Author Affiliations: Mayo Medical School, College of Medicine (Mr Balin), Department of Dermatology (Drs Wetter and Pittelkow) and Divisions of Hematopathology (Dr Kurtin) and Hematology (Dr Letendre), Mayo Clinic, Rochester, Minnesota.
Granulomatous dermatitis has rarely been reported as a manifestation of leukemia or myelodysplastic syndrome (MDS). We describe a case of widespread granulomatous dermatitis that preceded the diagnosis of MDS by 2 years.
A 71-year-old man developed a generalized, mildly pruritic eruption that slowly progressed over a 2-year period. Punch biopsy specimens demonstrated interstitial dermal granulomatous inflammation. A complete blood cell count with differential showed marked monocytosis, and the findings of a subsequent biopsy of the bone marrow confirmed MDS. Lenalidomide therapy was initiated, and the patient's skin condition improved after 6 weeks of treatment; however, his MDS progressed to acute myeloid leukemia, and he died shortly thereafter.
There is a paucity of literature documenting the occurrence of granulomatous dermatitis as a manifestation of an underlying hematologic disorder. This case illustrates a striking example of widespread granulomatous dermatitis heralding the onset of MDS. It is imperative that the dermatologic community recognize the rare association of granulomatous dermatitis with myelodysplasia, because the cutaneous manifestations may be the presenting finding and can precede the development of leukemia by several years.
The granulomatous dermatitides are a group of skin diseases that are characterized by a predominantly dermal inflammatory infiltrate composed largely of histiocytes; examples include sarcoidosis, granuloma annulare (GA), interstitial granulomatous dermatitis, necrobiosis lipoidica, necrobiotic xanthogranuloma, and rheumatoid nodules.
We describe a case of generalized granulomatous dermatitis that occurred as the heralding symptom of underlying myelodysplastic syndrome (MDS), which progressed to acute myeloid leukemia (AML). This case represents an important association that has been infrequently reported in the literature. We also summarize other reports of granulomatous dermatitides occurring in association with hematologic malignant conditions (excluding necrobiotic xanthogranuloma, which has been well documented to be associated with paraproteinemia and underlying hematologic malignancies, including multiple myeloma).1 We propose that the possibility of an underlying hematologic malignancy should be investigated in patients with generalized granulomatous cutaneous findings of indeterminate cause.
A 71-year-old white man was initially evaluated at an outside institution for a generalized rash of 10 months' duration. The cutaneous eruptions, which were occasionally pruritic and were described as lichenoid, began on the hands but then spread to involve the upper part of the arms, face, trunk, and lower extremities. The initial biopsy specimens were interpreted as interstitial GA. Treatment with high-potency topical corticosteroids (clobetasol propionate) and intramuscular injection of triamcinolone acetonide resulted in no improvement. Additional biopsy specimens were obtained and showed granulomatous inflammation with a subtle palisading pattern. Treatment with hydroxychloroquine sulfate (200 mg by mouth twice daily) for approximately 4 months did not provide any benefit. Of note, the patient had received 20 U of blood over the preceding 3 years because of gastrointestinal tract blood loss resulting from 2 arteriovenous malformations, but records of his blood cell counts and differential before his referral to our institution were not available.
On initial evaluation at our institution approximately 2 years after the onset of the cutaneous eruption, the patient had diffuse erythematous patches and widespread papules that coalesced into large plaques on the trunk, upper extremities, and lower extremities and covered approximately 80% of his body surface area (Figure 1). Facial erythema and nonscarring alopecia of the scalp were also present. Relative areas of sparing were noted on the lateral aspect of the thighs, buttocks, and upper chest area. Of note, a review of systems revealed 27.3 kg of unintentional weight loss during the preceding year. With hematoxylin-eosin staining, punch biopsy specimens showed interstitial dermal granulomatous inflammation with many multinucleated giant cells (Figure 2). Gomori methenamine silver and acid-fast bacillus stains were negative for microorganisms. Immunoperoxidase studies (for CD3, CD4, CD5, CD7, CD8, and CD20) performed on formalin-fixed, paraffin-embedded sections of tissue demonstrated a reactive T-cell infiltrate within the granulomas that was composed of a mixed population of CD4+ and CD8+ cells. Tissue cultures were negative for bacterial, fungal, and mycobacterial infection.
Diffuse granulomatous eruption. A 71-year-old man had a diffuse granulomatous eruption manifested by erythematous patches and coalescing papules on the trunk (A) and lower extremities (B). Close-up images of the axilla (C), thigh (D), and chest (E) highlight the cutaneous morphological features.
Hematoxylin-eosin–stained skin biopsy specimen showing diffuse interstitial dermal granulomatous inflammation with many multinucleated giant cells. A, Original magnification ×40. B, Original magnification ×100.
Extensive laboratory evaluations were performed. Abnormalities were found in values for monocytes, neutrophils, erythrocyte sedimentation rate, hemoglobin, glucose, rheumatoid factor, and antinuclear antibody. All other results were negative or normal (Table 1), including calcium; angiotensin-converting enzyme; aldolase; cyclic citrullinated peptide; immunoglobulins A, M, D, total IgG, IgG2, IgG3, and IgG4; antibodies to myeloperoxidase, proteinase 3, double-stranded DNA, and extractable nuclear antigens (SS-A, SS-B, RNP, Sm, Jo-1, and Scl-70); tuberculin skin test; serum protein electrophoresis; and urinalysis. Peripheral blood flow cytometric immunophenotyping revealed no clonal B- or T-lymphocyte abnormality and no quantitative subset abnormality. The results of peripheral blood T-cell receptor gene rearrangement analysis were negative. Computed tomograms of the chest, abdomen, and pelvis demonstrated mediastinal and abdominal adenopathy (without evidence of hilar or paratracheal adenopathy) and borderline splenomegaly.
Because of the markedly increased monocyte count in the peripheral blood, in conjunction with the patient's skin findings, weight loss, and adenopathy noted on computed tomograms, a bone marrow biopsy specimen was obtained. The biopsy specimen showed increased monocytes, promonocytes, and blast cells, consistent with a diagnosis of MDS. Cytogenetic studies showed no abnormalities. Treatment with lenalidomide was initiated, and after 6 weeks, the patient's skin condition improved (Figure 3). During the 12 weeks between his initial evaluation at our institution and completion of 6 weeks of treatment with lenalidomide, his peripheral monocyte count decreased from 42% to 7%, but his leukocyte count increased from 6200/μL to 18 800/μL (to convert to ×109/L, multiply by 0.001) and contained 63% blast cells. Because the MDS was believed to have progressed, a diagnosis of AML was made. Shortly thereafter, pneumonia developed, and the patient died.
Changes in the cutaneous eruption. After 6 weeks of lenalidomide therapy, fading and flattening of the cutaneous eruption on the trunk (A) and lower extremities (B) are evident.
Skin involvement may be the first sign of an occult underlying malignancy. Cutaneous presentations can vary and include recalcitrant dermatitis.2 Several reports have described granulomatous dermatitis in the setting of underlying malignant conditions, including lymphoma,3,4 leukemia,5- 8 and various solid organ malignancies.9,10
The largest study examining granulomatous dermatitis in association with malignancy described 13 patients with malignant lymphoma and GA.3 The GA eruptions occurred from 5 years before diagnosis to 27 years after the diagnosis of the underlying malignancy. Four of the 13 patients had generalized eruptions (as did our patient) that were largely asymptomatic. The lesions were pruritic in only 1 patient, who had Sézary syndrome. Whether GA was the presenting symptom in any of the patients with lymphoma in these cases is not known.
Several reports have documented granulomatous dermatitis to be the presenting symptom of an underlying hematopoietic malignancy (Table 2). Anan et al5 described a 65-year-old woman with granulomatous inflammation in the subcutis, and 6 months later acute myelomonocytic leukemia was diagnosed. In another report, a 66-year-old woman with a 3-month history of a generalized disseminated cutaneous granulomatous eruption was found to have underlying MDS on further workup.7 The MDS later progressed to AML, as in our patient. Kawakami et al14 described a 70-year-old man with a 3-month history of “GA-like” lesions on his arms; on further workup, he was found to have underlying adult T-cell leukemia. Another report described a 57-year-old man with a 9-month history of a pruritic eruption that was found to be annular elastolytic giant cell granuloma13; further workup revealed underlying AML.
Hinckley et al6 reported 2 cases in which GA was the presenting feature of chronic myelomonocytic leukemia. The first involved a 76-year-old white man with a 7-month history of a generalized pruritic eruption that started on his trunk and spread to his arms; further workup revealed chronic myelomonocytic leukemia. The second case involved a 56-year-old African American man with edema and weight loss who subsequently developed hyperpigmented indurated papules on the extensor aspect of his extremities. Findings of a skin biopsy showed that the lesions were GA. Further evaluation in this case revealed an abnormal population of white blood cells in the bone marrow sample that expressed granulocytic markers. The patient died several months after diagnosis.
Vestey et al12 described 2 patients with granulomatous lesions associated with underlying MDS. The findings of biopsy revealed that the lesions had features of GA in one patient and cutaneous papular sarcoidosis in the other. Both patients had underlying MDS, which progressed to AML in 1 patient. Treatment with chemotherapy was reported to be effective in that case.
Horiuchi et al11 described a 69-year-old man with a 3-year history of “itchy nodules.” On biopsy, the nodules showed histopathologic changes consistent with GA; further workup showed underlying chronic myelomonocytic leukemia. The skin lesions were thought to represent a form of leukemia cutis on the basis of the abnormal appearance of cells in the biopsy specimens.
It is unclear whether the granulomatous dermatitis in the present case represents a novel form of leukemia cutis or a cutaneous reaction due to the underlying MDS. On the basis of the observed cutaneous histopathologic findings, we suspect that the monocytes initially causing the peripheral monocytosis were the same as most of the cells making up the granulomatous cutaneous infiltrate. We believe that these cells were different from the dysplastic cells in the bone marrow sample because the granulomatous dermatitis improved with the resolution of the peripheral monocytosis, whereas the dysplastic blast cells increased in the peripheral blood sample during this time. Unfortunately, the leukemic cells in the bone marrow sample lacked specific fluorescence in situ hybridization markers; therefore, we were unable to definitively show that these cells were not the same ones that caused the granulomatous dermatitis.
Several reports have examined cutaneous manifestations and presentations of leukemia cutis and other cases of MDS. In 1984, Su et al15 examined 42 cases of leukemia cutis and described the clinical presentations; Buechner et al16 then documented the histopathologic presentations in these same 42 cases. Granulomas were not reported in any of the 42 cases examined, nor was granulomatous dermatitis found to be a manifestation of leukemia cutis in any of these cases.15,16
It is unclear why the granulomatous dermatitis in the current case improved but the MDS progressed to AML. One possibility is that the lenalidomide therapy successfully treated the underlying granulomatous dermatitis without treating the MDS. Silapunt and Chon17 described a patient with necrobiotic xanthogranuloma and underlying monoclonal gammopathy of undetermined significance in which the skin condition responded very well to lenalidomide therapy. Whether the necrobiotic xanthogranuloma resolved partly because of the resolving monoclonal gammopathy of undetermined significance or whether the drug had a direct effect on the granulomatous skin eruption in this patient could not be determined.
In summary, we present an illustrative case involving a patient with a 2-year history of a generalized granulomatous eruption that heralded the onset of underlying MDS, which ultimately progressed to AML. Our case shows that granulomatous dermatitides may be the first sign of underlying MDS; therefore, the dermatologic community should be aware of this important and rarely reported association. We hope that clinicians will consider looking for underlying MDS in patients with unexplained granulomatous skin eruptions.
Correspondence: David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email@example.com).
Accepted for Publication: July 23, 2010.
Author Contributions: Mr Balin and Dr Wetter had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wetter and Pittelkow. Acquisition of data: Balin, Wetter, Letendre, and Pittelkow. Analysis and interpretation of data: Balin, Wetter, Kurtin, Letendre, and Pittelkow. Drafting of the manuscript: Balin, Wetter, and Pittelkow. Critical revision of the manuscript for important intellectual content: Balin, Wetter, Kurtin, Letendre, and Pittelkow. Administrative, technical, or material support: Pittelkow. Study supervision: Wetter, Kurtin, and Pittelkow. Consultant caring for patient: Wetter and Letendre.
Financial Disclosure: None reported.
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