Review
Cutaneous manifestations of immunoglobulin G4-related disease: what dermatologists need to know Garrett C. Lowe1, MD, Ryan R. Bogner2, MS, Rokea A. el-Azhary1, MD, PhD, Tania M. Gonzalez-Santiago1, MD, Scott A. Kindle1, MD, Julia S. Lehman1,3, MD, and Lawrence E. Gibson1,3, MD
1
Department of Dermatology, Mayo Clinic, Mayo Clinic College of Medicine, and 3 Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 2
Abstract In this review, we summarize the recent literature and use case examples to reach diagnostic criteria for the diagnosis of immunoglobulin G4 (IgG4)-related diseases that may be of relevance to the practicing dermatologist.
Correspondence Rokea A. el-Azhary, MD Department of Dermatology Mayo Clinic 200 First Street Southwest Rochester, MN 55905 USA E-mail: [email protected] Funding: None. Conflicts of interest: None.
Introduction Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory condition that can affect virtually every organ in the body, including the skin. The disease shows a middle-aged to elderly male predominance, and its pathogenesis is currently thought to be autoimmunerelated. It is difficult to recognize in clinical practice, and patients can remain undiagnosed for years. Herein, we review selected current literature with special emphasis on how IgG4-RD may present to the dermatologist. Two cases will be presented to exemplify the pitfalls and difficulties encountered in diagnosing such disease, especially on the basis of cutaneous findings.
and salivary glands are very common. These mass-forming lesions are characteristically seen on the face, around the orbits, or elsewhere on the head and neck. In addition, diffuse lymphadenopathy is frequently observed, with no evidence of systemic lymphoma. Sclerotic autoimmune diseases affecting the blood vessels, as in aortitis, or the biliary apparatus, as in sclerosing cholangitis, have also been described.1 Numerous other organs have been reported to be involved in sclerotic autoimmune diseases such as IgG4-RD, and multi-organ involvement is common. Less commonly involved sites include the lungs, kidneys, liver, bile duct, retroperitoneum, breast, pituitary gland, prostate, and skin.3,4 Current status
Literature overview The first disease to be directly associated with increased levels of IgG4 was autoimmune pancreatitis.1,2 As experience with the disease evolved, it was recognized as presenting with either sclerotic or tumescent lesions, or both, accompanied by the hallmark of dense lymphoplasmacytic infiltrates. Mass-forming lesions primarily affecting the secretory epithelial linings of the pancreas and lacrimal
A constellation of previously identified diseases are now known to be included in the category of IgG4-RD, all of which show increased levels of IgG4 in serum or tissue.5 Specific histopathologic features and IgG4+ plasma cells are essential for the diagnosis if serum IgG4 levels are normal. The main microscopic findings in tissue include a lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia.1 377
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Although no widely accepted diagnostic criteria are available, typical values used in diagnosis include a serum IgG4 level of >135 mg/dl, an IgG4+/IgG4 plasma cell ratio of >40%, and >10 IgG4+ plasma cells per highpower field.6,7 Although the presence of IgG4+ plasma cells is required to establish a diagnosis, their presence alone is not a diagnostic finding because they are seen in many other inflammatory conditions.5,8 It is also important to note that although increased IgG4+ plasma cell density and IgG4+/IgG4 plasma cell ratios are necessary for the diagnosis, these features are not entirely specific for IgG4-RD in the skin. All of this information points to a complicated clinical picture. How might the dermatologist contribute to the diagnosis of IgG4-RD? Two specific case examples may be used to illustrate the dermatologic diagnosis of IgG4-RD. The first example refers to a 55-year-old man with a history of chronic pancreatitis and previous eye enucleation secondary to orbital masses. He was admitted to hospital with acute onset of obstructive jaundice, fever, and a non-healing ulceration on the right base of the neck and shoulder adjacent to a recent surgical scar from a parotidectomy; the ulceration had been diagnosed elsewhere as pyoderma gangrenosum (PG) (Fig. 1). His medical history was significant for lacrimal gland enlargement, cervical lymphadenopathy, and bilateral parotid masses. A diagnosis of pseudolymphoma had been made after several biopsies of lymph nodes and masses proved negative for lymphoma. An IgG4 serum level measured at the time of hospital admission was normal. A dermatologic consultation was ordered for evaluation of the non-healing ulcer. This cutaneous lesion showed some clinical similarity to PG and was responsive to corticosteroids. Given the unusual nature of the patient’s cutaneous disease, the dermatologist requested available tissue blocks from prior specimens obtained in the
(a)
patient’s past procedures. Additional tissue for stains for IgG and IgG4 were obtained from the right parotid gland, right lacrimal gland and nerve, and right orbit. In all tissue specimens examined, a lymphoplasmacytic infiltrate was present, with increased IgG4+ plasma cell staining compared with IgG (Fig. 2). A higher-magnification image (not shown) revealed many plasma cells in all areas of inflammation. There was no evidence of increased plasma cells in the skin biopsy of the PG lesion. A unifying diagnosis of IgG4-RD was confirmed, but the patient died secondary to sepsis. This case highlights three educational points. Firstly, the constellation of findings in this patient over the years should have alerted the treating clinicians to the fact that this disease process represented an IgG4-RD despite a normal serum IgG4 level. Secondly, it is important to remember that an increased IgG4 serum level may not be required for the diagnosis. An increased serum IgG4 concentration9 is not a specific diagnostic marker for IgG4RD because serum concentrations will often be normal, as in the present patient. Normal IgG4 levels may delay diagnosis, and thus it is best to look at pathologic sections from several different organs, if available or possible, when IgG4-RD is suspected. Thirdly, PG is a dermatosis that frequently heralds the presence of an underlying systemic disorder. Although an association between PG and IgG4-RD has not been documented previously, the development of PG in this patient prompted the reappraisal of his systemic illnesses. This re-evaluation of his medical condition ultimately led to an accurate, unifying diagnosis of IgG4-RD. The second case illustrates the issue of whether an increased serum IgG4 level is sufficient to diagnose IgG4RD. A 66-year-old woman presented with a rash, for which our Department of Dermatology was consulted. She had been admitted to hospital for cough, fever, weight
(b)
Figure 1 (a) On examination, Patient 1, a 55-year-old man, was found to have severe jaundice, his right eye had been enucleated and he had a surgical scar secondary to the excision of a mass in the right parotid gland. (b) Ulceration in the right clavicular area was diagnosed as pyoderma gangrenosum International Journal of Dermatology 2015, 54, 377–382
ª 2015 The International Society of Dermatology
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Figure 2 Histopathologic examination of salivary gland tissue in Patient 1 showed (a) obliterative phlebitis and surrounding fibrosis, and (b) lymphoid follicles. (Hematoxylin and eosin stain; original magnification [a] 910, [b] 94) (c, d) Immunohistochemistry staining for immunoglobulin G4 (IgG4) showed a dense population of IgG4+ plasma cells within lymphoid follicles. (Original magnification [c] 910, [d] 920)
Cutaneous IgG4-related disease
(a)
(b)
(c)
(d)
loss, and massive neck lymphadenopathy. The skin eruption was generalized, appeared lichenoid, and showed a morbilliform pattern involving the upper chest, face, back and thighs (Fig. 3). Skin biopsy showed an interface tissue reaction with abundant plasma cells mimicking lupus erythematosus, but direct immunofluorescence was negative. Workup revealed diffuse lymphadenopathy and splenomegaly on computed tomography, with polyclonal plasmacytosis found on blood evaluation. Two lymph node biopsies from the axillary and cervical areas showed reactive changes with no evidence of lymphoma. A bone marrow biopsy showed a polyclonal lymphoplasmacytic infiltrate with positivity for Epstein–Barr virus (EBV) and EBV blood copies of 528,000. The circulating IgG4 level was increased at 275 mg/dl (reference range: 2.4– 121.0 mg/dl). At this point, IgG4-RD was strongly considered, but bone marrow and skin biopsies were both negative for IgG4+ plasma cells. A third neck lymph node biopsy was obtained and showed angioimmunoblastic T cell lymphoma. This latter diagnosis better explained both the clinical findings and the EBV positivity. The increased
Review
IgG4 serum level, above the cut-off of 121 mg/dl (purported as a cut-off value in the diagnosis of IgG4-RD), was clearly misleading. In addition, the copious plasma cells in the skin biopsy obscured the primary pathologic analysis and thus were misleading, suggesting a connective tissue disease or possibly a B cell or plasmacytic process in the skin. The patient was treated with rituximab, prednisone, and etoposide and did very well, achieving the resolution of her lymphadenopathy and skin eruption. Further chemotherapy is planned for the angioimmunoblastic T cell lymphoma. This case demonstrates two very important points. Firstly, serum IgG4 level does not confirm or exclude the diagnosis of IgG4-RD. A recent article by Carruthers et al.10 showed the lack of specificity of increased IgG4 serum levels in diagnosing IgG4-RD. Increased serum IgG4 levels can be associated with many non-IgG4 inflammatory and neoplastic conditions. Secondly, EBVrelated lymphomas can be mistaken for IgG4-RD. Wada et al.11 recently highlighted the need to rule out lymphoma in all patients under consideration for IgG4-RD
(a)
(b)
Figure 3 Clinical examination of Patient 2, a 66-year-old woman, showed (a) bilateral lymphadenopathy and an erythematous eruption on the chest, and (b) a papular lichenoid eruption on the lower extremity ª 2015 The International Society of Dermatology
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who present with lymphadenopathy, B symptoms, and EBV positivity. In our patient, the presence of polyclonal cells in the marrow was particularly deceiving and did not easily lead to the ultimate diagnosis of a T cell lymphoma. Moreover, the interface lupus-like pattern noted on skin biopsy was most likely secondary to the underlying lymphoproliferative disorder and was reactive in nature, similarly to the PG-like presentation in the first case. From these two cases, we highlight certain features necessary for the diagnosis of IgG4-RD. The diagnosis is first considered when there is a clinical constellation of findings suggestive of IgG4-RD. Lymphadenopathy, tumors on the head or neck, including the orbits and salivary glands, as well as autoimmune diseases such as hepatitis and pancreatitis, should all raise this suspicion. Serum IgG4 level may also raise suspicion but is not specific for IgG4-RD. Tissue histopathology showing dense lymphoplasmacytic infiltrates, with immunostains showing an IgG4+ plasma cell predominance in the tissue with the ratios described earlier, may clinch the diagnosis, but careful clinical correlation is still required, as demonstrated in the patients reported above. Other features that raise the possibility of IgG4-RD include dense plasmacytic infiltrates in tissue, including the skin, polyclonal plasmacytosis, and a high level of circulating IgG4. The criteria for the diagnosis of IgG4-RD in the literature are still in evolution, as currently addressed by Fernandez-Flores12 and Stone et al.1 Criteria considered for diagnosis are: (i) tumors of the head and neck area that do not show malignancy; (ii) a constellation of autoimmune or sclerosing diseases such as sclerosing cholangitis or autoimmune pancreatitis; (iii) generalized lymphadenopathy; (iv) the ruling out of lymphoma or EBV lymphoproliferative disorder; and (v) tissue-dense lymphoplasmacytic infiltrates, few eosinophils, storiform fibrosis, with IgG4+ plasma cell predominance (IgG4+/IgG4 plasma cell ratio >40% and >10 IgG4+ plasma cells per high-power field6,7). Several other diseases are similar to IgG4-RD in that they involve an IgG4 immune-mediated response. Pemphigus vulgaris, pemphigus foliaceus, idiopathic membranous glomerulonephritis, and thrombotic thrombocytopenic purpura all produce IgG4 antibodies against specific molecular targets.5 Other conditions also present with increased serum and tissue IgG4 concentrations, including primary inflammatory bowel disease and Hashimoto thyroiditis. However, it is unknown whether any of these conditions have an association with IgG4-RD. In terms of histopathologic analysis, lymphomas, particularly B cell lymphoplasmacytic variants, present with very similar findings to IgG4-RD, and clonality studies are often required to distinguish between these conditions. International Journal of Dermatology 2015, 54, 377–382
Dermatologic significance Dermatologists may be consulted to evaluate several seemingly disparate skin problems associated with IgG4RD, which may include prurigo-like nodules,3 nonspecific rosacea-like papules and pustules,1 scleroderma-like skin changes,13 xanthogranulomas,14 papules and nodules mimicking angiolymphoid hyperplasia with eosinophilia,15 and lymphoma-like presentations with striking swelling of secretory glands and lymph nodes, especially in the head and neck region.3 Skin lesions have been documented most frequently on the upper trunk, neck, scalp, auricle, postauricular area, submandibular area, and over the zygomatic arch.16 Hattori et al.17 reported a rare case of IgG4-RD located on the great toe. Ikeda et al.16 compared five cases of IgG4-RD with skin manifestations and identified three common features in the skin lesions of each patient. These included: (i) localization near the main area of IgG4-RD involvement; (ii) infiltration of IgG4+ plasma cells and eosinophils in the dermis and subcutis; and (iii) the appearance of lesions after the onset of systemic IgG4-RD. It is important to note that most patients with confirmed skin involvement also had extracutaneous involvement of some sort, diagnosed either before or after the development of cutaneous lesions. Skin lesions may indicate the progression of systemic IgG4-RD.16 However, some documented cases of isolated skin findings have also met the criteria for IgG4-RD.6,17 Cheuk et al.18 investigated 14 patients with cutaneous pseudolymphoma and found that skin lesions in two of them showed increased IgG4+ plasma cells. They suggested that these may indicate a solitary cutaneous counterpart to the systemic form of IgG4-RD, rather than represent cases of cutaneous pseudolymphoma. It remains important to distinguish IgG4-RD from other conditions that have potentially similar and non-diagnostic clinical presentations. Moreover, several diseases may mimic IgG4-RD on a histopathologic level, making it essential to incorporate information from both realms when investigating and diagnosing these diseases. The diseases most commonly discussed in the literature that show clinical and histopathologic similarities to IgG4-RD include cutaneous plasmacytosis,9,19 angiolymphoid hyperplasia with eosinophilia and Kimura disease,15,17 necrobiotic xanthogranuloma,14,20 Rosai–Dorfman disease,3 Mikulicz disease,15 multicentric Castleman disease,21 and cutaneous pseudolymphoma.18 Pyoderma gangrenosum is known to be associated with lymphoproliferative disease, and our case of PG-like ulceration in the setting of IgG4RD appears to be the first reported. As information regarding skin manifestations in IgG4-RD emerges, more comprehensive and detailed ª 2015 The International Society of Dermatology
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investigations into this condition are warranted. It is important for dermatologists to be aware of IgG4-RD because of the possible development of cutaneous lesions, either as the initial presentation or as an indication of progression of disease.22 Perhaps most importantly, dermatologists should maintain a high index of suspicion when investigating lesions for which a firm diagnosis is lacking because of the extensive overlap between IgG4RD and other conditions, be they autoimmune or malignant. Questions (answers listed after references)
1 The skin lesions of IgG4-related disease (IgG4-RD): Arise late in the disease process Herald extracutaneous involvement Occur in isolation Signal progression of disease All of the above 2 The vast majority of patients with IgG4-RD have significant extracutaneous involvement before the development of skin lesions. Which of the following was the first to be directly associated with increased IgG4 levels? a) Autoimmune pancreatitis b) Periaortitis and periarteritis c) Sclerosing cholangitis d) Submandibular and/or parotid gland enlargement, with or without sialadenitis e) Mass lesion in orbit 3 Skin involvement in IgG4-RD can be difficult to distinguish clinically and/or histopathologically from: a) Angiolymphoid hyperplasia with eosinophilia and Kimura disease b) Cutaneous plasmacytosis c) Pseudolymphoma d) Multicentric Castleman disease e) All of the above 4 What is the key morphologic feature seen on histopathologic analysis of IgG4-RD? a) Granulomatous dermatitis b) Lymphoplasmacytic infiltrate c) Neutrophilic dermatosis d) Gyrate erythema e) Vascular proliferation 5 If IgG4-RD is suspected in a patient with normal serum IgG4 levels, what would be the next logical step? a) Check total immunoglobulin level b) Evaluate all pathologic specimens for changes typically seen in IgG4-RD c) Repeat serum IgG4 level measurement d) Treat empirically with systemic immunosuppression e) Obtain imaging studies of lymph nodes 6 Mass-forming lesions affecting the epithelial linings of organs on the face, around the orbits, and elsewhere a) b) c) d) e)
ª 2015 The International Society of Dermatology
Cutaneous IgG4-related disease
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on the head and neck in IgG4-RD can be difficult to distinguish from: a) Adult T cell leukemia/lymphoma b) Epstein–Barr virus-related lymphoproliferative disease c) Kaposis sarcoma d) Necrobiotic xanthogranuloma e) Granulomatosis with polyangiitis References 1 Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: 539–551. 2 Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006; 4: 1010–1016. 3 Kakuchi Y, Yamada K, Suzuki Y, et al. IgG4-related skin lesions in a patient with IgG4-related chronic sclerosing dacryoadenitis and sialoadenitis. Intern Med 2011; 50: 1465–1469. 4 Nakazawa T, Naitoh I, Hayashi K, et al. Diagnosis of IgG4-related sclerosing cholangitis. World J Gastroenterol 2013; 19: 7661–7670. 5 Lehman JS, Smyrk TC, Pittelkow MR. Increased immunoglobulin (Ig) G4-positive plasma cell density and IgG4/IgG ratio are not specific for IgG4-related disease in the skin. Am J Clin Pathol 2014; 141: 234–238. 6 Ingen-Housz-Oro S, Ortonne N, Elhai M, et al. IgG4-related skin disease successfully treated by thalidomide: a report of 2 cases with emphasis on pathological aspects. JAMA Dermatol 2013; 149: 742– 747. 7 Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25: 1181–1192. 8 Lehman JS, Pittelkow MR, Smyrk TC. IgG4-related skin disease. JAMA Dermatol 2013; 149: 1439–1440. 9 Miyagawa-Hayashino A, Matsumura Y, Kawakami F, et al. High ratio of IgG4-positive plasma cell infiltration in cutaneous plasmacytosis: is this a cutaneous manifestation of IgG4-related disease? Hum Pathol 2009; 40: 1269–1277. 10 Carruthers MN, Khosroshahi A, Augustin T, et al. The diagnostic utility of serum IgG4 concentrations in IgG4related disease. Ann Rheum Dis 2015; 74: 14–18. 11 Wada Y, Kojima M, Yoshita K, et al. A case of EpsteinBarr virus-related lymphadenopathy mimicking the clinical features of IgG4-related disease. Mod Rheumatol 2013; 23: 597–603. 12 Fernandez-Flores A. The role of IgG4 in cutaneous pathology. Rom J Morphol Embryol 2012; 53: 221–231. 13 Reddi DM, Cardona DM, Burchette JL, et al. Scleroderma and IgG4-related disease. Am J Dermatopathol 2013; 35: 458–462. 14 Mudhar HS, Bhatt R, Sandramouli S. Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques. Int Ophthalmol 2011; 31: 245–248. International Journal of Dermatology 2015, 54, 377–382
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15 Hamaguchi Y, Fujimoto M, Matsushita Y, et al. IgG4related skin disease, a mimic of angiolymphoid hyperplasia with eosinophilia. Dermatology 2011; 223: 301–305. 16 Ikeda T, Oka M, Shimizu H, et al. IgG4-related skin manifestations in patients with IgG4-related disease. Eur J Dermatol 2013; 23: 241–245. 17 Hattori T, Miyanaga T, Tago O, et al. Isolated cutaneous manifestation of IgG4-related disease. J Clin Pathol 2012; 65: 815–818. 18 Cheuk W, Lee KC, Chong LY, et al. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol 2009; 33: 1713–1719. 19 Kato K, Satoh T, Tanaka-Fujimoto T, et al. IgG4-positive cells in skin lesions of cutaneous and systemic plasmacytosis. Eur J Dermatol 2013; 23: 255–256.
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20 Singh K, Rajan KD, Eberhart C. Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. Ocul Immunol Inflamm 2010; 18: 373–378. 21 Sato Y, Kojima M, Takata K, et al. Multicentric Castlemans disease with abundant IgG4-positive cells: a clinical and pathological analysis of six cases. J Clin Pathol 2010; 63: 1084–1089. 22 Kempeneers D, Hauben E, De Haes P. IgG4-related skin lesions: case report and review of the literature. Clin Exp Dermatol 2014; 39: 479–483.
Answer key 1 (e); 2 (a); 3 (e); 4 (b); 5 (b); 6 (b)
ª 2015 The International Society of Dermatology
Cutaneous manifestations of immunoglobulin G4-related disease: what dermatologists need to know Garrett C. Lowe1, MD, Ryan R. Bogner2, MS, Rokea A. el-Azhary1, MD, PhD, Tania M. Gonzalez-Santiago1, MD, Scott A. Kindle1, MD, Julia S. Lehman1,3, MD, and Lawrence E. Gibson1,3, MD
1
Department of Dermatology, Mayo Clinic, Mayo Clinic College of Medicine, and 3 Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 2
Abstract In this review, we summarize the recent literature and use case examples to reach diagnostic criteria for the diagnosis of immunoglobulin G4 (IgG4)-related diseases that may be of relevance to the practicing dermatologist.
Correspondence Rokea A. el-Azhary, MD Department of Dermatology Mayo Clinic 200 First Street Southwest Rochester, MN 55905 USA E-mail: [email protected] Funding: None. Conflicts of interest: None.
Introduction Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory condition that can affect virtually every organ in the body, including the skin. The disease shows a middle-aged to elderly male predominance, and its pathogenesis is currently thought to be autoimmunerelated. It is difficult to recognize in clinical practice, and patients can remain undiagnosed for years. Herein, we review selected current literature with special emphasis on how IgG4-RD may present to the dermatologist. Two cases will be presented to exemplify the pitfalls and difficulties encountered in diagnosing such disease, especially on the basis of cutaneous findings.
and salivary glands are very common. These mass-forming lesions are characteristically seen on the face, around the orbits, or elsewhere on the head and neck. In addition, diffuse lymphadenopathy is frequently observed, with no evidence of systemic lymphoma. Sclerotic autoimmune diseases affecting the blood vessels, as in aortitis, or the biliary apparatus, as in sclerosing cholangitis, have also been described.1 Numerous other organs have been reported to be involved in sclerotic autoimmune diseases such as IgG4-RD, and multi-organ involvement is common. Less commonly involved sites include the lungs, kidneys, liver, bile duct, retroperitoneum, breast, pituitary gland, prostate, and skin.3,4 Current status
Literature overview The first disease to be directly associated with increased levels of IgG4 was autoimmune pancreatitis.1,2 As experience with the disease evolved, it was recognized as presenting with either sclerotic or tumescent lesions, or both, accompanied by the hallmark of dense lymphoplasmacytic infiltrates. Mass-forming lesions primarily affecting the secretory epithelial linings of the pancreas and lacrimal
A constellation of previously identified diseases are now known to be included in the category of IgG4-RD, all of which show increased levels of IgG4 in serum or tissue.5 Specific histopathologic features and IgG4+ plasma cells are essential for the diagnosis if serum IgG4 levels are normal. The main microscopic findings in tissue include a lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia.1 377
ª 2015 The International Society of Dermatology
International Journal of Dermatology 2015, 54, 377–382
378
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Lowe et al.
Cutaneous IgG4-related disease
Although no widely accepted diagnostic criteria are available, typical values used in diagnosis include a serum IgG4 level of >135 mg/dl, an IgG4+/IgG4 plasma cell ratio of >40%, and >10 IgG4+ plasma cells per highpower field.6,7 Although the presence of IgG4+ plasma cells is required to establish a diagnosis, their presence alone is not a diagnostic finding because they are seen in many other inflammatory conditions.5,8 It is also important to note that although increased IgG4+ plasma cell density and IgG4+/IgG4 plasma cell ratios are necessary for the diagnosis, these features are not entirely specific for IgG4-RD in the skin. All of this information points to a complicated clinical picture. How might the dermatologist contribute to the diagnosis of IgG4-RD? Two specific case examples may be used to illustrate the dermatologic diagnosis of IgG4-RD. The first example refers to a 55-year-old man with a history of chronic pancreatitis and previous eye enucleation secondary to orbital masses. He was admitted to hospital with acute onset of obstructive jaundice, fever, and a non-healing ulceration on the right base of the neck and shoulder adjacent to a recent surgical scar from a parotidectomy; the ulceration had been diagnosed elsewhere as pyoderma gangrenosum (PG) (Fig. 1). His medical history was significant for lacrimal gland enlargement, cervical lymphadenopathy, and bilateral parotid masses. A diagnosis of pseudolymphoma had been made after several biopsies of lymph nodes and masses proved negative for lymphoma. An IgG4 serum level measured at the time of hospital admission was normal. A dermatologic consultation was ordered for evaluation of the non-healing ulcer. This cutaneous lesion showed some clinical similarity to PG and was responsive to corticosteroids. Given the unusual nature of the patient’s cutaneous disease, the dermatologist requested available tissue blocks from prior specimens obtained in the
(a)
patient’s past procedures. Additional tissue for stains for IgG and IgG4 were obtained from the right parotid gland, right lacrimal gland and nerve, and right orbit. In all tissue specimens examined, a lymphoplasmacytic infiltrate was present, with increased IgG4+ plasma cell staining compared with IgG (Fig. 2). A higher-magnification image (not shown) revealed many plasma cells in all areas of inflammation. There was no evidence of increased plasma cells in the skin biopsy of the PG lesion. A unifying diagnosis of IgG4-RD was confirmed, but the patient died secondary to sepsis. This case highlights three educational points. Firstly, the constellation of findings in this patient over the years should have alerted the treating clinicians to the fact that this disease process represented an IgG4-RD despite a normal serum IgG4 level. Secondly, it is important to remember that an increased IgG4 serum level may not be required for the diagnosis. An increased serum IgG4 concentration9 is not a specific diagnostic marker for IgG4RD because serum concentrations will often be normal, as in the present patient. Normal IgG4 levels may delay diagnosis, and thus it is best to look at pathologic sections from several different organs, if available or possible, when IgG4-RD is suspected. Thirdly, PG is a dermatosis that frequently heralds the presence of an underlying systemic disorder. Although an association between PG and IgG4-RD has not been documented previously, the development of PG in this patient prompted the reappraisal of his systemic illnesses. This re-evaluation of his medical condition ultimately led to an accurate, unifying diagnosis of IgG4-RD. The second case illustrates the issue of whether an increased serum IgG4 level is sufficient to diagnose IgG4RD. A 66-year-old woman presented with a rash, for which our Department of Dermatology was consulted. She had been admitted to hospital for cough, fever, weight
(b)
Figure 1 (a) On examination, Patient 1, a 55-year-old man, was found to have severe jaundice, his right eye had been enucleated and he had a surgical scar secondary to the excision of a mass in the right parotid gland. (b) Ulceration in the right clavicular area was diagnosed as pyoderma gangrenosum International Journal of Dermatology 2015, 54, 377–382
ª 2015 The International Society of Dermatology
Lowe et al.
Figure 2 Histopathologic examination of salivary gland tissue in Patient 1 showed (a) obliterative phlebitis and surrounding fibrosis, and (b) lymphoid follicles. (Hematoxylin and eosin stain; original magnification [a] 910, [b] 94) (c, d) Immunohistochemistry staining for immunoglobulin G4 (IgG4) showed a dense population of IgG4+ plasma cells within lymphoid follicles. (Original magnification [c] 910, [d] 920)
Cutaneous IgG4-related disease
(a)
(b)
(c)
(d)
loss, and massive neck lymphadenopathy. The skin eruption was generalized, appeared lichenoid, and showed a morbilliform pattern involving the upper chest, face, back and thighs (Fig. 3). Skin biopsy showed an interface tissue reaction with abundant plasma cells mimicking lupus erythematosus, but direct immunofluorescence was negative. Workup revealed diffuse lymphadenopathy and splenomegaly on computed tomography, with polyclonal plasmacytosis found on blood evaluation. Two lymph node biopsies from the axillary and cervical areas showed reactive changes with no evidence of lymphoma. A bone marrow biopsy showed a polyclonal lymphoplasmacytic infiltrate with positivity for Epstein–Barr virus (EBV) and EBV blood copies of 528,000. The circulating IgG4 level was increased at 275 mg/dl (reference range: 2.4– 121.0 mg/dl). At this point, IgG4-RD was strongly considered, but bone marrow and skin biopsies were both negative for IgG4+ plasma cells. A third neck lymph node biopsy was obtained and showed angioimmunoblastic T cell lymphoma. This latter diagnosis better explained both the clinical findings and the EBV positivity. The increased
Review
IgG4 serum level, above the cut-off of 121 mg/dl (purported as a cut-off value in the diagnosis of IgG4-RD), was clearly misleading. In addition, the copious plasma cells in the skin biopsy obscured the primary pathologic analysis and thus were misleading, suggesting a connective tissue disease or possibly a B cell or plasmacytic process in the skin. The patient was treated with rituximab, prednisone, and etoposide and did very well, achieving the resolution of her lymphadenopathy and skin eruption. Further chemotherapy is planned for the angioimmunoblastic T cell lymphoma. This case demonstrates two very important points. Firstly, serum IgG4 level does not confirm or exclude the diagnosis of IgG4-RD. A recent article by Carruthers et al.10 showed the lack of specificity of increased IgG4 serum levels in diagnosing IgG4-RD. Increased serum IgG4 levels can be associated with many non-IgG4 inflammatory and neoplastic conditions. Secondly, EBVrelated lymphomas can be mistaken for IgG4-RD. Wada et al.11 recently highlighted the need to rule out lymphoma in all patients under consideration for IgG4-RD
(a)
(b)
Figure 3 Clinical examination of Patient 2, a 66-year-old woman, showed (a) bilateral lymphadenopathy and an erythematous eruption on the chest, and (b) a papular lichenoid eruption on the lower extremity ª 2015 The International Society of Dermatology
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who present with lymphadenopathy, B symptoms, and EBV positivity. In our patient, the presence of polyclonal cells in the marrow was particularly deceiving and did not easily lead to the ultimate diagnosis of a T cell lymphoma. Moreover, the interface lupus-like pattern noted on skin biopsy was most likely secondary to the underlying lymphoproliferative disorder and was reactive in nature, similarly to the PG-like presentation in the first case. From these two cases, we highlight certain features necessary for the diagnosis of IgG4-RD. The diagnosis is first considered when there is a clinical constellation of findings suggestive of IgG4-RD. Lymphadenopathy, tumors on the head or neck, including the orbits and salivary glands, as well as autoimmune diseases such as hepatitis and pancreatitis, should all raise this suspicion. Serum IgG4 level may also raise suspicion but is not specific for IgG4-RD. Tissue histopathology showing dense lymphoplasmacytic infiltrates, with immunostains showing an IgG4+ plasma cell predominance in the tissue with the ratios described earlier, may clinch the diagnosis, but careful clinical correlation is still required, as demonstrated in the patients reported above. Other features that raise the possibility of IgG4-RD include dense plasmacytic infiltrates in tissue, including the skin, polyclonal plasmacytosis, and a high level of circulating IgG4. The criteria for the diagnosis of IgG4-RD in the literature are still in evolution, as currently addressed by Fernandez-Flores12 and Stone et al.1 Criteria considered for diagnosis are: (i) tumors of the head and neck area that do not show malignancy; (ii) a constellation of autoimmune or sclerosing diseases such as sclerosing cholangitis or autoimmune pancreatitis; (iii) generalized lymphadenopathy; (iv) the ruling out of lymphoma or EBV lymphoproliferative disorder; and (v) tissue-dense lymphoplasmacytic infiltrates, few eosinophils, storiform fibrosis, with IgG4+ plasma cell predominance (IgG4+/IgG4 plasma cell ratio >40% and >10 IgG4+ plasma cells per high-power field6,7). Several other diseases are similar to IgG4-RD in that they involve an IgG4 immune-mediated response. Pemphigus vulgaris, pemphigus foliaceus, idiopathic membranous glomerulonephritis, and thrombotic thrombocytopenic purpura all produce IgG4 antibodies against specific molecular targets.5 Other conditions also present with increased serum and tissue IgG4 concentrations, including primary inflammatory bowel disease and Hashimoto thyroiditis. However, it is unknown whether any of these conditions have an association with IgG4-RD. In terms of histopathologic analysis, lymphomas, particularly B cell lymphoplasmacytic variants, present with very similar findings to IgG4-RD, and clonality studies are often required to distinguish between these conditions. International Journal of Dermatology 2015, 54, 377–382
Dermatologic significance Dermatologists may be consulted to evaluate several seemingly disparate skin problems associated with IgG4RD, which may include prurigo-like nodules,3 nonspecific rosacea-like papules and pustules,1 scleroderma-like skin changes,13 xanthogranulomas,14 papules and nodules mimicking angiolymphoid hyperplasia with eosinophilia,15 and lymphoma-like presentations with striking swelling of secretory glands and lymph nodes, especially in the head and neck region.3 Skin lesions have been documented most frequently on the upper trunk, neck, scalp, auricle, postauricular area, submandibular area, and over the zygomatic arch.16 Hattori et al.17 reported a rare case of IgG4-RD located on the great toe. Ikeda et al.16 compared five cases of IgG4-RD with skin manifestations and identified three common features in the skin lesions of each patient. These included: (i) localization near the main area of IgG4-RD involvement; (ii) infiltration of IgG4+ plasma cells and eosinophils in the dermis and subcutis; and (iii) the appearance of lesions after the onset of systemic IgG4-RD. It is important to note that most patients with confirmed skin involvement also had extracutaneous involvement of some sort, diagnosed either before or after the development of cutaneous lesions. Skin lesions may indicate the progression of systemic IgG4-RD.16 However, some documented cases of isolated skin findings have also met the criteria for IgG4-RD.6,17 Cheuk et al.18 investigated 14 patients with cutaneous pseudolymphoma and found that skin lesions in two of them showed increased IgG4+ plasma cells. They suggested that these may indicate a solitary cutaneous counterpart to the systemic form of IgG4-RD, rather than represent cases of cutaneous pseudolymphoma. It remains important to distinguish IgG4-RD from other conditions that have potentially similar and non-diagnostic clinical presentations. Moreover, several diseases may mimic IgG4-RD on a histopathologic level, making it essential to incorporate information from both realms when investigating and diagnosing these diseases. The diseases most commonly discussed in the literature that show clinical and histopathologic similarities to IgG4-RD include cutaneous plasmacytosis,9,19 angiolymphoid hyperplasia with eosinophilia and Kimura disease,15,17 necrobiotic xanthogranuloma,14,20 Rosai–Dorfman disease,3 Mikulicz disease,15 multicentric Castleman disease,21 and cutaneous pseudolymphoma.18 Pyoderma gangrenosum is known to be associated with lymphoproliferative disease, and our case of PG-like ulceration in the setting of IgG4RD appears to be the first reported. As information regarding skin manifestations in IgG4-RD emerges, more comprehensive and detailed ª 2015 The International Society of Dermatology
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investigations into this condition are warranted. It is important for dermatologists to be aware of IgG4-RD because of the possible development of cutaneous lesions, either as the initial presentation or as an indication of progression of disease.22 Perhaps most importantly, dermatologists should maintain a high index of suspicion when investigating lesions for which a firm diagnosis is lacking because of the extensive overlap between IgG4RD and other conditions, be they autoimmune or malignant. Questions (answers listed after references)
1 The skin lesions of IgG4-related disease (IgG4-RD): Arise late in the disease process Herald extracutaneous involvement Occur in isolation Signal progression of disease All of the above 2 The vast majority of patients with IgG4-RD have significant extracutaneous involvement before the development of skin lesions. Which of the following was the first to be directly associated with increased IgG4 levels? a) Autoimmune pancreatitis b) Periaortitis and periarteritis c) Sclerosing cholangitis d) Submandibular and/or parotid gland enlargement, with or without sialadenitis e) Mass lesion in orbit 3 Skin involvement in IgG4-RD can be difficult to distinguish clinically and/or histopathologically from: a) Angiolymphoid hyperplasia with eosinophilia and Kimura disease b) Cutaneous plasmacytosis c) Pseudolymphoma d) Multicentric Castleman disease e) All of the above 4 What is the key morphologic feature seen on histopathologic analysis of IgG4-RD? a) Granulomatous dermatitis b) Lymphoplasmacytic infiltrate c) Neutrophilic dermatosis d) Gyrate erythema e) Vascular proliferation 5 If IgG4-RD is suspected in a patient with normal serum IgG4 levels, what would be the next logical step? a) Check total immunoglobulin level b) Evaluate all pathologic specimens for changes typically seen in IgG4-RD c) Repeat serum IgG4 level measurement d) Treat empirically with systemic immunosuppression e) Obtain imaging studies of lymph nodes 6 Mass-forming lesions affecting the epithelial linings of organs on the face, around the orbits, and elsewhere a) b) c) d) e)
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on the head and neck in IgG4-RD can be difficult to distinguish from: a) Adult T cell leukemia/lymphoma b) Epstein–Barr virus-related lymphoproliferative disease c) Kaposis sarcoma d) Necrobiotic xanthogranuloma e) Granulomatosis with polyangiitis References 1 Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: 539–551. 2 Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006; 4: 1010–1016. 3 Kakuchi Y, Yamada K, Suzuki Y, et al. IgG4-related skin lesions in a patient with IgG4-related chronic sclerosing dacryoadenitis and sialoadenitis. Intern Med 2011; 50: 1465–1469. 4 Nakazawa T, Naitoh I, Hayashi K, et al. Diagnosis of IgG4-related sclerosing cholangitis. World J Gastroenterol 2013; 19: 7661–7670. 5 Lehman JS, Smyrk TC, Pittelkow MR. Increased immunoglobulin (Ig) G4-positive plasma cell density and IgG4/IgG ratio are not specific for IgG4-related disease in the skin. Am J Clin Pathol 2014; 141: 234–238. 6 Ingen-Housz-Oro S, Ortonne N, Elhai M, et al. IgG4-related skin disease successfully treated by thalidomide: a report of 2 cases with emphasis on pathological aspects. JAMA Dermatol 2013; 149: 742– 747. 7 Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25: 1181–1192. 8 Lehman JS, Pittelkow MR, Smyrk TC. IgG4-related skin disease. JAMA Dermatol 2013; 149: 1439–1440. 9 Miyagawa-Hayashino A, Matsumura Y, Kawakami F, et al. High ratio of IgG4-positive plasma cell infiltration in cutaneous plasmacytosis: is this a cutaneous manifestation of IgG4-related disease? Hum Pathol 2009; 40: 1269–1277. 10 Carruthers MN, Khosroshahi A, Augustin T, et al. The diagnostic utility of serum IgG4 concentrations in IgG4related disease. Ann Rheum Dis 2015; 74: 14–18. 11 Wada Y, Kojima M, Yoshita K, et al. A case of EpsteinBarr virus-related lymphadenopathy mimicking the clinical features of IgG4-related disease. Mod Rheumatol 2013; 23: 597–603. 12 Fernandez-Flores A. The role of IgG4 in cutaneous pathology. Rom J Morphol Embryol 2012; 53: 221–231. 13 Reddi DM, Cardona DM, Burchette JL, et al. Scleroderma and IgG4-related disease. Am J Dermatopathol 2013; 35: 458–462. 14 Mudhar HS, Bhatt R, Sandramouli S. Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques. Int Ophthalmol 2011; 31: 245–248. International Journal of Dermatology 2015, 54, 377–382
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15 Hamaguchi Y, Fujimoto M, Matsushita Y, et al. IgG4related skin disease, a mimic of angiolymphoid hyperplasia with eosinophilia. Dermatology 2011; 223: 301–305. 16 Ikeda T, Oka M, Shimizu H, et al. IgG4-related skin manifestations in patients with IgG4-related disease. Eur J Dermatol 2013; 23: 241–245. 17 Hattori T, Miyanaga T, Tago O, et al. Isolated cutaneous manifestation of IgG4-related disease. J Clin Pathol 2012; 65: 815–818. 18 Cheuk W, Lee KC, Chong LY, et al. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol 2009; 33: 1713–1719. 19 Kato K, Satoh T, Tanaka-Fujimoto T, et al. IgG4-positive cells in skin lesions of cutaneous and systemic plasmacytosis. Eur J Dermatol 2013; 23: 255–256.
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20 Singh K, Rajan KD, Eberhart C. Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. Ocul Immunol Inflamm 2010; 18: 373–378. 21 Sato Y, Kojima M, Takata K, et al. Multicentric Castlemans disease with abundant IgG4-positive cells: a clinical and pathological analysis of six cases. J Clin Pathol 2010; 63: 1084–1089. 22 Kempeneers D, Hauben E, De Haes P. IgG4-related skin lesions: case report and review of the literature. Clin Exp Dermatol 2014; 39: 479–483.
Answer key 1 (e); 2 (a); 3 (e); 4 (b); 5 (b); 6 (b)
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