Key words: diagnosis, immunoglobulin G4, immunoglobulin G4-related diseases, immunohistochemistry, pseudolymphoma. CASE HISTORY

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1 doi: / Journal of Dermatology 2013; 40: ORIGINAL ARTICLE Case of immunoglobulin G4-related skin disease: Possible immunoglobulin G4-related skin disease cases in cutaneous pseudolymphoma only by immunohistochemical analysis Yohei IWATA, 1 Yoshikazu MIZOGUCHI, 2 Masayuki TAKAHASHI, 1 Beni TANAKA, 1 Makoto KURODA, 2 Akiko YAGAMI, 1 Kayoko MATSUNAGA 1 1 Departments of Dermatology, and 2 Pathology, Fujita Health University School of Medicine, Toyoake, Japan ABSTRACT Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized disease characterized by elevated serum IgG4 levels, tissue infiltration rich in IgG4 + plasma cells. We report on a case which was first considered as pseudolymphoma from the histopathological analysis, but finally diagnosed as IgG4-related skin lesions. As the morphological features of cutaneous involvement of IgG4-RD are consistent with those of cutaneous pseudolymphoma, we tried immunostaining past potential cases of IgG4-RD. Thirty-two skin specimens (15 men and 17 women; mean age, 53 years) diagnosed as having pseudolymphoma were retrieved from the archives to conduct hematoxylin eosin, IgG and IgG4 staining. Out of the 32 cases of cutaneous pseudolymphoma, germinal center formation was seen in 22 cases, and moderate severe fibrosis was seen in seven cases. Eleven cases showed more than 10 IgG4 + plasma cell infiltration/high-power field, and among these 11 cases, seven cases (22%) showed A ratio of IgG4 + /IgG + cells of more than 40%. Thus, out of the 32 cases of cutaneous pseudolymphomas, two cases (6.3%) satisfied IgG4-RD histopathological diagnostic criteria. As clinical presentations and histopathological features of skin involvement of IgG4-RD are analogous to cutaneous B-cell pseudolymphoma, careful identification is required through systemic examination, serum IgG4 measurement and other means. Key words: diagnosis, immunoglobulin G4, immunoglobulin G4-related diseases, immunohistochemistry, pseudolymphoma. INTRODUCTION Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized clinical disease characterized by elevated serum IgG4 concentration, tumefaction or tissue infiltration rich in IgG4 + plasma cells. 1,2 IgG4-RD can affect multiple organs, including the pancreas, hepatobiliary tract, lacrimal glands, salivary glands, lungs, kidneys, retroperitoneum, prostate, aorta and lymph nodes. 1,3 5 IgG4-RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm and inflammatory pseudotumor. 2 IgG4-RD has histopathological features such as prominent lymphocyte or plasma cell infiltrate, fibrosis and frequent formation of lymphoid follicles. Although IgG4-RD patients often have an excellent response to steroid therapy 1,2,6 and proper diagnosis is imperative, the condition has often been misdiagnosed as a malignant tumor, lymphoma, Sj ogren s syndrome or other diseases. 2 Although skin involvement of IgG4-RD has been rarely reported, 3,7 11 IgG4-related skin disease is still not widely recognized. The present study covers a case which was first considered as pseudolymphoma from the histopathological analysis of skin biopsy specimens, but finally diagnosed as IgG4-RD manifested as skin lesions through systemic examination including blood tests, magnetic resonance imaging and computed tomography. As the morphological features of cutaneous involvement of IgG4-RD are consistent with cutaneous pseudolymphoma, skin lesions conventionally diagnosed as cutaneous pseudolymphoma might have included IgG4-RD. We conducted immunostaining to search potential cases of IgG4-RD from the previous cutaneous pseudolymphomasdiagnosed cases. CASE HISTORY A 60-year-old man presented with itching subcutaneous nodules over a wide area, from the left cheek to the mandible, and many erythematous nodules on the extremities (Fig. 1a,b). It was 10 years ago when the patient first noticed soybean-sized Correspondence: Yohei Iwata, M.D., Department of Dermatology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi , Japan. iwayou@fujita-hu.ac.jp Received 11 June 2013; accepted 29 August Japanese Dermatological Association

2 IgG4-related disease in pseudolymphoma (b) (a) Figure 1. There was itching subcutaneous nodules over a wide area from the left cheek to the mandible (a). There were erythematous nodules on the right arm (b). Face magnetic resonance imaging revealed tumefaction in the subcutaneous tissue over a wide area from the left cheek to the mandible (c). nodules in front of the left ear, and they gradually grew in size. He had noticed subcutaneous tumors of various sizes on the extremities 5 years before. Physical examinations showed that these nodules were elastic hard and not well defined. Face magnetic resonance imaging revealed tumefaction in the subcutaneous tissue over the wide area from the left cheek to the mandible (Fig. 1c). Biopsy specimens taken from his face, neck and the right arm revealed dense lymphocytic or plasma cell infiltration with fibrosis in the region from the dermis to subcutaneous adipose tissue, part of which presented a lymphoid follicle structure (Fig. 2a c). Initial pathological diagnosis was of pseudolymphoma. However, the following laboratory investigation showed elevated serum IgG (2242 mg/dl; normal range, mg/dl), IgG4 (1310 mg/dl; normal range, mg/dl) and IgE (547 mg/dl; normal range, 0 99 mg/dl). This made us perform IgG, IgG4 and CD138 immunostaining of biopsy specimens. The number of IgG4 + and IgG + plasma cells was 113 and 114 per high-power field (HPF), respectively (Figs 2d f). Computed tomography showed no additional organ involvement, and ophthalmologic or otolaryngological examination also found no involvement for IgG4-RD. Considering the above clinical presentations and test results, the present case was diagnosed as having IgG4-related skin disease. All skin lesions diminished and serum IgG4 levels also lowered after the administration of prednisolone at a dose of 20 mg/day for 2 months (IgG, 1121 mg/dl; IgG4, 327 mg/dl; and IgE, 254 mg/dl). METHODS To examine the rate at which pseudolymphoma cases meet IgG4-RD histopathological diagnostic criteria 12 retrospectively, (c) 32 skin specimens (15 men and 17 women; mean age, 53 years; age range, years) which had been diagnosed as pseudolymphoma at the Department of Diagnostic Pathology, Fujita Health University, between January 2000 and December 2012 were retrieved from the archives to conduct hematoxylin eosin (HE), CD138, IgG and IgG4 staining. Immunostaining was performed on paraffin sections using an HX system discovery automated immunostainer (Roche, Tokyo, Japan) using a polymer-based detection system. The primary antibodies used were as follows: mouse antihuman CD138 (1:50, clone MI15; DAKO, Glostrup, Denmark), rabbit antihuman IgG, specific for c-chains (1:2000; DAKO), and mouse antihuman IgG4 (1:200, clone HP6025; Invitrogen, San Diego, CA, USA). To check the monoclonality of lymphocytes, we stained kappa/lambda immunostaining in all 32 cases of cutaneous pseudolymphoma. In all pseudolymphoma cases, the ratios of kappa or lambda positive cells were almost similar and there was no monoclonality. In addition, follicular colonization, which is typical for cutaneous marginal zone lymphoma, was not observed in all pseudolymphoma cases. Immunoglobulin G + or IgG4 + plasma cells were enumerated in areas with the highest density of positive cells. Three different HPF (910 eyepiece and 940 objective lenses) in each section were counted, and an average number of positive cells per HPF was calculated. Fibrosis, germinal center formation, eosinophil infiltration and obliterative phlebitis were also evaluated. Unless specified otherwise, all data are represented as the mean values. RESULTS Histopathological features of cutaneous pseudolymphomas are summarized in Table 1. Out of the 32 cases of cutaneous pseudolymphoma, lymphocyte infiltration was seen in all patients. Plasma cell infiltration was seen in 31 patients. CD138 + cell infiltration was seen in 28 patients. Eosinophil infiltration was seen in 15 cases. Germinal center formation was seen in 22 cases. Obliterative phlebitis was seen in three cases. Moderate severe fibrosis was seen in seven cases. Regarding infiltration of IgG4 + plasma cells, 11 cases showed more than 10 IgG4 + plasma cells/hpf, and among these 11 cases, seven (22%) showed a ratio of IgG4 + /IgG + cells of more than 40% (Fig. 3). Thus, out of the 32 cases of cutaneous pseudolymphomas, two cases (6.3%) satisfied IgG4-RD histopathological diagnostic criteria. DISCUSSION Immunoglobulin G4-RD is a newly recognized disease of unknown etiology with multi-organ involvement. 2 In the case presented here, subcutaneous tumors were observed over the range from the left cheek to the mandible as well as on the extremities. Histological examination of skin biopsy specimens revealed dermal and subcutaneous involvement with nodular lymphoid infiltration often interspersed with lymphoid follicles and sclerotic stroma. The infiltrate was rich in plasma cells and 2013 Japanese Dermatological Association 999

3 Y. Iwata et al. (a) (e) (i) (b) (f) (j) (c) (g) (l) (d) (h) (m) Figure 2. Histopathological examination of skin biopsy taken from the left face (a d), neck (e h) and right arm (i m). Dense lymphocytic or plasma cell infiltration with fibrosis in the region between the dermis to subcutaneous adipose tissue, part of which presented lymphoid follicle structure (a,e,i). The infiltrate contained numerous lymphocytes, plasma cells and eosinophils (b,f,j). The plasma cells were positive for immunoglobulin (Ig)G (c,g,l) and IgG4 (d,h,m) as assessed by immunohistochemistry Japanese Dermatological Association

4 IgG4-related disease in pseudolymphoma Table 1. Clinicopathological features of cutaneous pseudolymphomas Case Lesion number Lesion size and morphological features Lymphocyte Plasma cell CD138 + cell IgG4/IgG ratio (%) IgG4 + cell (/HPF) Intensity of fibrosis GC Obliterative phlebitis Eo 1 S Brown nodule of the face ++ + Mild S 2 S Round-shaped nodule ++ + F+ Mild L 3 S 6-mm red nodule in the face Mild L + 4 M Multiple invasive erythema in the back Mild S 5 S mm round nodule in the ear ++ + F Mild S 6 S Erythema and swelling in the right eyelid ++ + F+ 7 S Brown papule in the nose ++ + F S Brown papule in the nose ++ + F+ 9 S 10-mm hard mass in the cheek Severe L + 10 S Flat elevated erythematous lesion Mild S + 11 M Multiple brown nodules in the face and back M Swelling in the eyelid Mild S + 13 S Red papule in the nose ++ + F Mild S + 14 M Multiple red papules in the face Severe S 15-mm subcutaneous hard mass ++ + F Severe S +/ M Multiple red papules and nodules in the face Moderate S +/ + 17 S 5-mm red papule in the nose ++ + F+ Mild S 18 M Red nodule in the face, brown papule in the hand, and multiple dark-red papules in the knee + 19 M Multiple red papules in the back Moderate M Multiple red nodules in the cheek, nose and lip L 21 S mm red nodule in the left axilla M Multiple erythema in cheeks and nose Moderate +/ + 23 S Red papule in the forehead Mild SL +/ 24 S 30-mm subcutaneous soft mass in the forehead Mild L +/ M Multiple 3 4-mm subcutaneous masses in the face ++ + F LL 26 S Nodule in the left ear Mild L 27 S Erythema in the left cheek L 28 M Erythema in the lip and forehead Mild L +/ 29 M Multiple red nodules in the forehead, nose and lip Mild S +/ 30 S Brown nodule in the right elbow Moderate +/ + 31 S mm dark red nodule in the left shoulder Mild S + 32 M Multiple brown papules in the face and neck ++ + F Mild S +/ + F, focal; Eo, eosinophils; GC, germinal center; HPF, high-power field; L, large; LL, large and large; S, small; SL, small and large Japanese Dermatological Association 1001

5 Y. Iwata et al. (a) (e) (i) (m) (b) (f) (j) (n) (c) (g) (k) (o) (d) (h) (l) (p) Figure 3. Light microscopy findings and immunostaining for immunoglobulin (I)gG4 of representative pseudolymphoma cases in which IgG4 + plasma cells were observed. Case 4: (a,e) hematoxylin eosin (HE); (i) IgG; (m) IgG4. Case 9: (b,f) HE; (j) IgG; (n) IgG4. Case 24: (c,g) HE; (k) IgG; (o) IgG4. Case 30: (d,h) HE; (l) IgG; (p) IgG4. small lymphocytes, where eosinophils and histiocytes are mixed. Based on these histopathological features, the initial diagnosis of the patient was pseudolymphoma. However, IgG4 immunostaining, conducted due to high serum IgG4 detected in the blood test, found a lot of IgG4 + plasma cell infiltration. As no complication was found in the lungs, kidneys and other internal organs, we diagnosed this case as having IgG4-related skin disease finally. It was not until recently that IgG4-related skin lesions were widely recognized, and clinicopathological findings are reported by some studies. 3,11 Yamada et al. studied 80 IgG4- RD cases and found that five cases (6.3%) had some sort of skin involvement. 11 Such skin lesions were typically erythematous nodules/papules and brown papules like prurigo nodularis, which developed on the face, head and neck in four patients. All five patients had sialadenitis and/or dacryoadenitis. On the other hand, Sato et al. studied 10 IgG4-RD cases with skin involvement. 3 All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek and mandible regions, except for one patient, whose forearm and waist skin were affected. Those with a mere skin involvement were only two cases, and the remaining eight patients had extracutaneous lesions: lymph node in six, lacrimal gland in three, parotid gland in three, and kidney in one patient. Thus, clinical features of IgG4-related skin disease are typically erythematous itchy plaques or nodules/papules, which developed particularly in the periauricular, cheek and mandible regions. In addition, IgG4-related skin disease usually accompanies extracutaneous symptoms, and presenting only skin lesions as observed in the present case is rare in IgG4-RD. Regarding histological immunohistochemical findings in IgG4-RD, Yamada et al. reported five cases. 11 According to the study, lymphocyte and plasma cell infiltrations were seen in the dermis and subcutaneous tissue. Eosinophil infiltration was detected in all patients. Germinal center formation was seen in three patients, and fibrosis was seen in all patients. According to Sato et al., 3 IgG4-related skin disease cases were Japanese Dermatological Association

6 IgG4-related disease in pseudolymphoma classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes and eosinophils, and the majority of the plasma cells were IgG4 +. Taking into consideration what Yamada et al. and Sato et al. have reported, 3,11 some of the clinical and pathological findings of IgG4-related skin lesions are similar to those of cutaneous B-cell pseudolymphoma. The term cutaneous pseudolymphoma is used to describe non-malignant accumulation of T and B lymphocytes in the skin, and etiology is unknown in most of the cases. 13,14 Face, chest and upper extremities are commonly involved sites. Lesions are usually asymptomatic, solitary, skin-colored to violaceous plaques or nodules. 13,14 The histological feature of cutaneous B-cell pseudolymphoma is predominantly nodular or diffused infiltrate of lymphocytes admixed with a variable number of histiocytes, eosinophils and plasma cells. 13,14 The hallmark of cutaneous B-cell pseudolymphoma is the formation of lymphoid follicles containing a mixed population of lymphoid cells. 14 Thus, both clinical and histopathological features are similar between IgG4-related skin disease and cutaneous pseudolymphoma. Actually, the present case was also first diagnosed as pseudolymphoma, and it was after serum IgG4 determination and IgG4 immunostaining that the patient was finally diagnosed as having IgG4-RD. Therefore, in the case of cutaneous pseudolymphoma, differential diagnosis for IgG4-RD is considered imperative. Therefore, we examined the ratio that satisfies IgG4-RD histopathological diagnostic criteria by conducting CD138, IgG4 and IgG immunostaining for 32 cases, which had diagnosed as pseudolymphoma in the past (Table 1). Out of the 32 cases, moderate severe fibrosis was seen in seven cases. Regarding infiltration of IgG4 + plasma cells, 11 cases showed more than 10 IgG4 + plasma cell infiltration/hpf, and among these 11 cases, seven cases (22%) showed a ratio of IgG4 + / IgG + cells of more than 40%. Collectively, two cases (6.3%) satisfied the histopathological diagnostic criteria for IgG4-RD (Fig. 3). 12 Definite diagnosis of IgG4-RD is impossible because serum IgG4 levels was not known in these cases. In addition, Takeuchi et al. has reported a case of cutaneous multicentric Castleman s disease that fulfilled the IgG4-RD histopathological diagnostic criteria. 15 Therefore, the diagnosis of IgG4-RD should be comprehensively done according to the serum IgG4 levels, histopathological findings and the existence of various organ involvements. Nevertheless, the present results may suggest the possibility that IgG4-RD is one of the etiologies of cutaneous pseudolymphoma, and it may be hidden in cutaneous pseudolymphoma-diagnosed cases. Therefore, it is important to examine a patient who seems to have pseudolymphoma with suspicion of the possibility of IgG4- related skin disease. In conclusion, cutaneous IgG4-RD, which had only skin involvement as in the present case, is rare in IgG4-RD as a whole. As clinical presentations and histopathological findings of skin involvement of IgG4-RD are similar to those of cutaneous B-cell pseudolymphoma, careful identification of IgG4-RD using systemic examination by means of computed tomography or magnetic resonance imaging, IgG and IgG4 immunostaining of skin specimens, and blood test (checking serum IgG4 levels) are required. CONFLICT OF INTEREST: None. REFERENCES 1 Hamano H, Kawa S, Horiuchi A et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: Umehara H, Okazaki K, Masaki Y et al. A novel clinical entity, IgG4- related disease (IgG4RD): general concept and details. Mod Rheumatol 2012; 22: Sato Y, Takeuchi M, Takata K et al. Clinicopathologic analysis of IgG4-related skin disease. Mod Pathol 2013; 26: Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: historical overview and pathology of hematological disorders. 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