A 57-year-old female with upper eyelid swelling
Ibrahim Robadi MD and Jeffrey A. Vos MD.
A 57-year-old female presented to a local healthcare facility complaining of left upper eyelid swelling for several months. The patient reported no other systemic symptoms except for chronic fatigue. Magnetic resonance imaging (MRI) revealed bilateral lacrimal gland enlargement, left greater than right, with mild associated exophthalmos. Laboratory evaluation revealed normal TSH, T4 and ACE levels. Sedimentation rate (ESR) and C-reactive protein (CRP) were slightly elevated.
The patient underwent excision of the left lacrimal gland mass. H & E stained tissue sections showed glandular tissue with a marked chronic inflammatory infiltrate consisting of predominantly small lymphocytes with occasional germinal center formation (Figure 1 A&B). Scattered histiocytes, eosinophils (including occasional eosinophilic abscesses), and plasma cells were present as well as small foci of necrosis. No polarizable foreign material or foreign body giant cells were identified. The inflammatory process extended into the periglandular adipose tissue and focal fibrosis was noted (Figure 1C).
By immunohistochemistry, CD3 and CD20 highlighted T- and B-cells, respectively, the former of which were greater in numbers. CD138 highlighted numerous plasma cells which were polyclonal by kappa and lambda in-situ hybridization stains (Figure 2). No organisms were identified by GMS or AFB stains.
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IgG4-related disease is a newly recognized fibroinflammatory condition characterized by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often but not always, elevated serum IgG4 concentrations. IgG4-related disease has been described in essentially every organ system. While a spectrum of histopathologic findings may be encountered, the salient features, as described above and as seen in the current case, are similar regardless of presentation1.
The epidemiology of the disease remains poorly defined, likely related to the still poor recognition of this disorder both clinically and pathologically. The demographic features are interesting in that the majority of patients are men (62-83%) and greater than 50 years of age2.
Two common findings in IgG4-related disease are tumefactive lesions and allergic disease. IgG4-related disease in general tends to form mass-like lesions, and as a result, patients are often suspected of having a malignancy. IgG4-related disease typically comes to medical attention because of single organ involvement, but more widespread disease is often observed following a detailed evaluation. Involvement by IgG4-related disease of different organs can occur either simultaneously or metachronously, with the emergence of one newly affected organ following another3.
The radiographic features are generally non-specific and do not permit reliable distinction between IgG4-related disease, other inflammatory processes or carcinoma.
A vast majority of IgG4-related disease cases tend to have a high of serum IgG4 level. Although this range can vary from case to another. Nearly thirty percent of cases have normal serum IgG4 levels, even with typical histopathological and immunohistochemical findings in the removed lesion4. Ongoing evaluation for IgG4 levels detects early relapse, although relapse occurs in ten percent of cases with normal IgG4 levels5. The patient in the current case demonstrated a mildly elevated IgG4 level.
As the clinical and serologic findings may not be specific, histologic evaluation of the lesion remains the gold standard for diagnosing IgG4-related disease6. The Major four histopathological features of IgG4-related disease are a dense lymphoplasmacytic infiltrate with a great percentage of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia. Minor features, including lymphoid follicles, germinal centers, obliterative arteritis, and non-obliterative phlebitis, are also found in many cases (see Table 1). The current case showed 3 of the 4 major pathologic features (lymphoplasmacytic infiltrate with numerous IgG4+ cells, fibrosis and eosinophilia) as well as some of the minor findings.
- The lymphoplasmacytic infiltrate is composed of a mixture of T and B lymphocytes. The B-cells are localized mainly in germinal centers, whereas the T-cells are diffusely spread throughout the entire lesion. For diagnosing IgG4-related disease, the presence of IG4-positive plasma cells is required. However, IgG4-positive plasma cells can be found in a variety of inflammatory disorders, so the detection of large numbers of the IgG4-positive plasma cells alone is not diagnostic. Applying immunohistochemical staining may help in differentiating IgG4-related disease from other inflammatory disorders. Different cutoff points have been proposed to fulfill criteria for IgG4-related disease, ranging from more than 10 to more than 50 IgG4-positive plasma cells per high-power field7.Another, possibly more reliable, approach is calculating the ratio of IgG4-positive plasma cells to total IgG plasma cells. Applying this method, a ratio of greater than 50% may allow confirmation of the diagnosis of IgG4-related disease.
- Fibrosis: The storiform type of fibrosis that characterizes IgG4-related disease represents an unusual pattern of collagen deposition. However, in late phase organ involvement, IgG4-related disease can be more of a diagnostic dilemma, when fewer plasma cells are present and fibrosis may extensively involve some tissues. The key to diagnosis under such circumstances may be the storiform morphology of the fibrosis. This so-called “burnt out” phase of IgG4-related disease may be characterized by relatively acellular, patternless fibrosis, resulting in diagnostic difficulty.
- Obliterative phlebitis: Obliterative phlebitis involves the lumina of small and medium-sized veins resulting in partial or complete occlusion by an inflammatory infiltrate composed of lymphocytes and plasma cells similar to the inflammatory infiltrate found elsewhere in the lesion. The finding of obliterative lesions of blood vessels is of immense diagnostic value because this histologic feature appears to be unique to IgG4-related disease. The biology underlying this pattern of vasculitis is currently unknown8.
- Eosinophils: Eosinophils are present in the majority of cases. In some cases, eosinophils may be the predominant finding (i.e., eosinophilic cholangitis), and therefore be mistaken for an allergic disease prior to recognition of the underlying IgG4-related process.
Pathological hallmarks of IgG4-related disease
Lymphoplasmacytic infiltrate >50% IgG4-positive plasma cells
Mild or moderate tissue eosinophilia
Obliterative arteritis (Lung)
Glucocorticoids are typically the first line of therapy which appears to be effective initially in the majority of patients with IgG4-related disease; however, the disease is often marked by frequent flares9. For patients with recurrent or refractory disease, B-cell depletion with rituximab appears to be a useful approach10. The degree of fibrosis within the affected organs is a major determinant of responsiveness to glucocorticoid therapy. In general, greater degrees of fibrosis are less responsive to corticosteroid therapy. However, in individual cases with advanced fibrosis, the amount of fibrous tissue may gradually diminish over time with therapy, indicating a more favorable prognosis in these patients. The patient in our case presentation received steroid therapy following diagnosis and showed marked improvement of her symptoms and exophthalmos.
- Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982-984.
- Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009;361(22):2135-2142.
- Stone JH, Khosroshahi A, Hilgenberg A, Spooner A, Isselbacher EM, Stone JR. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis & Rheumatism. 2009;60(10):3139-3145. doi: 10.1002/art.24798.
- Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol. 2011;23(1):108-113. doi: 10.1097/BOR.0b013e3283413469 [doi].
- Cornell LD, Chicano SL, Deshpande V, et al. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol. 2007;31(10):1586-1597. doi: 10.1097/PAS.0b013e318059b87c [doi].
- Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64(3):237-243. doi: 10.1136/jcp.2010.085613 [doi].
- Chari ST. Diagnosis of autoimmune pancreatitis using its five cardinal features: Introducing the mayo clinic's HISORt criteria. J Gastroenterol. 2007;42(18):39-41.
- Zen Y, Nakanuma Y. IgG4-related disease: A cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34(12):1812-1819. doi: 10.1097/PAS.0b013e3181f7266b [doi].
- Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58(11):1504-1507. doi: 10.1136/gut.2008.172908 [doi].
- Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4‐related systemic disease. Arthritis & Rheumatism. 2010;62(6):1755-1762.