cell markers, including EMA, GLUT-1 and claudin-1, but usually negative for S-100 protein [4, 5]. BPNST generally consists of Schwann cells, fibroblasts and perineurial cells in various proportions. There have been several recent reports describing hybrid BPNSTs, such as neurofibroma and schwannoma, neurofibroma and perineurioma, perineurioma and granular cell tumor, and schwannoma and perineurioma [6]. To our knowledge, only a few cases of composite perineurioma have been documented in association with NF-1 [1-3, 7, 8]. Zamecnik and Michal analyzed the immunohistochemical features of 99 neurofibromas [8, 9]. Eight tumors contained EMA-positive perineurial cells inside the neurofibromatous lesions, four of which showed perceivable perineurial cell differentiation by routine hematoxylin and eosin (H&E) staining. Given the similar histopathology between perineurioma and neurofibroma, perineurial differentiation in neurofibroma is easily overlooked. Therefore, hybrid tumors of perineurioma-neurofibroma may be more common than recognized. Plexiform neurofibromas are characterized by a nodular growth pattern that may be attributed to the presence of a perineurial component circumscribing the Schwann cell proliferation. In our case, the perineurial GLUT-1 component was mainly located at the edge of the nodule, and this perineurial component might be more developed than in the majority of NF-1 plexiform tumors. The current patient’s hybrid tumor had developed in the plexiform neurofibroma as a painful nodule. In such cases, the primary differential diagnosis should be MPNST, but a hybrid tumor can occur. MPNST typically arises as a rapidly growing, painful mass in a pre-existing plexiform neurofibroma, with dismal prognosis. Using H&E staining alone, it is sometimes difficult to distinguish perineurioma from other spindle cell neoplasms [4, 10]. In the current case, the perineuriomatous areas showed definite expression of EMA, GLUT-1 and claudin-1 but lacked S-100 protein and CD34 expression, whereas the neurofibromatous areas showed the opposite characteristics, with the staining pattern clearly highlighted these two lesions. We should be aware that hybrid perineurioma-neurofibroma can, in NF-1 patients, mimic MPNST. Disclosure. Financial support: none. Conflict of interest: none. 1
Department of Dermatology Department of Anatomic Pathology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan 2
Yusuke INATOMI1 Takamichi ITO1 Konosuke NAGAE1 Yuichi YAMADA2 Mari KIYOMATSU1 Misa NAKANONAKAMURA1 Hiroshi UCHI1 Yoshinao ODA2 Masutaka FURUE1
1. Schaefer I, Strobel P, Thiha A, et al. Soft tissue perineurioma and other unusual tumors in a patient with neurofibromatosis type 1. Int J Clin Exp Pathol 2013; 6: 3003-8. 2. Lassmann H, Jurecka W, Lassmann G, Matras H, Watzek G. Different types of benign nerve sheath tumors. Light microscopy, electron microscopy and autoradiography. Virchows Arch A Path Anat And Histol 1977; 375: 197-210. EJD, vol. 24, n◦ 3, May-June 2014
3. Theaker JM, Gatter KC, Puddle J. Epithelial membrane antigen expression by the perineurium of peripheral nerve and in peripheral nerve tumours. Histopathology 1988; 13: 171-9. 4. Hornick JL, Fletcher CDM. Soft tissue perineurioma. Clinicopathologic analysis of 81 cases including those with atypical histologic features. Am J Surg Pathol 2005; 29: 845-58. 5. William A, Robert V, Bolette L, Dylan V, Andrew L. GLUT-1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms. Human Pathology 2008; 39: 1519-26. 6. Requena L, Sitthinamsuwan P, Fried I, et al. A benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma. Am J Surg Pathol 2013; 37: 845-52. 7. Ausmus GG, Piliang MP, Bergfeld WF, Goldblum JR. Soft-tissue perineurioma in a 20-year-old patient with neurofibromatosis type 1 (NF1): report of a case and review of the literature. J Cutan Pathol 2007; 34: 726-30. 8. Kacerovska D, Michal M, Kuroda N, et al. Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. Am J Dermatopathol 2013; 35: 641-9. 9. Zamecnik M, Michal M. Perineurial cell differentiation in neurofibromas. Report of eight cases including a case with composite perineurioma-neurofibroma features. Pathol Res Pract 2001; 197: 53744. 10. Folpe AL, Billings SD, McKenney JK, Walsh SV, Nusrat A, Weiss SW. Expression of claudin-1, a recently described tight junctionassociated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002; 26: 1620-6. doi:10.1684/ejd.2014.2353
Omeprazole-induced drug reaction with eosinophilia and systemic symptoms (DRESS) We report here a case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) following treatment with omeprazole, which, to our knowledge has not been reported before. An 88-year-old woman with a history of arterial hypertension, chronic renal failure (creatinine clearance estimated by MDRD: 34.8 ml/min) and chronic lymphocytic leukemia (CLL) diagnosed in 2005, presented with a cutaneous rash and pruritus. Despite treatment with hydroxyzine, the rash became widespread and pruritus persisted. The patient was hospitalized 8 days later with facial and cervicobrachial oedema, difficulty in swallowing and dysphonia. She had begun treatment with omeprazole 53 days prior to, and discontinued it 7 days before hospitalization. Her current treatment included celiprolol, furosemide, losartan, lysine acetylsalicylate and acetaminophen. Physical examination showed a maculopapular exanthema on the trunk and the face converging with wide patches with purpuric lesions (including the hard palate) and unremitting pruritus over the whole body. Maculopapular lesions were scattered on the limbs. Examination also revealed right axillary lymphadenopathy and fever (38 ◦ C) after stopping acetaminophen. At admission, blood tests showed leukocytosis, lymphocytosis (probably related to untreated CLL), inflammatory syndrome and hepatic and renal dysfunction. Between days 3 and 9 after admission, the patient’s blood tests deteriorated (table 1). Given these features, the diagnosis of DRESS was made. A skin biopsy showed a lichenoid
413
Table 1. Evolution of blood tests of the patient
Leukocytes Lymphocytes Eosinophils CRP Uremia Serum creatinine (creatinine clearance estimated by MDRD mL/min/1.73 m2 ) ALAT ASAT ␥-GT PAL
Normal values
At admission
3 days after admission
9 days after admission
15 days after admission
4-10 G/L 1-4.5 G/L 0.04-0.5 G/L C in intron 3 in both patients. The other four family members and seven healthy controls carried heterozygous c.115+6T>C mutations. However, 161 healthy controls carried the wild types of IL36RN (figure 1F). The c.115+6T>C mutation can cause skipping of exon 3, leading to a frameshift and an immediate premature termination codon in transcription and translation of IL36RN [3, 4]. Loss of expression and/or function of IL-36Ra EJD, vol. 24, n◦ 3, May-June 2014
A A A G G T T G
G C G A T
A A A G G T T G
G T/C G A T
Homozygous
Heterozygous A A A G G T T
G
G
T G
A T
Wildtype
Figure 1. A) Pedigree of the Chinese Daur family, solid symbols indicated affected family members; B) Pigmentation and atrophic scars on the lower legs in patient 1; C) Erythema and crusts on the trunk and arms in patient 1; D) Pustular erythema on the trunk in patient 2; E) Spongiosis of Kogoj and acanthosis in the epidermis of the pustular lesion(H-E staining, bar = 100 m) in patient 2. F) Sequence chromatogram of the IL36RN.
are predicted to induce hyperactivation of the IL36/IL36R signaling and subsequent overexpression of inflammatory cytokines [4], which may be involved in the pathogenesis of DITRA. Combined with clinical manifestations, histopathological and gene examinations, the two patients were diagnosed as DITRA. Homozygous or compound heterozygous mutations of the IL36RN gene detected from familial GPP [2, 3], some cases of sporadic GPP [4-7], and our cases further supported the hypothesis. It is interesting that patient 1 had an earlier onset, more severe, longer course and more frequent attacks of GPP than patient 2, and had hypopigmented atrophic scars which are uncommon in GPP patients. In addition to the IL36RN mutation, potential environmental triggers, genetic modifiers and immune responses may also be involved in the pathogenesis of DITRA. Moreover, we also detected 7 healthy controls carrying heterozygous c.115+6T>C mutations and the minor allele frequency (MAF) C equaled 0.0208, which is far above the value (C = 0.0037) in the African population and approaches the value (C = 0.0412) of Han Chinese in Beijing from the 1000 Genomes Project. Whether the c.115+6T>C mutation is the founder mutation in Chinese DITRA patients remains to be explored. In conclusion, we report for the first time two siblings with DITRA, from a Chinese Daur family, who both carried the homozygous IL36RN c.115+6T>C mutation. We speculate
415
Department of Dermatology Department of Anatomic Pathology, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan 2
Yusuke INATOMI1 Takamichi ITO1 Konosuke NAGAE1 Yuichi YAMADA2 Mari KIYOMATSU1 Misa NAKANONAKAMURA1 Hiroshi UCHI1 Yoshinao ODA2 Masutaka FURUE1
1. Schaefer I, Strobel P, Thiha A, et al. Soft tissue perineurioma and other unusual tumors in a patient with neurofibromatosis type 1. Int J Clin Exp Pathol 2013; 6: 3003-8. 2. Lassmann H, Jurecka W, Lassmann G, Matras H, Watzek G. Different types of benign nerve sheath tumors. Light microscopy, electron microscopy and autoradiography. Virchows Arch A Path Anat And Histol 1977; 375: 197-210. EJD, vol. 24, n◦ 3, May-June 2014
3. Theaker JM, Gatter KC, Puddle J. Epithelial membrane antigen expression by the perineurium of peripheral nerve and in peripheral nerve tumours. Histopathology 1988; 13: 171-9. 4. Hornick JL, Fletcher CDM. Soft tissue perineurioma. Clinicopathologic analysis of 81 cases including those with atypical histologic features. Am J Surg Pathol 2005; 29: 845-58. 5. William A, Robert V, Bolette L, Dylan V, Andrew L. GLUT-1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms. Human Pathology 2008; 39: 1519-26. 6. Requena L, Sitthinamsuwan P, Fried I, et al. A benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma. Am J Surg Pathol 2013; 37: 845-52. 7. Ausmus GG, Piliang MP, Bergfeld WF, Goldblum JR. Soft-tissue perineurioma in a 20-year-old patient with neurofibromatosis type 1 (NF1): report of a case and review of the literature. J Cutan Pathol 2007; 34: 726-30. 8. Kacerovska D, Michal M, Kuroda N, et al. Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. Am J Dermatopathol 2013; 35: 641-9. 9. Zamecnik M, Michal M. Perineurial cell differentiation in neurofibromas. Report of eight cases including a case with composite perineurioma-neurofibroma features. Pathol Res Pract 2001; 197: 53744. 10. Folpe AL, Billings SD, McKenney JK, Walsh SV, Nusrat A, Weiss SW. Expression of claudin-1, a recently described tight junctionassociated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002; 26: 1620-6. doi:10.1684/ejd.2014.2353
Omeprazole-induced drug reaction with eosinophilia and systemic symptoms (DRESS) We report here a case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) following treatment with omeprazole, which, to our knowledge has not been reported before. An 88-year-old woman with a history of arterial hypertension, chronic renal failure (creatinine clearance estimated by MDRD: 34.8 ml/min) and chronic lymphocytic leukemia (CLL) diagnosed in 2005, presented with a cutaneous rash and pruritus. Despite treatment with hydroxyzine, the rash became widespread and pruritus persisted. The patient was hospitalized 8 days later with facial and cervicobrachial oedema, difficulty in swallowing and dysphonia. She had begun treatment with omeprazole 53 days prior to, and discontinued it 7 days before hospitalization. Her current treatment included celiprolol, furosemide, losartan, lysine acetylsalicylate and acetaminophen. Physical examination showed a maculopapular exanthema on the trunk and the face converging with wide patches with purpuric lesions (including the hard palate) and unremitting pruritus over the whole body. Maculopapular lesions were scattered on the limbs. Examination also revealed right axillary lymphadenopathy and fever (38 ◦ C) after stopping acetaminophen. At admission, blood tests showed leukocytosis, lymphocytosis (probably related to untreated CLL), inflammatory syndrome and hepatic and renal dysfunction. Between days 3 and 9 after admission, the patient’s blood tests deteriorated (table 1). Given these features, the diagnosis of DRESS was made. A skin biopsy showed a lichenoid
413
Table 1. Evolution of blood tests of the patient
Leukocytes Lymphocytes Eosinophils CRP Uremia Serum creatinine (creatinine clearance estimated by MDRD mL/min/1.73 m2 ) ALAT ASAT ␥-GT PAL
Normal values
At admission
3 days after admission
9 days after admission
15 days after admission
4-10 G/L 1-4.5 G/L 0.04-0.5 G/L C in intron 3 in both patients. The other four family members and seven healthy controls carried heterozygous c.115+6T>C mutations. However, 161 healthy controls carried the wild types of IL36RN (figure 1F). The c.115+6T>C mutation can cause skipping of exon 3, leading to a frameshift and an immediate premature termination codon in transcription and translation of IL36RN [3, 4]. Loss of expression and/or function of IL-36Ra EJD, vol. 24, n◦ 3, May-June 2014
A A A G G T T G
G C G A T
A A A G G T T G
G T/C G A T
Homozygous
Heterozygous A A A G G T T
G
G
T G
A T
Wildtype
Figure 1. A) Pedigree of the Chinese Daur family, solid symbols indicated affected family members; B) Pigmentation and atrophic scars on the lower legs in patient 1; C) Erythema and crusts on the trunk and arms in patient 1; D) Pustular erythema on the trunk in patient 2; E) Spongiosis of Kogoj and acanthosis in the epidermis of the pustular lesion(H-E staining, bar = 100 m) in patient 2. F) Sequence chromatogram of the IL36RN.
are predicted to induce hyperactivation of the IL36/IL36R signaling and subsequent overexpression of inflammatory cytokines [4], which may be involved in the pathogenesis of DITRA. Combined with clinical manifestations, histopathological and gene examinations, the two patients were diagnosed as DITRA. Homozygous or compound heterozygous mutations of the IL36RN gene detected from familial GPP [2, 3], some cases of sporadic GPP [4-7], and our cases further supported the hypothesis. It is interesting that patient 1 had an earlier onset, more severe, longer course and more frequent attacks of GPP than patient 2, and had hypopigmented atrophic scars which are uncommon in GPP patients. In addition to the IL36RN mutation, potential environmental triggers, genetic modifiers and immune responses may also be involved in the pathogenesis of DITRA. Moreover, we also detected 7 healthy controls carrying heterozygous c.115+6T>C mutations and the minor allele frequency (MAF) C equaled 0.0208, which is far above the value (C = 0.0037) in the African population and approaches the value (C = 0.0412) of Han Chinese in Beijing from the 1000 Genomes Project. Whether the c.115+6T>C mutation is the founder mutation in Chinese DITRA patients remains to be explored. In conclusion, we report for the first time two siblings with DITRA, from a Chinese Daur family, who both carried the homozygous IL36RN c.115+6T>C mutation. We speculate
415
