Sellar germinoma mimicking IgG4-related hypophysitis: a case report

Background The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar germinoma is usually infiltrated by lymphocytes or plasma cells, and may be confused with hypophysitis. Case presentation A 36-year-old man with diabetes insipidus, elevated serum IgG4 level (336 mg/dl), and sellar mass was suspected to have IgG4-related hypophysitis, and no other lesion of IgG4-related disease was detected. After treated by prednisone and mycophenolate mofetil, the serum IgG4 decreased to 214 mg/dl. However, after withdrawal of the drugs, the IgG4 level increased to 308 mg/dl. Endocrine assessments revealed panhypopituitarism, and the sellar mass enlarged. Transsphenoidal sellar exploration and biopsy was conducted. Pathological examination showed that the lesion was germinoma with lymphocytes and plasma cells infiltration, and IgG4-staining was positive (70/HPF, IgG4/IgG ratio = 10%). The patient was then treated by cisplatin and etoposide. After four cycles of chemotherapy, the serum IgG4 was 201 mg/dl, and the sellar mass was invisible. Conclusion Sellar germinoma can mimic the clinical characteristics of IgG4-related hypophysitis. Poor response to glucocorticoids can be used as an exclusion criterion in the clinical diagnosis of IgG4-related hypophysitis.

Serum IgG4 Concentration is a Potential Predictive Biomarker in Glucocorticoid Treatment for Idiopathic Retroperitoneal Fibrosis

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR and partial response groups: PR), and each parameter was compared statistically.Results: Male-female ratio was 5: 1, and median age at diagnosis was 69 (33-86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6mg/dL vs 255mg/dL, 206mg/dL, P=0.0059 and 0.0078). ROC analysis was performed between the non-responder (NC) and responder groups (CR+PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC was 0.793 and the values of sensitivity and specificity were 0.85 and 0.64, respectively, under the cut-off values of 67.6mg/dL. Conclusions: In the majority of iRPF patients, glucocorticoid therapy resulted in a favorable response. Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study

BackgroundIgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features.MethodsWe collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD.ResultsA significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD.ConclusionOur observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

IgG4-Related Sclerosing Cholangitis: Rarely Diagnosed, but not a Rare Disease

IgG4-related sclerosing cholangitis, a biliary manifestation of an IgG4-related disease, belongs to the spectrum of sclerosing cholangiopathies which result in biliary stenosis. It presents with signs of cholestasis and during differential diagnosis it should be distinguished from cholangiocarcinoma or from other forms of sclerosing cholangitis (primary and secondary sclerosing cholangitis). Despite increasing information and recently established diagnostic criteria, IgG4-related sclerosing cholangitis remains underdiagnosed in routine clinical practice. The diagnosis is based on a combination of the clinical picture, laboratory parameters, histological findings, and a cholangiogram. Increased serum IgG4 levels are nonspecific but are indeed a part of the diagnostic criteria proposed by the Japan Biliary Association and the HISORt criteria for IgG4-SC. High serum IgG4 retains clinical utility depending on the magnitude of elevation. Approximately 90% of patients have concomitant autoimmune pancreatitis, while 10% present with isolated biliary involvement only. About 26% of patients have other organ involvement, such as IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, or IgG4-related renal lesions. A full-blown histological finding characterized by IgG4-enriched lymphoplasmacytic infiltrates, obliterative phlebitis, and storiform fibrosis is difficult to capture in practice because of its subepithelial localization. However, the histological yield is increased by immunohistochemistry, with evidence of IgG4-positive plasma cells. Based on a cholangiogram, IgG-4 related sclerosing cholangitis is classified into four subtypes according to the localization of stenoses. The first-line treatment is corticosteroids. The aim of the initial treatment is to induce clinical and laboratory remission and cholangiogram normalization. Even though 30% of patients have a recurrent course, in the literature data, there is no consensus on chronic immunosuppressive maintenance therapy. The disease has a good prognosis when diagnosed early.

Clinical Characteristics and Therapeutic Response of Immunoglobulin G4-Related Disease: a Retrospective Study of 127 Chinese Patients

Background & Aims: Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. The aim of the present study was to characterize the clinical features and therapeutic response of patients with IgG4-RD and identify risk factors for disease relapse.Methods: We collected baseline data of eligible patients with IgG4-RD and analyzed clinical feature by interview and review of medical records. The patients who received medical therapy with at least 3 months follow-up were used to characterize the therapeutic response and identify risk factors for relapse. Result: Totally 127 IgG4-RD patients, including 92 males and 35 females, were included in the present study. The median age at diagnosis was 63.0 years, ranging from 23 to 86. The pancreas, bile duct and lymph nodes were the most frequently involved organs. The serum IgG4 level was elevated in 94.5% of the patients and was correlated with the number of organs involved. Patients classified as head and neck limited group were more likely to be female. Patients classified as pancreato-hepatobiliary group had highest aminotransferase, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin level (all p＜0.05). Mikulicz syndrome and systemic involvement group had the highest IgG-RI score, serum globulin, IgG and IgG4 level. Among 92 patients who received medical therapy with at least 3 months follow-up,76 received glucocorticoids (GC) alone or in combination with immunosuppressive agents and 16 patients did not take GC. 74 out of the 76 patients (97.3%) achieved remission, with 59 of them remained in remission and 15 of them relapsed. Wheras16 patients did not take GC, among them, 6 patients achieved remission with one patient relapsed. On multivariate analysis, higher initial score of ACR/EULAR IgG4-RD Classification Criteria, GC monotherapy and GC withdrawal were independent predictors for relapse.Conclusion: Different phenotypes of IgG4-RD showed different demographic and serological features. The risk factors of relapse were GC withdrawal, GC monotherapy and higher score of ACR/EULAR IgG4-RD Classification Criteria.

IgG4-related pachymeningitis masquerading as foramen magnum meningioma: illustrative case

BACKGROUND Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory condition with potential multiorgan involvement. Common manifestations include autoimmune pancreatitis and retroperitoneal fibrosis. Pathological analysis reveals lymphoplasmacytic infiltrate rich in IgG4-positive cells and characteristic storiform fibrosis. Early treatment with glucocorticoids may prevent progression to poorly responsive fibrotic disease. OBSERVATIONS A 63-year-old female patient presented with reports of left-sided headaches, nausea, and photophobia in addition to recently diagnosed chronic rhinosinusitis (CRS). Neurological examination revealed dysarthria secondary to left hypoglossal nerve palsy. Computed tomography (CT) revealed a contrast-enhancing extraaxial mass at the left craniocervical junction, CRS with secondary hyperostotic reaction, and multiple hypodense lesions involving the occipital bone. Magnetic resonance imaging revealed a dural-based lesion involving the foramen magnum and invading the left hypoglossal canal. The patient underwent a far-lateral craniotomy. Histopathological analysis revealed severe lymphoplasmacytic inflammation, storiform fibrosis and rich plasma-cell population positive for IgG4. Serum IgG4 was markedly elevated. Total-body CT showed no systemic involvement. The patient was diagnosed with IgG4-RD and was prescribed prednisone, with normalization of her IgG4 levels after 1 month. LESSONS IgG4-RD may mimic a variety of diseases, including skull-base meningiomas and CRS. Accurate diagnosis and expedited administration of steroids may prevent unnecessary interventions and progression to treatment-resistant fibrosis.

Clinicopathological characteristics of IgG4-related lung disease

Background Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. We retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD to improve the diagnosis rate and reduce the risk of misdiagnosis. Methods We screened the pathological reports of 4838 patients with pulmonary surgery and/or biopsy specimens from April 2017 to April 2021 at Sun Yat-Sen Memorial Hospital affiliated with Sun Yat-Sen University, and specimens from 65 patients with suspected IgG4-RLD were subjected to immunohistochemical staining for IgG4 and IgG. Finally, 10 patients with definite IgG4-RLD that was pathologically confirmed were enrolled and analyzed. Results The incidence of pathologically confirmed IgG4-RLD was 0.2% (10/4838). The ten patients had an average age of 59.7 years at diagnosis, and the male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, and cough was the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Serum tumor marker levels were within the normal range or were slightly elevated. Computed tomography (CT) of the chest and/or 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well. Conclusions The results of our study suggest that multiple imaging findings, an elevated serum IgG4 concentration, and no significant increase in serum tumor biomarkers could provide diagnostic support for IgG4-RLD, especially for isolated IgG4-RLD or IgG4-RLD that includes other organ involvement that does not aid in establishing the diagnosis.

IgG4-related chronic sclerosing sialadenitis in a child with recurrent parotitis: a case report

Background IgG4-related disease (IgG4-RD) includes a group of immune-mediated diseases histologically characterized by lymphoplasmacytic infiltrate with a prevalence of IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. Autoimmune pancreatitis, sialadenitis, dacryoadenitis and retroperitoneal fibrosis are the most frequent manifestations. IgG4-related sialadenitis usually affects submandibular glands and is very rare in children. Here we report the case of IgG4-related sialadenitis in a six-year-old patient previously diagnosed as juvenile recurrent parotitis. Case presentation A six-year-old patient was referred to our Centre for left parotid swelling of 4 × 3 cm, that was tender, soft in consistency, with overlying red and warm skin. His general condition was good but he was subfebrile; general examination revealed mild enlargement of left cervical lymph nodes. In the last 2 years he had had five episodes of parotitis, diagnosed by another pediatric Center as juvenile recurrent parotitis. On ultrasound examination the left parotid gland appeared enlarged, inhomogeneous, with a colliquative intraparotid lymph node and no evidence of sialolithiasis. Laboratory tests showed an increase of white blood cells and anti-VCA IgM and IgG positivity, with anti-EBNA e anti-EA I negativity. The patient was initially treated with oral antibiotics, but after 10 days the parotid became fluctuating, requiring surgical biopsy and drainage. Postoperative course was regular, with complete remission under oral antibiotic and steroid therapy. Microbiological tests, including cultures for aerobic and anaerobic bacteria, mycobacteria and Bartonella, were negative. Surprisingly, histology showed marked fibrosis and histiocytic and lymphoplasmacellular infiltrate with polyclonal plasma cells mostly expressing IgG4 immunoglobulins. Thus, the diagnosis of IgG4 related chronic sialadenitis in recurrent parotitis and recent EBV infection was made. Conclusions IgG4-related sialadenitis is very unusual in children. Histology plays a key role in diagnosis, considering that up to 30% of patients have normal serum IgG4 levels, as shown in our case. The lack of previous histological data makes it impossible to attribute our patient’s previous episodes of parotitis to IgG4-RD, though it is a very consistent possibility.

Ophthalmic involvement disparities in clinical characteristics of IgG4-related disease: a retrospective study of 573 patients

Purpose To investigate the clinical manifestations of orbital involvement in a large cohort of Chinese patients with IgG4-related disease (IgG4-RD). Methods A total of 573 patients with IgG4-related disease were included. We described and compared the demographic, clinical, laboratory and histopathologic findings from 314 patients with IgG4-related ophthalmic disease (IgG4-ROD) and 259 with extra-ophthalmic IgG4-RD. Results Male predominance was found significant in extra-ophthalmic IgG4-RD only. Patients with IgG4-ROD showed younger age at diagnosis and longer duration from onset till diagnosis. In patients with extra-ophthalmic IgG4-RD, the most commonly involved extra-ophthalmic organ was pancreas; while in IgG4-ROD patients, salivary gland was most frequently affected. Multivariate analysis exhibited IgG4-ROD was associated with allergy history, higher serum IgG4/IgG ratio, multiple organs involvement and sialoadenitis. Orbital images were reviewed in 173 (55.1%) IgG4-ROD patients. Fifty-one (29.5%) patients had multiple lesions. Lacrimal gland involvement was detected in 151 (87.3%) patients, followed by extraocular muscles (40, 23.1%), other orbital soft tissue (40, 23.1%) and trigeminal nerve (8, 4.6%). Biopsy was performed from various organs in 390 cases. A dense lymphoplasmacytic infiltration and fibrosis were the main feature in orbital specimens. Storiform fibrosis and obliterative phlebitis were absent in lacrimal gland. Conclusions Lacrimal gland involvement was the most common orbital manifestation of IgG4-ROD. Patients with IgG4-ROD showed different characteristic in demographic, clinical, laboratory findings compared to patients with extra-ophthalmic IgG4-RD. These features might indicate potential differences in the pathogenesis of these two subgroups of IgG4-RD.

Unique Ultrasonographic Findings of Isolated IgG4-Related Lymphadenopathy

IgG4-related disease is a rare immune-mediated disease that can involve many organs in the body. The lymph node is also where IgG4-related diseases occur, but its histological structure is different from that of other organs. For this reason, pathologists have difficulty diagnosing IgG4-related lymphadenopathy. If there were specific imaging findings of IgG4-related lymphadenopathy, it would be of great help to pathologists. A 64-year-old male visited our hospital with right ankle pain. On physical examination, the right lower extremity showed severe swelling with wound dehiscence, and infection was suspected. On CT (128-MDCT, Somatom Definition Flash, Siemens Healthcare) taken at the lower extremity, multiple enlarged lymph nodes were incidentally noted in the right inguinal area. On ultrasonography, a “starry night sign” resembling hyperechoic follicles was observed in the enlarged lymph node. A core needle biopsy was performed, and IgG4-related lymphadenopathy was diagnosed. Laboratory examination showed hypergammaglobulinemia with marked elevated serum IgG4, corresponding to IgG4-related disease. Chest and abdominal imaging were evaluated, but there was no extranodal IgG4-related disease. IgG4-related lymphadenopathy showed a very unique ultrasonography imaging finding. The cortex was filled with diffusely scattered hyperechoic foci and some bright foci gathered to form a follicle. This imaging finding may help diagnose IgG4-related lymphadenopathy.