansen KK, Rabinowitz LG, Esterly NB: Pyoderma gangrenosum in infants and children. Pediatric Dermatology 11:10-17,1994. ok
  5. Jorizzo JL, Solomon AR, Zanolli M, Leshin B: Neutrophilic vascular reactions. J Am Acad Dermatol 19:983-1005,1988.
  6. Koester G, Tarnower A, Levisohn D, Burgdorf W: Bullous pyoderma gangrenosum. J Am Acad Dermatol 29:875-878,1993.
  7. Magro CM, Crowson AN. Vesiculopustular lesions in association with liver disease. Int J Dermatol 1997;36:837-844.


PUSTULAR HYPERSENSITIVITY STATES

Introduction/Clinical
Pustular hypersensitivity reactions present clinically as diffuse pustules with striking involvement of the palms and soles, sometimes accompanied by severe constitutional symptoms including fever and malaise. The appellation generalized exanthematous pustulosis has been used for this distinct form of pustular hypersensitivity.

Pathogenesis
The reactions are triggered by the administration of certain drugs, including antibiotics such as the aminoglycosides, cephalosporines, and amoxicillin, the anticonvulsants and diltiazem. In the anticonvulsant hypersensitivity syndrome, there may also be accompanying lymphadenopathy. As well, a less severe form of pustular hypersensitivity presenting as a more localized process involving primarily the palms and soles has occurred following exposure to mercury, and with ingestion of herbal teas and licorice. The lesions being with lymphocytic exocytosis reflecting a delayed-type hypersensitivity reaction. Presumptively, because of the cytokine milieu, a dominant chemotaxis of neutrophils occurs eventuating in a pustular morphology.

Histopathology
The hallmark of pustular hypersensitivity is one of a pustular reaction involving hair follicles and acrosyringia. Although the intra-epithelial infiltrate is dominated by neutrophils, there may be concomitant exocytosis of lymphocytes.


Sweet\'s Syndrome

There may or may not be accompanying vasculitis, as manifested by luminal and mural fibrin deposition with angiocentric disintegrating neutrophilic infiltrates. Pustular hypersensitivity with vasculitis is typical for those cases of pustular hypersensitivity triggered by calcium channel blocker therapy. As these patients are frequently very ill, prompt recognition of this syndrome is critical. Treatment includes withdrawal of the drug and administration of high-dose systemic prednisone. Because of the unfamiliarity of the pathologist with this distinctive syndrome, such cases are frequently misinterpreted as miliaria or folliculitis.

Differential Diagnosis
The differential diagnosis is primarily with pustular vasculitis unrelated to drug therapy, namely as a distinctive manifestation of Behcet's disease, antecedent streptococcal infection, Henoch-Schonlein purpura in the setting of antecedent mucosal infection, and underlying inflammatory bowel disease. Patients with Reiter's disease may manifest a pustular vasculitic morphology in biopsies obtained from lesions of keratodermia blenorrhagicum. Lastly, patients with psoriasis who develop vasculitic hypersensitivity reactions, regardless of the antigenic trigger (ie drug, food, infection) typically Koebnerize vasculitis with an overlying macropustular response recapitulating the morphology of a pustular vasculitis. Other diagnostic considerations include subcorneal pustular dermatosis, a condition which does not, however, manifest acrosyringeal or follicular accentuation. Clinically, it is very distinctive as it is a chronic relapsing vesiculopustular dermatosis with a predilection for the intertriginous zones and flexural aspects of the limbs. In contrast, acute generalized exanthanatous pustolosis is a dramatic syndrome accompanied by marked constitutional symptomatology. Other considerations include impetigo, a condition that can be diagnosed definitely with culture and special stains, and IgA pemphigus. IgA pemphigus can be triggered by drug therapy; immunofluorescent testing is diagnostic.

References

  1. Katagiri K, Takayasu S. Drug induced acute generalized exanthematous pustolosis. J Dermatol 1996;23:623-627.
  2. Magro CM, Crowson AN, Peeling R. Vasculitis as the basis of cutaneous lesions of Reiter's disease. Hum Pathol 1995;26:633-638.
  3. Magro CM, Crowson AN. The clinical and histological spectrum of IgA-associated vasculitis. Am J Dermatopathol 1999;21:234-240.
  4. Tranvan A, Pezen DS, Madenica M, Michelson GC, Vogelzang N, Soltani KM. Interleukin-2 associated linear IgA bullous dermatosis. J AmAcad Dermatol 1996;35:865-7.


GRANULOMA FACIALE

Introduction/Clinical
In granuloma faciale, the lesions are localized to the face and do not involve the extremities; there is no accompanying fever or malaise.

Histopathology
At a light microscopic level, granuloma faciale manifests a heavy neutrophilic dermal infiltrate with nuclear debris and there is deposition of fibrin within and around the blood vessels. Older lesions show a shift to histiocytes and lymphocytes. The infiltrates in granuloma faciale are closely opposed to blood vessels in contrast with the prominent interstitial component observed in Sweet's syndrome, and as well, Sweet's syndrome lesions do not manifest vascular fibrin deposition.

Differential Diagnosis
In suppurative lesions of inflammatory bowel disease and Wegener's granulomatosus, concomitant granulomatous foci are observed, a finding not identified in Sweet's syndrome. In the pustular vasculitic syndrome, the hallmark is one of intra-epithelial pustulation in concert with a neutrophilic vascular reaction of either leukocytoclastic and/or Sweet's-like type. In Sweet's syndrome and granuloma faciale, intra-epithelial pustulation is not observed. The Sweet's-like vascular reaction in pustular vasculitis is one of disintegrating angiocentric neutrophils rather than the dominant histiocytoid populace in and around the vessel observed in Sweet's syndrome.

URTICARIA

Introduction/Pathogenesis
Urticarias are common transient eruptions that affect roughly fifteen percent of the population at some time in life. There is increasing evidence that a delayed reaction may play a role in some cases of chronic urticaria. The main mediators are histamine prostaglandins and interleuken 1, the liberation of which is provoked by types 1 and 3 immune reactions. Non-immunological mechanisms causing mast cell or basophil degranulation may be operative. The latter is seen with opiates and foods such as strawberries and shellfish. In IgE mediated urticaria, antigen specific reactions to foods, drugs and insect bites are operative. In complement mediated urticaria, the various causes include C1q esterase deficiency and circulating immune complexes which may be of either endogenous or exogenous origin, the latter often comprising drug or microbial antigens. Among the underlying endogenous causes are collagen vascular disease and mixed cryoglobulinemia. As well, complement activation can be seen as a sequela of exposure to cold, heat or pressure for which the appellation physical urticaria is used. A deficiency of complement inhibiitor (C1) associated with urticaria may be a manifestation of internal malignancy.

Clinical
Clinically the lesions are papules or wheels that lack surface alteration and wax and wane without a clinical residuum. Lesions may at times form an arcuate or annular morphology. Urticaria may be acute or chronic (see Table). In acute urticaria etiologic triggers are frequently identifiable. Chronic urticarias are those that last longer than six weeks and may be either idiopathic or of physical, cholinergic, IgE, or histamine releasing agent mediating types, and complement mediated urticaria .

Histopathology
In idiopathic and IgE mediated urticaria, the histology is one of a sparse interstitial and perivascular mononuclear cell and eosinophilic infiltrate with accompanying dermal edema. In the complement-mediated forms of urticaria, be it in the context of underlying collagen vascular disease, C1q esterase inhibitor deficiency or occurring as a consequence of exposure to physical stimuli, the hallmarks are interstitial and perivascular neutrophilic infiltrates with concomitant dermal edema. There may be a minor lymphocytic and eosinophilic cell populace.

Differential Diagnosis
The main differential diagnosis with respect to IgE and idiopathic urticaria is a delayed hypersensitivity reaction as seen with delayed contact dermatitis, drug reactions, and insect bite reactions. Usually in such cases, the intersitital component is less prominent than what is observed in urticaria. In neutrophilic urticaria, the main diagnostic challenge is urticarial vasculitis. However, the etiology of urticarial vasculitis is virtually identical to complement-mediated urticaria excluding the subset of neutrophilic urticaria referred to as physical urticaria. In urticarial vasculitis, one usually sees concomitant leukocytoclasia and hemorrhage with or without accompanying fibrin deposition. Whether one is dealing with neutrophilic urticaria or incipient urticarial vasculitis, evaluation for sources of complement activation should be performed.

References

  1. Crowson AN. Superficial and deep perivascular dermatitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York: McGraw-Hill Co, 1998:69-81.
  2. Toppe E, Haas N, Henz BM. Neutrophilic urticaria: clinical features, histological changes and possible mechanisms. Br J Dermatol 1998;138:248-251.
  3. Greaves MW. Chronic urticaria. N Engl J Med 1995;332:1767-1772.
  4. Reinhold U, Bruske T, Schupp G. Paraneoplastic urticaria in a patient with ovarian carcinoma. J Am Acad Dermatol 1996;35:988-9.

TABLE 9
THE COMMON FORMS OF CHRONIC URTICARIAS
Type of Urticaria Principal Clinical Features Angioedema Diagnostic Test
Chronic idiopathic Profuse or sparse edematous papules or wheals, often annular with itching Yes
Symptomatic dermatographism Itchy, linear wheals with a surrounding bright red flare at sites of scratching or rubbing No Light stroking of skin causes an immediate wheal with itching

Other Physical Urticarias
Cold Itchy pale or red swelling at sites of contact with cold surfaces or fluids Yes 10-minute application of ice pack causes wheal within 5 min of ice removal
Pressure Large painful or itchy red swelling at sites of pressure lasting 24 hours or more No Application of pressure produces persistent red swelling after a latent period of 1 to 4 hours
Solar Itchy pale or red swelling at site of exposure to ultraviolet or visible light Yes Irradiation by a 2.5 kW (290-690 nm) source for 30 to 120 seconds causes wheals in 30 minutes
Cholinergic Itchy wheals on trunk, neck and limbs Yes Exercise or a hot shower elicits eruption