Superficial cutaneous sporotrichosis in specific anergic patient

700

International Journal of Dermatology 1999, 38, 700–711 © 1999 Blackwell Science Ltd

Cameo

Superficial cutaneous sporotrichosis in specific anergicpatient

Alexandro Bonifaz, MB, Amado Saul, MD, Griselda Montes-de-Oca, MD, andPatricia Mercadillo, MD

From the Dermatology Service, A 25-year-old man from Coscomatepec, Veracruz (400 km south-east of Mexico City), andDepartment of Mycology, and currently resident at this location, presented with dermatosis on the face, affecting theDermatopathology Service, General

frontal region, dorsum of the nose, and malar region, composed of two nodular orHospital of Mexico, Mexico D.F.,

verrucose plaques with an irregular diameter and form, with infiltrated borders,Mexicoulcerations, and bloody and honey crusts; the plaques developed over 4 years after

Correspondence trauma due to a horse kick (Fig. 1a.)Alexandro Bonifaz, MB Symptoms were moderate pruritus and some pain on examination. The patient hadZempoala 60–101

previously received topical treatment with steroids and procaine penicillin in an irregularNarvarte, CP 03020

form. At the beginning, the presumptive clinical diagnosis was verrucose tuberculosis;Mexico D.F.thus a tuberculin skin test (purified protein derivative, PPD) was applied with a responseMexico

of 3 3 2 cm of induration and erythema; later, a biopsy was taken to confirm theDrug names diagnosis. Based on these results, antituberculosis treatment with ethambutol, 1.2 g/day,amphotericin B: Fungizone

and isoniazid, 300 mg/day, plus copper sulfate baths, was instituted for 1 month.ethambutol 1 isoniazid: Myambuthol

Histopathology revealed a parakeratotic epidermis with moderate irregular acanthosis;fluconazole: Diflucanzones of spongiosis and exocytosis formed in some areas with crusts and cellularketoconazole: Nizoral

itraconazole: Sporanox detritus. In the superficial and medial dermis layers, a wide inflammatory infiltrate formedterbinafine: Lamisil from lymphocytes, epithelial histiocytes, some plasmocytes, and giant multinucleated

Langhans-type cells and some dilated and congested capillary vessels were observed.

Through Schiff’s and Grocott’s stains, long yeast-like structures of approximately 5–8 µm

were observed. The histopathologic diagnosis was a tuberculoid granuloma with mycotic

elements suggesting blastomycosis (Fig. 2).

Based on the histologic examination, the following mycologic tests were performed:

direct examination with potassium hydroxide (KOH) and with Gram stain revealed yeast-

like, oval and elongated cells of approximately 5–10 µm. Cultures of Sabouraud and

Micosel agar grew Sporothrix schenckii. Skin tests of sporotrichin M and Y (from mycelial

and yeast antigens) were applied several times at different concentrations, always with

negative results; therefore, the immunologic profile was performed (summary in Table 1).

Hematology, liver function tests, and urinalysis were within normal ranges. A chest X-

ray was normal. The CD4/CD8 lymphocyte ratio was 1.25 cell/mm3, i.e. within normal

values. Two evaluations of human immunodeficiency virus (HIV) antibodies performed in

two different periods were negative to Western blot (WB) and enzyme-linked

immunoabsorbent assay (ELISA) tests.

During the past 8 years, we have observed the patient; he has received several

treatments and has achieved considerable clinical improvement; nevertheless, each time

treatment is discontinued, new superficial and discrete lesions appear with positive

cultures to S. schenckii; sporotrichin tests were applied every year (8 times), and yielded

a positive result.

Figure 3 summarizes the treatment period as well as the drugs used. In summary, the

patient was managed as follows: he initially received oral potassium iodide, 3–6 g/day for

8 months; this treatment was repeated many times in several episodes of reactivation of

the disease or as supportive treatment; ketoconazole, 400 mg/day for 6 months;

amphotericin B for 2 months at a dose level of 0.50 mg/kg/day; itraconazole, 300–

400 mg/day for several treatment periods; fluconazole, 300 mg/day for 4 months;

Bonifaz et al. Superficial cutaneous sporotrichosis Cameo 701

terbinafine, 500 mg/day for 4 months. During the use of all these systemic antimycotic

agents, monitoring of hematology and renal and liver function tests were performed with

no alterations observed.

As a consequence of the initial trauma and its cicatrization, the patient presented

retraction of the left eyelid, for which he underwent a surgical process; bridal tissues were

released and a graft was placed later on with a satisfactory functional and cosmetic result.

Currently, the patient is alternately taking, with resting periods of up to 3 months,

potassium iodide at a dose of 0.5–1.0 g/day or itraconazole 100 mg/day. At the last visit

(March 1998), the patient showed excellent clinical improvement; however, cultures are

still positive.

Discussion

Sporothrix is a subcutaneous mycosis caused by a

dimorphic fungus Sporothrix schenckii. It is a poly-

morphic affection that may appear in different clinical

forms, depending on the patient’s immune condition. In

general, the most common clinical types are the lymphocut-

aneous and the fixed cutaneous; however, when the patient

presents a severe immunosuppression, the disease is mani-

fested as cutaneous-disseminated hematogenous, pulmon-

ary, etc.1–3

The purpose of this study is to report an exceptional

case of a superficial cutaneous sporotrichosis in a patient

with an immunologic base of specific anergy to S. schenckii

antigens; the therapeutic management of the patient is also

described. The patient has been controlled but not cured.

Sporotrichosis is one of the most frequent subcutaneous

mycoses in Mexico; the clinical variety commonly observed

in patients with good immunologic response is lympho-

cutaneous and, in a smaller proportion, fixed cutaneous;

however, in immunocompromised patients, the types

observed are cutaneous hematogenous, pulmonary, and

visceral forms.1,4 The present case is exceptional due to

the fact that it is a rare superficial cutaneous form and

cannot be classified under any of the above-mentioned

types. It has been previously reported by some authors.4,5

It is also important to mention that, at the beginning, it

was considered to be a verrucose tuberculosis because of

its form and its strong response to intradermal tuberculin,

as well as its frequency in Mexico.

The diagnosis of sporotrichosis is based on fungus culture

and the skin test response to mycelial sporotrichin; it is

worth noting that our patient has never responded in a

positive manner to both forms of the antigen and, according

to the immunologic studies performed, the amount of CD4

and CD8 lymphocytes was normal as their ratio was greater

than unity; in addition, he was positive to most antigens

in intradermal form and maintains a normal activity to

phagocytosis, which is considered an important barrier in

the course of sporotrichosis;6,7 however, negative responses

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 700–711

were always found when specific antigens to S. schenckii

(mycelial and yeast form) were used in vivo and in vitro.

Owing to these results, we consider that our patient

represents an extraordinary case of specific anergy: there

is no immune response, especially of the cellular type, to

S. schenckii antigens and this is probably the reason for

the unusual clinical form as well as the course of the

disease.4,8

From the histologic point of view, it is important to

Figure 1 (a) Initial appearance. (b) After 7 years of various

treatments

702 Cameo Superficial cutaneous sporotrichosis Bonifaz et al.

Figure 2 Skin biopsy: yeast cells of

Sporothrix schenckii (Grocott’s stain,

original magnification 3100)

Table 1 Immunologic features

Antigens Skin tests MIF (%)

PPD (tuberculin) 3 3 2 cm 77Candidin 2 3 2 cm 60Trichophytin 1 3 1 cm 36Streptokinase-streptodornase (varidase) Negative 20Sporotrichin Y (yeast) Negative 0Sporotrichin M (mycelial) Negative 0

MIF, macrophage inhibition factor.

Figure 3 Treatment and course of the disease

underline that basically a tuberculoid granuloma is present,

which clearly shows that there is a good immunologic

response; nevertheless, many yeast-like forms of S. schenckii

cells appear, which are only observed in immuno-

compromised patients, mainly in the hematogenous and

disseminated cases; this means that there is a bivalent


behavior, with a strong defensive process (granuloma), but

which does not eliminate the fungus.9,10

The treatment of choice for sporotrichosis is potassium

iodide; it is important to mention that most cases respond

well to this treatment;1,4 also most of the systemic anti-

mycotic agents, such as griseofulvin, amphotericin B, keto-

conazole, itraconazole, fluconazole, and terbinafine, have

been used with good results.4,11–14 The mechanism of action

of potassium iodide is not well known; most investigators

consider that it possibly causes an immunologic stimulation

of polymorphonuclear leukocytes; this is why it is not very

useful in immunodepressed patients, such as those with

acquired immunodeficiency syndrome (AIDS), where the

use of a real antimycotic agent, such as those mentioned

above, is recommended.

Figure 3 shows the course of the disease, as well as the

antimycotic agents used throughout the 8 years of follow-

up; it can be seen that practically all the antimycotic agents

have been used in the appropriate dose and for the period

recommended by most authors; however, when the different

therapies have been discontinued, new small lesions appear,

from which S. schenckii has been isolated. We believe that

this is undoubtedly due to the specific anergy condition

which does not allow the eradication of the fungus.

Currently, the patient shows an important clinical

improvement (Fig. 1b), but he remains mycologically active,

being controlled with periods of low doses of potassium

iodide (0.5–1 g/day) and, alternatively, with itraconazole

(100 mg/day). We are aware that this treatment cannot be

maintained, as adverse events such as iodism or liver

damage may occur. It is important to note that the type of

disease presented by the patient is not life threatening nor

disseminating; one treatment which might help to eradicate

Peretz et al. Vegetative pyoderma gangrenosum Cameo 703

the fungus may be immunostimulation therapy with a

specific transference factor; however, donors with a positive

response to intradermal sporotrichin are needed for its

preparation.

The objective of this study was to present an exceptional

case of sporotrichosis from several points of view—clinical,

histologic, and therapeutic—allowing us to understand

more about the versatility of sporotrichosis.

References

1 Lavalle P, Mariat F. Sporotrichosis. Bull Inst Pasteur

1983; 81: 295–322.

2 Win RE. Sporotrichosis. Infect Clin Dis North Am 1988;

2: 899–911.

3 Werner AH, Werner BE. Sporotrichosis in man and

animal. Int J Dermatol 1994; 33: 692–700.

4 Saul A. Sporotrichosis. In: Jacobs PH, Nall L, eds.

Antifungal Drug Therapy. New York: Marcel Dekker,

1990: 53–59.

5 Campos P, Arenas R, Coronado H. Epidemic cutaneous

sporotrichosis. Int J Dermatol 1994; 33: 38–41.

6 Cunningham KM, Blumer GS, Rhoades ER.

Cameo

Vegetative pyoderma gangrenosum: an unusual presentationEyal Peretz, MD, Emanuela Cagnano, MD, Marcelo H. Grunwald, MD,Dafna Hallel-Halevy, MD, and Sima Halevy, MD

From the Department of Dermatology, A 44-year-old woman presented with a 6-month history of subcutaneous nodules involvingFaculty of Health Sciences, Soroka her face and shins. Her past history revealed myomatous uterus with menometrorrhagia,Medical Center, Ben-Gurion resulting in an iron deficiency anemia, treated by ferrum sulfate tablets. She also hadUniversity of the Negev, Beer-Sheva,

diabetes mellitus type II treated by glibenclamide and metformin tablets. There was noIsraelevidence of bromide or iodide ingestion. On initial examination, several firm, tender,

Correspondence erythematous subcutaneous nodules, 2–4 cm in diameter, were present on the faceEyal Peretz, MD (Fig. 1) and shins (Fig. 2), two with normal overlying skin. Within a few weeks, the noduleDepartment of Dermatology on the left shin enlarged and several superficial ulcers appeared, surrounded by purplishSoroka Medical Center

borders, secreting sinuses, and a vegetative exophytic surface (Fig. 3). PhysicalBen-Gurion University of the Negevexamination was normal. Incisional biopsies from the ulcer margins showedBeer-Sheva

Israel pseudoepitheliomatous hyperplasia, diffuse neutrophilic infiltration with microabscess

formation (Fig. .4), and the presence of a dense infiltrate composed of epithelioid cells,

giant cells, and a few lymphocytes forming non-necrotizing granulomas within the dermis

and subcutaneous lobules (Fig. 5). Leukocytoclastic vasculitis was also present in the

lower dermis. Routine blood tests and urine analysis were normal, except for a high

erythrocyte sedimentation rate (120/h) and anemia with a hemoglobin level of 10 g%. The

results of the following laboratory tests were found to be within normal limits: rheumatoid

factor; antinuclear antibody; C3; C4; serum immunoglobulins; serum protein

electrophoresis; stool for parasites and occult blood; X-ray of the chest, left shin, hands,

and facial bones; isotopic bone scanning; abdominal ultrasonography; chest and


Phagocytosis: an intracellular fate of Sporothrix

schenckii. J Infect Dis 1979; 140: 815–817.

7 Ramos-Zepeda R, Gonzalez-Mendoza A. Metabolic

activity of phagocytes in experimental sporotrichosis.

Mycopathologia 1986; 93: 109–112.

8 Everett MA. Atypical sporotrichosis. J Okla State Med

Assoc 1963; 56: 483–485.

9 Lurie HL. Histopathology of sporotrichosis. Arch Pathol

1963; 75: 121–137.

10 Novales J. Histopatologıa de las micosis profundas.

Dermat Rev Mex 1983; 27: 128–155.

11 Cullen S, Maucer AA, Warner N. Successful treatment of

disseminated cutaneous sporotrichosis with

ketoconazole. J Am Acad Dermatol 1992; 27: 463–464.

12 Sharkey-Mahis PK, Kauffman CA, Graybill JR, et al.

Treatment of sporotrichosis with itraconazole. Am J

Med 1993; 95: 279–285.

13 Castro LG, Belda W, Cuce LC, et al. Successful

treatment of sporotrichosis with oral fluconazole: a

report of three cases. Br J Dermatol 1993; 128:

352–356.

14 Hull PR, Vismer HF. Treatment of cutaneous

sporotrichosis with terbinafine. Br J Dermatol 1992;

126: 51–55.

704 Cameo Vegetative pyoderma gangrenosum Peretz et al.

abdominal computerized tomography. Repeated smears and tissue cultures for bacteria,

nmycobacteria, and fungi obtained from several ulcer sites were negative. Smears and

cultures for Leishmania and polymerase chain reaction (PCR) for Leishmania were

negative. Based on the clinical and histologic picture, our case was diagnosed as

vegetative pyoderma gangrenosum. The lesions did not respond to systemic antibacterial

agents including minocycline and cotrimoxazole. A marked improvement was observed

following treatment with prednisone at an initial dose of 40 mg/day. Relapse of the lesions

was observed after several attempts to reduce the steroid dose. Using dapsone as an

adjuvant therapy in increasing dose up to 250 mg/day induced significant improvement,

which allowed us to reduce the dose of prednisone to 10 mg/day. Dapsone was

discontinued after 3 weeks of treatment due to acute hepatitis induced by the drug. A few

days after cessation of dapsone, the cutaneous lesions recurred, and were only partially

controlled by a prednisone regimen of 10/20 mg on alternate days. Complete remission

was achieved after 6 months of therapy, leaving a small cribriform scar on the leg.

Discussion

The classic ulcerative form of pyoderma gangrenosum (PG)

is known to have three variants, including pustular, bullous,

and vegetative forms. Vegetative pyoderma gangrenosum

(VPG), also known as pyoderma vegetans and superficial

granulomatous pyoderma, is a recently recognized variant

of PG, having unique clinical, histologic, and therapeutic

characteristics.1,2 Unlike the ulcerative form of PG

(Table 1), the initial lesion of VPG is a nodule or plaque,

solitary or multiple,1 which evolves to form superficial

ulcers with a clean base and purple borders.3 The lesions

may be exophytic, vegetative, slowly progressive, and

relatively nonpainful,4 most commonly located on the

back, but can involve any part of the trunk and limbs.1,3

Histologically, a three-layer inflammatory reaction is pre-

sent.5 The first layer consists of superficial abscess formation

in the upper dermis. The second layer demonstrates granul-

oma formation with histiocytes and multinucleated giant

cells. The surrounding third layer is composed of a mixed

Figure 1 Erythematous nodule on the chin


inflammatory infiltrate with lymphocytes, numerous plasma

cells, neutrophils, and eosinophils. Pseudoepitheliomatous

hyperplasia of the epidermis may be present.5 Treatment

with topical steroids or with antimicrobial agents, such as

tetracycline, minocycline, dapsone, and sulfapyridine, is

usually sufficient to control the disease activity.3 The unique

Figure 2 Erythematous vegetative lesion on the leg

Peretz et al. Vegetative pyoderma gangrenosum Cameo 705

Table 1 Comparative features between VPG and PG

VPG PG

Location Most commonly the trunk and upper limbs Most commonly the lower limbs

Primary lesion Nodule or plaque Pastule

Number (lesions) Solitary or multiple Usually solitary

Ulcer (characteristics) Superficial, purplish determined border, clean base, may Deep, purplish undetermined border, purulent base,be exophytic, vegetative, slowly progressive, usually not rapidly enlarges, painfulpainful

Histology Three layers: dermal neutrophilic abscesses, Extensive dermal neutrophilic abscesses, sometimesgranulomas, mixed inflammatory infiltrate vasculitis

Treatment Response to simple modes of therapy (topical steroids, Aggressive therapy (systemic steroids,antibacterial agents) immunosuppressive agents)

Associated disease Usually no associated disease Frequently present (IBD, monoclonal gammopathy)

IBD, inflammatory bowel disease.

Figure 3 Superficial ulcers with vegetative surface surrounded

by purplish border

findings in this case in comparison with previous reports

of VPG include the unusual location on the face, the

associated tenderness of the lesions, and the presence of


Figure 4 Microabscess formation in the dermis (hematoxylin

and eosin stain; 3100)

nodules with normal overlying skin. Histologically, in

addition to as the characteristic findings of VPG, the

biopsies demonstrated some other unique findings, such

as vasculitis and granulomatous panniculitis. The partial

resistance of the lesions to systemic steroids is also an

unexpected behavior of VPG. The differential diagnosis of

our case should include the following diseases: periarteritis

nodosa, deep leukocytoclastic vasculitis, and local granulo-

matous vasculitis. Periarteritis nodosa and deep leuko-

cytoclastic vasculitis, unlike VPG, involve mainly the

subcutaneous septae, while in our case the subcutaneous

lobules were primarily involved. Furthermore, granulomas

are not present in these entities. Although VPG is considered

to be a superficial variant of ulcerative PG, it may also be

classified as a variant of granulomatous vasculitis.

706 Cameo Henoch–Schonlein purpura Goldberg, Shoji, and Sapadin

Figure 5 Granuloma formation in the deep dermis and

subcutis (hematoxylin and eosin stain; 3400)

Cameo

Henoch–Scho nlein purpura induced by clarithromycin

Elizabeth I. Goldberg, MD, Toru Shoji, MD, PhD, and Allen N. Sapadin, MD

From the Department of Dermatology, An 84-year-old Indian woman with no significant past medical history and no known drugMount Sinai School of Medicine, allergies had been prescribed clarithromycin (250 mg twice daily) for pneumonia. TheNew York, New York patient was receiving no other medications. Ten days after starting treatment, the patient

developed a mild fever, eruption, and swelling of the ankles. Several days later, theCorrespondencepatient developed a spreading, nonpainful, nonpruritic eruption, joint pain, gastrointestinalAllen N. Sapadin, MD

One Gustave L. Levy Place bleeding, and general malaise. Skin examination revealed numerous palpable purpuricBox 1048 macules and papules and petechiae on the lower extremities, mostly below the knees,New York, NY 10029 and on the right hand. There were large blistering lesions around both ankles, some of

which had ulcerated and had a necrotic center (Fig. 1). Blood streaked stool was notedDrug namesduring rectal examination. Laboratory tests showed a normal white blood cell count,clarithromycin: Biaxin

omeprazole: Prilosec hematocrit, and hemoglobin. Serum urea nitrogen was 22 mg/dL (8–18 mg/dL) and

creatinine was normal. Urinalysis revealed proteinuria of 0.9 g/24 h (,0.15 g/24 h) and a

microscopic hematuria. Antistreptolysin O, antinuclear antibodies, cryoglobulins, and

hepatitis serologies were all negative. Histology of the skin showed leukocytoclastic


In summary, we have presented a case of VPG, a variant

of PG with unusual clinical and histologic characteristics.

Our case shows that even a variant of PG can have a broad

spectrum of clinical and histologic features.

References

1 Wilson-Jones E, Winkelmann RK. Superficial

granulomatous pyoderma: a localized vegetative form of

pyoderma gangrenosum. J Am Acad Dermatol 1988; 18:

511–521.

2 Quimby SR, Gibson LE, Winkelmann RK. Superficial

granulomatous pyoderma: clinicopathologic spectrum.

Mayo Clin Proc 1989; 64: 37–43.

3 Lichter MD, Welykyi SE, Gradini R, et al. Superficial

granulomatous pyoderma. Int J Dermatol 1991; 30:

418–421.

4 Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum.

Classification and management. J Am Acad Dermatol

1996; 34: 395–409.

5 Schorter AL. Superficial granulomatous pyoderma,

Editorial. Mayo Clin Proc 1989; 64: 123–124.

Goldberg, Shoji, and Sapadin Henoch–Schonlein purpura Cameo 707

vasculitis of superficial vessels with extravasation of red blood cells (Fig. 2). Direct

immunofluorescence revealed immunoglobulin A (IgA) in superficial dermal vessels.

Treatment with prednisone (1 mg/kg/day) was started and the arthralgias, hematochezia,

and eruption resolved over the next 3 days. Renal function remained impaired, however,

and the patient was discharged with a proteinuria of 0.56 g/24 h (,0.15 g/day) on

prednisone and omeprazole.

Discussion

Clarithromycin is a macrolide antibiotic with improved

pharmacokinetics and lower frequency of adverse effects

relative to the parent compound erythromycin. It is used

for the treatment of mild to moderate upper and lower

respiratory tract infections, skin and soft tissue infections,

and infection due to Mycobacterium avium complex and

other nontuberculous mycobacteria.1 Adverse effects occur

in approximately 15–20% of patients and are almost

always mild. These primarily involve the gastrointestinal

tract.2 Cutaneous effects are rare. Two reported cases of

leukocytoclastic vasculitis due to clarithromycin have been

described.3,4

Henoch–Schonlein purpura (HSP) is an immune complex

disorder with leukocytoclastic vasculitis of the small vessels

of affected organs. This syndrome typically involves the

skin, joints, gastrointestinal tract, and kidneys. Although

more prevalent in the pediatric population, it may occur

in adults, in whom it is more likely to present with

ulcerative or necrotic cutaneous lesions.5 Most patients

will recover with an uncomplicated course lasting about 4

weeks, but 1–2% of patients will have persistent renal

function impairment.6 Corticosteroids have been reported

to relieve symptoms but not to alter the course.

Although the etiology remains unknown, several anti-

gens, including medications and infections, have been

Figure 1 Extensive purpura on the distal legs. Overlying the

medial malleolus of the left ankle is a large crusted erosion.

An ischemic but intact blister roof is apparent at the

periphery


implicated. Drug-induced HSP is a common association in

adults.7 Cases, although rare, have been reported related

to the macrolide antibiotics, including erythromycin,8 spira-

mycin,9 and midecamycin.10

The close temporal relation between drug exposure and

the onset of symptoms suggests that clarithromycin was

the most likely etiologic agent for HSP in our patient. To

our knowledge, this is the first case of HSP associated with

clarithromycin. Although rare, clinicians must be aware of

the possibility of HSP as a severe adverse effect when

prescribing such a widely used drug.

Figure 2 Medium power picture showing fibrinoid necrosis

of superficial vessels, neutrophilic infiltrate, and

karyorrhectic debris (hematoxylin and eosin, 3100)

708 Cameo Lichen sclerosus et atrophicus in GVHD Cordoba et al.

References

1 Wood MJ. The tolerance and toxicity of clarithromycin.

J Hosp Infect 1991; 19 (Suppl A): 39–46.

2 Pichotta P, Gupta S, Prokocimer P, Pernet A. The overall

safety of oral clarithromycin in comparative clinical

studies (abstract 1332). In: Abstracts of the

30th Interscience Conference on Antimicrobial Agents

and Chemotherapy, Atlanta, GA, 1990.

3 Gavura SR, Nusinowitz S. Leukocytoclastic vasculitis

associated with clarithromycin. Ann Pharmacother

1998; 32: 543–545.

4 de Vega T, Blanco S, Lopez C, et al. Clarithromycin-

induced leukocytoclastic vasculitis. Eur J Clin Microbiol

Infect Dis 1993; 12: 563.

5 Michel BA, Hunder GG, Bloch DA, Calabrese LH.

Hypersensitivity vasculitis and Henoch–Schonlein

Cameo

Lichen sclerosus et atrophicus in sclerodermatous chronicgraft-versus-host disease

Susana Cordoba, MD, Erich Vargas, MD, Javier Fraga, MD, PhD,Maximiliano Aragues, MD, Jesus Fernandez-Herrera, MD, PhD, andAmaro Garcıa-Dıez, MD, PhD

From the Departments of In May 1994, a 40-year-old woman with chronic myeloid leukemia received an allogeneicDermatology bone marrow transplant (BMT) from her human leukocyte antigen (HLA) identical sister,and Pathology, Hospital Universitario after a conditioning regimen with cyclophosphamide and busulfan. Graft-versus-hostde la Princesa, Madrid, Spain

disease (GVHD) prophylaxis consisted of cyclosporine (CsA) and methotrexate. Facial

and palmoplantar erythema and moderate cholestasis developed on day 14 after theCorrespondenceSusana Cordoba, MD BMT. A diagnosis of acute GVHD was made and she was successfully treated with lowServicio de Dermatologıa doses of corticosteroids. On day 150 after the BMT, despite the prophylactic treatment ofHospital Universitario de la Princesa GVHD with CsA (150 mg/12 h), she developed several burning white plaque-like striaeC/Diego de Leon 62

over the buccal mucosa and numerous itching violaceous lichenoid papules on the28006 Madridfingertips. Biopsy specimens obtained from both the skin of the fingertips and the oralSpainmucosa (Fig. 1) revealed patchy to diffuse subepithelial lymphocytic inflammation and

necrosis of individual squamous cells, consistent with a diagnosis of chronic lichenoid

GVHD. Despite therapy with CsA, topical and systemic corticosteroids (prednisone 60 mg/

24 h), the oral lichenoid lesions persisted. On day 750 after the BMT, 2 months after

withdrawal of immunosuppressive therapy, she developed several erythematous,

pruriginous, and slight indurated lesions over the neck. These lesions coalesced into

plaques, adopting a white atrophic-like appearance with follicular plugs similar to lichen

sclerosus et atrophicus (Fig. 2). Histopathologic examination showed hyperkeratosis with

follicular plugging, atrophy of the stratum Malpighii with hydropic degeneration of the

basal cells, homogenization of the collagen, incontinence of the pigment, and a discrete

lymphoplasmocytic inflammatory infiltrate in the upper dermis (Fig. 3). Systemic

corticosteroid therapy was re-introduced. On day 850 after the BMT, physical examination

revealed patchy hyperpigmentation affecting the back and limbs, and diffuse thickening

and hardening of the skin of the legs, forearms, and dorsa of the hands, resulting in


purpura: a comparison between the two disorders. J

Rheumatol 1992; 19: 721–728.

6 Heng MCY. Henoch–Schonlein purpura. Br J Dermatol

1974; 109: 664.

7 Cream JJ, Gumpel JM, Peachy RDG. Schonlein–Henoch

purpura in the adult. Q Med 1970; 39: 461–484.

8 Handa SP. The Schonlein–Henoch purpura:

glomerulonephritis following erythromycin. South Med J

1972; 65: 917–920.

9 Valero PI, Calvo CJ, Hortelano ME, et al. Schonlein–

Henoch purpura associated with spiramycin and with

important digestive manifestations. Rev Esp Enferm Dig

1994; 85: 47–49.

10 Sanchez de Dios M, Sanchez Sanchez A, Garcia O.

Anaphylactoid Schonlein–Henoch purpura caused by

midecamycin. Rev Clin Esp 1992; 191: 230–231.

Cordoba et al. Lichen sclerosus et atrophicus in GVHD Cameo 709

a slight limitation of movements. Various smooth, shiny, and indurated plaques,

characteristic of morphea, were present on the flexural areas of the arms (at vein

puncture sites). Lichenoid lesions over the oral mucosa and the atrophic plaques on the

neck were still present. No dysphagia was observed. Liver function tests revealed a

pattern of cholestasis. Antinuclear antibodies were detected (1 : 80); no antibodies against

centromere antigens and DNA topoisomerase I (SCL70) were found. Reduced lacrimal

secretion (Schirmer test ,10 mm in 5 min) and a reduced forced expiratory volume in 1 s

(FEV1) were documented. A biopsy specimen from a sclerodermatous area showed a

thickened reticular and papillary dermis with closely packed collagen bundles and

abundant melanophages in the dermis (Fig. 4). Azathioprine was added to the

corticosteroid therapy in an attempt to arrest the progression of the disease. Six months

after starting treatment, cutaneous lesions still persist, but the patient has not developed

any other systemic symptoms.

Discussion

Chronic graft-versus-host disease (GVHD) is the major late

complication of allogeneic bone marrow transplantation.

Between 25% and 45% of the long-term allogeneic sur-

vivors develop the polymorphous syndrome of chronic

GVHD.1–3 Clinically, pathologically, and immunologically

it resembles an autoimmune disease that shares features

with systemic sclerosis, lichen planus, Sjogren syndrome,

and primary biliary cirrhosis.2,4–6 Chronic GVHD is a

multi-organ disease in which skin involvement is almost a

constant feature. It is initially characterized by lichen

planus-like lesions, whereas sclerodermatous changes occur

later and far less frequently.1,3,6–8 We report a case of

chronic GVHD showing the coexistence of lichen sclerosus

et atrophicus and sclerodermatous lesions, which to the

best of our knowledge has not been reported before.

Cutaneous changes are virtually always present in chronic

Figure 1 Diffuse subepithelial

lymphocytic inflammation and

satellite cell necrosis of squamous cells

in oral mucosa (hematoxylin and

eosin, 325)


GVHD and two distinct patterns, lichenoid and scleroderm-

atous, may be identified. We must emphasize the simultan-

eous coexistence of lichen sclerosus et atrophicus changes

and indurated morphea-like plaques in our patient. The

concurrent relationship of lichen sclerosus to localized

scleroderma is well recognized,9–11 and it has been noted

that the coexistence of the two entities is not uncommon.11

Our working group has reported several cases in which

changes of both morphea and lichen sclerosus et atrophicus

were present in the same lesion.10 An inflammatory cellular

infiltrate that extends from the deep dermis to the subcuta-

neous fat is the main finding in morphea. In lichen sclerosus,

however, it involves the upper reticular and papillary

dermis with hyalinization of the collagen. Some authors

have proposed that lichen sclerosus et atrophicus is a

superficial form of morphea.9 These pathologic findings

support the concept that the localized sclerodermatous

710 Cameo Lichen sclerosus et atrophicus in GVHD Cordoba et al.

conditions are a spectrum of diseases. Histopathologic

changes are variable and correlate with the clinical appear-

ance. Chronic GVHD is a pseudosclerodermatous condition

that may mimic the skin and extracutaneous manifestations

found in localized and systemic scleroderma. Some authors,

however, have found several differences in the sclerotic

phase of chronic GVHD, when compared with the ultra-

structural findings of idiopathic scleroderma; in the former,

inflammation and fibrosis are first observed in the papillary

dermis and the staining for procollagen I and III and

collagen III is heavier in the papillary dermis.12 Antismooth

muscle, antimitochondrial and antinuclear antibodies can

be detected in chronic GVHD, but they are usually found

in extensive disease with multiple organ involvement.5,13

As chronic GVHD involves the papillary dermis, it should

show a superficial morphea variant (lichen sclerosus et

atrophicus). For unknown reasons, however, it is uncom-

Figure 2 Atrophic and confluent plaques with follicular plugs

on the neck

Figure 3 Follicular plugging, atrophy

of the stratum Malpighii, hydropic

degeneration of basal cells with a split

visible at the dermoepidermal

junction, and homogenization of the

collagen in the upper dermis

(hematoxylin and eosin, 325)


mon. We have not found any previously reported case of

lichen sclerosus et atrophicus-like lesions in chronic GVHD.

In 1990, it was reported that the mucocutaneous manifesta-

tions of chronic GVHD may clinically resemble a wide

variety of skin diseases including lichen sclerosus et atro-

phicus.14 In 1992, two patients with chronic sclerodermat-

ous GVHD, in whom extensive sclerotic lesions were

associated with multiple atrophic pearly white plaques and

ulceration, were described.1 The lesions resembled lichen

sclerosus et atrophicus-like lesions in clinical appearance.

The clinical outcome was fatal in both cases and this

atrophic and sclerotic pattern was considered as a marker

of severe chronic GVHD. Limited chronic GVHD has a

favorable prognosis, whereas patients with extensive dis-

ease require early treatment before clinical deterioration.

References

1 Chosidow O, Bagot M, Vernant JP. Sclerodermatous

chronic graft-versus-host disease. Analysis of seven cases.

J Am Acad Dermatol 1992; 26: 49–55.

2 Sullivan KM, Shulman HM, Storb R. Chronic graft-

versus-host disease in 52 patients: adverse natural course

and successful treatment with combination

immunosuppression. Blood 1981; 57: 267–276.

3 Aractingi S, Janin A, Devergie A, et al. Histochemical

and ultrastructural study of diffuse melanoderma after

bone marrow transplantation. Br J Dermatol 1996; 134:

325–331.

4 Atkinson K. Chronic graft-versus-host disease. Rev Bone

Marrow Transplant 1990; 5: 69–82.

5 Siegert W, Stemerowicz R, Hopf U. Antimitochondrial

antibodies in patients with chronic graft-versus-host

disease. Bone Marrow Transplant 1992; 10: 221–227.

Cordoba et al. Lichen sclerosus et atrophicus in GVHD Cameo 711

Figure 4 Thick collagen bundles in

reticular and papillary dermis

(hematoxylin and eosin, 310)

6 Spielvogel MR, Goltz RW, Kersey JH. Scleroderma-like

changes in chronic graft-versus-host disease. Arch

Dermatol 1977; 113: 1424–1428.

7 Aragues M, Fraga J, Fernandez-Herrera JM, et al.

Enfermedad injerto contra huesped cutanea. Estudio

clınico e histopatologico. Actas Dermo-Sif 1987; 78:

7–11.

8 Graham-Brown RAC, Sarkany I. Scleroderma-like

changes due to chronic graft-versus-host disease. Clin

Exp Dermatol 1983; 8: 531–538.

9 Conelly MG, Winkelman RK. Coexistence of lichen

sclerosus et atrophicus, morphea and lichen planus.

J Am Acad Dermatol 1985; 12: 844–851.

10 Buezo GF, Penas PF, Dorado JM, et al. Liquen

escleroatrofico y morfea. Actas Dermo-Sif 1994; 85:

201–205.

From the collection of Lawrence Charles Parish, MD, Philadelphia,

Pennsylvania.


11 Jablonska S. Differential diagnosis of scleroderma-like

disorders. In: Clements PJ, Furst DE, eds. Systemic

Sclerosis. Baltimore: Williams & Wilkins, 1997: 99–119.

12 Tabata H, Yamakage A, Yamazaki S. Electron-

microscopic study of sclerodermatous chronic graft-

versus-host disease. Int J Dermatol 1996; 35: 862–866.

13 Shulman HM, Sullivan KM, Weiden PL. Chronic graft-

versus-host syndrome in man. A long-term

clinicopathologic study of 20 Seattle patients. Am J Med

1980; 69: 204–217.

14 Volc-Platzer B, Stingl G. Cutaneous graft-vs-host disease.

In: Burakoff SJ, et al. eds. Graft-Vs-Host Disease

Immunology, Pathophysiology and Treatment. New

York: Marcel Dekker, 1990: 245–253.

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