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A Case of Cutaneous Rosai-Dorfman Disease Refractory to Imatinib Therapy FREE

Carl Gebhardt, MD; Marco Averbeck, MD; Uwe Paasch, MD; Selma Ugurel, MD; Hjalmar Kurzen, MD; Patrick Stumpp, MD; Jan C. Simon, MD; Regina Treudler, MD
[+] Author Affiliations

Author Affiliations: Departments of Dermatology, Venereology, and Allergology (Drs Gebhardt, Averbeck, Paasch, Simon, and Treudler) and Radiology (Dr Stumpp), Universitätsklinikum Leipzig Anstalt öffentlichen Rechts, Leipzig, and Department of Dermatology, Venereology, and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, Mannheim (Drs Ugurel and Kurzen), Germany.


Arch Dermatol. 2009;145(5):571-574. doi:10.1001/archdermatol.2008.597.
Text Size: A A A
Published online

ABSTRACT

Background  Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that recently has been treated successfully with imatinib mesylate in a patient with a systemic variant of the disease.

Observations  We describe a 69-year-old man with cutaneous Rosai-Dorfman disease manifesting as progressive, deeply infiltrated skin lesions. Histopathologic examination of the lesions demonstrated dense dermal infiltrate positive for CD68, stabilin-1, and S-100, but not for CD1a. The histiocytes were positive for platelet-derived growth factor receptor α, the target molecule for imatinib. During the 5-year course of the disease, multiple therapeutic approaches (tuberculostatic drugs, topical and systemic glucocorticoids, thalidomide, isotretinoin, and methotrexate) did not result in significant improvement. Imatinib mesylate therapy (600 mg/d for 2½ weeks and then 400 mg/d for 10 weeks) had no effect, despite the expression of platelet-derived growth factor receptor α on the histiocytes.

Conclusions  Failure of imatinib therapy in our patient may be due to a lack of functioning target molecules, the therapy protocol, or the course of the disease. Cutaneous and systemic variants of Rosai-Dorfman disease may be different clinical entities or at least may respond differently to tyrosine kinase inhibitors.

Figures in this Article

Rosai-Dorfman disease (RDD) is a non–Langerhans cell histiocytosis and was first described by Rosai and Dorfman in 1969.1 Because the disease primarily involves lymph nodes, it is also known as sinus histiocytosis with massive lymphadenopathy. Extranodal manifestations have been reported in 43% of cases, most frequently affecting the skin.2 A cutaneous variant of RDD (C-RDD) was reported for the first time in 1978 by Thawerani et al.3 Since then, about 75 cases of C-RDD have been reported.4 Histologically, RDD is characterized by histiocytes with large vesicular nuclei and abundant cytoplasm. These cells are positive for markers typical in monocytes and macrophages (eg, CD68) and in dendritic and Langerhans cells (S100), while being negative for CD1a.46

Despite the clear histologic features, the clinical diagnosis of C-RDD is difficult because of a variable clinical appearance without lymphadenopathy. Most lesions are located on the face, followed by the back, chest, thigh, flank, and shoulder. Clinically, the morphologic structure of lesions ranges from nodules, pustules, and papules to plaques and patches.4 It has been suggested that C-RDD and systemic (S-RDD) variants of the disease are distinct clinical entities.4,5 Cutaneous RDD has a median age at onset of 43.5 years, shows a female preponderance (2:1), and predominantly affects persons of Asian and white race/ethnicity. In contrast, the median age at onset of S-RDD is 20.6 years, it occurs slightly more often in men (1.4:1), and patients are rarely of Asian race/ethnicity.5 Treatment of S-RDD is challenging. Because it is characterized as a benign, self-limiting disease, therapeutic approaches tend to be less aggressive. For example, the use of systemic glucocorticosteroid and antibiotic regimens, as well as cryotherapy, surgical excision, and radiation therapy for localized lesions, has been described.7 Case reports have documented the use of interferon alfa8 or acyclovir.9 Treatment options for C-RDD include surgery, liquid nitrogen, radiation therapy, and glucocorticosteroid or thalidomide regimens.4

Utikal and colleagues10 described a patient with complete remission of S-RDD after receipt of imatinib mesylate therapy. Therefore, we decided to use this drug in a patient with refractory C-RDD.

REPORT OF A CASE

A 69-year-old white man with an otherwise unremarkable medical history had developed progressive, deeply infiltrated skin lesions on the trunk and the upper and lower limbs in 2002. At the initial examination in 2006, we noted deeply infiltrated patches and plaques of dark red to light brown up to 25 cm in diameter that had begun in the gluteal region and later spread to the trunk and the limbs (Figure 1A and B). Hematoxylin-eosin staining of skin biopsy specimens revealed a dense dermal infiltrate, composed mainly of histiocytes and plasma cells, which extended into the subcutis (Figure 2). Lymphocytes were seen within the cytoplasm of these histiocytes (emperipolesis). The cells of the infiltrate were positive for CD68, stabilin-1, and S-100, but not for CD1a. Additional immunohistochemical stainings documented that the histiocytes were positive for platelet-derived growth factor receptor α (PDGFRα) (Figure 3), but not for PDGFRβ or macrophage colony-stimulating factor receptor (data not shown), all of which are target molecules of imatinib.1113 Successive magnetic resonance images and computed tomographic scans showed skin infiltrates but no organ involvement (Figure 1C). All routine laboratory variables were within normal ranges.

Place holder to copy figure label and caption
Figure 1.

Infiltrated patches and plaques of dark red to light brown of the gluteal region (A) and the lower left arm (B) before treatment with imatinib mesylate. Sagittal plane of T1-weighted magnetic resonance images (C and D) with fat suppression and intravenous contrast medium of the lower left arm before (C) and after (D) treatment with imatinib. The tumor (arrows), also seen in B, measures approximately 5.7 × 0.8 cm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Hematoxylin-eosin staining of a skin biopsy specimen. A, Dermal infiltrate of histiocytes and plasma cells extends into the subcutis. B and C, The thin arrows point to insets showing detail of lymphocytes (thick arrows) seen within the cytoplasm of these histiocytes (emperipolesis).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Immunohistochemical staining for platelet-derived growth factor receptor α (PDGFRα) in a skin biopsy specimen from lesional skin (A) and the corresponding negative control (B). In the infiltrate, multiple tumor cells show weak positive cytoplasmatic staining for PDGFRα (red and arrows). No reactivity is found in the corresponding slide stained with an isotype control primary monoclonal antibody.

Graphic Jump Location

During the 5-year course of the disease, the patient had received various treatments without significant improvement, including tuberculostatic drugs, glucocorticosteroids (topical and systemic), thalidomide, isotretinoin, and methotrexate. In 2004, radiation therapy (24 Gy) was performed on symptomatic plaques in the sacral region and on the back and the arms.

Because of the PDGFRα positivity of the tumor cells, imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) therapy was started at a dosage of 600 mg/d. The patient experienced constipation and spasmodic abdominal pain, which are known adverse effects of imatinib mesylate therapy, so the dosage was reduced after 2½ weeks to 400 mg/d, which was well tolerated and was continued for 10 more weeks. No significant response was detected after the 12½ weeks of imatinib therapy clinically or by magnetic resonance imaging of the marker lesions on the forearm. Therefore, imatinib treatment was discontinued.

COMMENT

Utikal et al10 successfully treated a patient having S-RDD with imatinib. In contrast, C-RDD in our patient was completely resistant to this treatment.

Imatinib is a tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia, eosinophilia, gastrointestinal stromal tumors, and dermatofibrosarcoma protuberans. It inhibits the tyrosine kinases BCR-ABL, PDGFRα and PDGFRβ, and Kit. Low dosages of imatinib mesylate (100 mg/d) are effective in diseases associated with the FIP1L1-PDGFRα tyrosine kinase, a “gain-of-function” mutation due to an 800-kB deletion on chromosome 4q12, which can be found in some cases of hypereosinophilic syndrome.14,15 Imatinib therapy is effective in diseases associated with the BCR-ABL fusion protein (such as chronic myeloid leukemia) or with PDGFRα and c-Kit (such as gastrointestinal stromal tumors).16,17 Because imatinib also targets the macrophage colony-stimulating factor receptor, it was recommended for use in diseases in which c-fms activation is implicated (eg, breast and ovarian cancer and inflammatory conditions).12,18 Montella et al13 reported successful therapy of cerebral Langerhans cell histiocytosis using imatinib.

There are several possible explanations for the failure of imatinib therapy. The following are applicable in our patient with C-RDD.

TARGET MOLECULES

In our patient, skin lesions stained weakly positive for PDGFRα and were negative for PDGFRβ and c-Kit, suggesting that the tumor cells might not express sufficient target molecules for imatinib therapy. In comparison, lesions in the patient treated by Utikal et al10 stained positive for the target molecules of imatinib PDGFRβ and Kit. Recently reported PDGFRα mutations, which cause resistance to imatinib,12 might also explain the failure of this drug in our patient. However, we were unable to test this hypothesis because our patient refused further investigations, believing they would be of no therapeutic benefit to him.

TREATMENT PROTOCOL

Utikal et al10 treated their patient for 10 weeks at a high dose of imatinib mesylate (600 mg/d). Because of gastrointestinal adverse effects in our patient, we had reduced the dose to 400 mg/d.

COURSE OF THE DISEASE

The course of the disease was much longer in our patient (5 years) than in the patient treated by Utikal et al10 (1½ years). Newer lesions may have higher turnover and shorter cell cycles and demonstrate better response to imatinib therapy, which abrogates the activation of multiple signal transduction pathways.

In conclusion, our case findings suggest that C-RDD and S-RDD may be distinct clinical entities. Therefore, they may respond differently to tyrosine kinase inhibition by imatinib therapy.4,5,19

ARTICLE INFORMATION

Correspondence: Carl Gebhardt, MD, Department of Dermatology, Venereology, and Allergology, Universitätsklinikum Leipzig Anstalt öffentlichen Rechts, Philipp-Rosenthal-Strasse 23-25, 04103 Leipzig, Germany (Carl.Gebhardt@mail.medizin.uni-leipzig.de).

Accepted for Publication: August 1, 2008.

Author Contributions: Drs Gebhardt, Averbeck, Simon, and Treudler had full access to all the data in the study and take responsibility for the integrity of the data. Study concept: Simon and Treudler. Acquisition of data: Gebhardt, Averbeck, Paasch, Kurzen, and Stumpp. Drafting of the manuscript: Gebhardt and Averbeck. Critical revision of the manuscript important for intellectual content: Ugurel, Kurzen, Simon, and Treudler. Study supervision: Simon and Treudler.

Financial Disclosure: None reported.

Funding/Support: Novartis Deutschland GmbH (Nürnberg, Germany) generously supplied the Gleevec.

REFERENCES

Rosai  JDorfman  RF Sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinicopathological entity. Arch Pathol 1969;87 (1) 63- 70
PubMed
Rosai  JDorfman  RF Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder: analysis of 34 cases. Cancer 1972;30 (5) 1174- 1188
PubMed Link to Article
Thawerani  HSanchez  RLRosai  J  et al.  The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch Dermatol 1978;114 (2) 191- 197
PubMed Link to Article
Wang  KHChen  WYLiu  HN Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol 2006;154 (2) 277- 286
PubMed Link to Article
Brenn  TCalonje  EGranter  SR Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol 2002;24 (5) 385- 391
PubMed Link to Article
Middel  PHemmerlein  BFayyazi  A Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship to macrophages and for a cytokine-related disorder. Histopathology 1999;35 (6) 525- 533
PubMed Link to Article
Pulsoni  AAnghel  GFalcucci  P Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol 2002;69 (1) 67- 71
PubMed Link to Article
Löhr  HFGodderz  WWolfe  T Long-term survival in a patient with Rosai-Dorfman disease treated with interferon-alpha. Eur J Cancer 1995;31A (13-14) 2427- 2428
PubMed Link to Article
Baildam  EMEwing  CID’Souza  SW Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): response to acyclovir. J R Soc Med 1992;85 (3) 179- 180
PubMed
Utikal  JUgurel  SKurzen  H Imatinib as a treatment option for systemic non–Langerhans cell histiocytoses. Arch Dermatol 2007;143 (6) 736- 740
PubMed Link to Article
Corless  CLSchroeder  AGriffith  D PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23 (23) 5357- 5364
PubMed Link to Article
Dewar  ALCambareri  ACZannettino  AC Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 2005;105 (8) 3127- 3132
PubMed Link to Article
Montella  LInsabato  LPalmieri  G Imatinib mesylate for cerebral Langerhans’-cell histiocytosis. N Engl J Med 2004;351 (10) 1034- 1035
PubMed Link to Article
Pardanani  ABrockman  SRPaternoster  SF FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104 (10) 3038- 3045
PubMed Link to Article
Pardanani  AKetterling  RPLi  CY FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006;30 (8) 965- 970
PubMed Link to Article
Siehl  JThiel  E C-kit, GIST, and imatinib. Recent Results Cancer Res 2007;176145- 151
PubMed
van Oosterom  ATJudson  IVerweij  J Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358 (9291) 1421- 1423
PubMed Link to Article
Paniagua  RTSharpe  OHo  PP Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 2006;116 (10) 2633- 2642
PubMed Link to Article
Frater  JLMaddox  JSObadiah  JM Cutaneous Rosai-Dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg 2006;10 (6) 281- 290
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Infiltrated patches and plaques of dark red to light brown of the gluteal region (A) and the lower left arm (B) before treatment with imatinib mesylate. Sagittal plane of T1-weighted magnetic resonance images (C and D) with fat suppression and intravenous contrast medium of the lower left arm before (C) and after (D) treatment with imatinib. The tumor (arrows), also seen in B, measures approximately 5.7 × 0.8 cm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Hematoxylin-eosin staining of a skin biopsy specimen. A, Dermal infiltrate of histiocytes and plasma cells extends into the subcutis. B and C, The thin arrows point to insets showing detail of lymphocytes (thick arrows) seen within the cytoplasm of these histiocytes (emperipolesis).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Immunohistochemical staining for platelet-derived growth factor receptor α (PDGFRα) in a skin biopsy specimen from lesional skin (A) and the corresponding negative control (B). In the infiltrate, multiple tumor cells show weak positive cytoplasmatic staining for PDGFRα (red and arrows). No reactivity is found in the corresponding slide stained with an isotype control primary monoclonal antibody.

Graphic Jump Location

Tables

References

Rosai  JDorfman  RF Sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinicopathological entity. Arch Pathol 1969;87 (1) 63- 70
PubMed
Rosai  JDorfman  RF Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder: analysis of 34 cases. Cancer 1972;30 (5) 1174- 1188
PubMed Link to Article
Thawerani  HSanchez  RLRosai  J  et al.  The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch Dermatol 1978;114 (2) 191- 197
PubMed Link to Article
Wang  KHChen  WYLiu  HN Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol 2006;154 (2) 277- 286
PubMed Link to Article
Brenn  TCalonje  EGranter  SR Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol 2002;24 (5) 385- 391
PubMed Link to Article
Middel  PHemmerlein  BFayyazi  A Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship to macrophages and for a cytokine-related disorder. Histopathology 1999;35 (6) 525- 533
PubMed Link to Article
Pulsoni  AAnghel  GFalcucci  P Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol 2002;69 (1) 67- 71
PubMed Link to Article
Löhr  HFGodderz  WWolfe  T Long-term survival in a patient with Rosai-Dorfman disease treated with interferon-alpha. Eur J Cancer 1995;31A (13-14) 2427- 2428
PubMed Link to Article
Baildam  EMEwing  CID’Souza  SW Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): response to acyclovir. J R Soc Med 1992;85 (3) 179- 180
PubMed
Utikal  JUgurel  SKurzen  H Imatinib as a treatment option for systemic non–Langerhans cell histiocytoses. Arch Dermatol 2007;143 (6) 736- 740
PubMed Link to Article
Corless  CLSchroeder  AGriffith  D PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23 (23) 5357- 5364
PubMed Link to Article
Dewar  ALCambareri  ACZannettino  AC Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 2005;105 (8) 3127- 3132
PubMed Link to Article
Montella  LInsabato  LPalmieri  G Imatinib mesylate for cerebral Langerhans’-cell histiocytosis. N Engl J Med 2004;351 (10) 1034- 1035
PubMed Link to Article
Pardanani  ABrockman  SRPaternoster  SF FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104 (10) 3038- 3045
PubMed Link to Article
Pardanani  AKetterling  RPLi  CY FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006;30 (8) 965- 970
PubMed Link to Article
Siehl  JThiel  E C-kit, GIST, and imatinib. Recent Results Cancer Res 2007;176145- 151
PubMed
van Oosterom  ATJudson  IVerweij  J Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358 (9291) 1421- 1423
PubMed Link to Article
Paniagua  RTSharpe  OHo  PP Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 2006;116 (10) 2633- 2642
PubMed Link to Article
Frater  JLMaddox  JSObadiah  JM Cutaneous Rosai-Dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg 2006;10 (6) 281- 290
PubMed

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