Multi-organ IgG4-related disease: Demystifying the diagnostic enigmaS Bhardwaj1, S Goyal1, AK Yadav1, A Goyal2
1 Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_778_16
Source of Support: None, Conflict of Interest: None
Keywords: Castleman's disease, IgG4-related disease, lymphoma
IgG4-related disease (IgG4-RD) is a relatively new clinicopathologic entity, described only about 10 years ago, that can affect multiple organs., It has been known previously as IgG4 multiorgan lymphoproliferative syndrome, IgG4 sclerosing disease, and IgG4-related systemic plasmacytic syndrome. Its main features are tumor-like swelling of the involved organs (mainly lacrimal glands, salivary glands, and pancreas) in association with lymphoplasmacytic infiltrate enriched in IgG4 positive plasma cells and variable degrees of fibrosis with a characteristic storiform pattern. Elevated IgG4 serum levels are found in 60%–70% of the patients.
Its exact incidence in the general population has not been reported yet. Owing to rarity, and lack of awareness, it is often misdiagnosed as disseminated lymphoma or malignancy as was seen in our case of a 25-year-old female. The present case deserves merit in view of its unusual and misleading diverse multisystemic clinical presentation.
A 25-year-old female presented with the chief complaints of swelling in bilateral upper lids since 1 year. Both these swellings were insidious in onset, painless, and progressively increasing in size. There was no history of diminution of vision, drying of eyes, xerostomia, or trauma. She also gave a history of weight loss, loss of appetite, and intermittent low-grade fever since 1 year. She developed multiple bilateral cervical swellings which were painless and progressively increasing in size. She complained of gradually progressive weakness in both the lower limbs since past few months, not associated with sensory loss, paresthesia, or bowel and bladder complaints. There was no significant past medical or surgical history.
On examination, the patient was cachectic and anemic. Bilateral cervical and left submandibular lymphadenopathy, varying in size from 0.5 cm to 1.5 cm in diameter was noted. The lymph nodes were mobile, nontender, nonmatted, and rubbery in consistency. On ophthalmological examination, swellings measuring 2.5 cm × 1 cm and 1 cm × 0.8 cm were palpable in the left and right supraorbital regions, respectively. They were nontender, partially mobile, noncompressible, nonreducible, and not fixed to the overlying skin. Fingers could be insinuated between the mass and the supraorbital margin, but the posterior margin of the mass could not be reached. Provisional clinical diagnosis of bilateral dacryoadenitis was made.
Chest radiograph was unremarkable. Noncontrast computed tomography (CT) orbits showed a homogeneous hyperdense lobulated soft tissue mass (2.5 cm × 1.0 cm) in the superotemporal region of the left orbit abutting the left globe and lateral rectus muscle with no intraconal extension [Figure 1]. A similar mass (0.9 cm × 0.8 cm) was seen on the superolateral aspect of the right orbit and extending to involve the upper lid. Both lacrimal glands were not seen separately. Ultrasound abdomen revealed gross left hydronephrosis with pelvi-ureteric junction obstruction. Contrast-enhanced CT revealed hypoenhancing mass lesion epicentred in the left renal sinus region, causing obstructive hydronephrosis [Figure 1]. Magnetic resonance imaging spine [Figure 2] revealed multiple well-defined nodular lesions along the course of spinal nerve roots at multiple levels in lumbar spine with significant vertebral foramina involvement at the lower lumbar levels. Dural-based lesion was also seen in prepontine location. Multiple enlarged lymph nodes were seen in the anterior and posterior triangle of neck and parapharyngeal spaces [Figure 2]. A radiological diagnosis of disseminated lymphoma was suggested.
The patient underwent excision biopsy of the cervical lymph node. Histopathological examination showed partial effacement of lymph node architecture by sheets of plasma cells in the interfollicular region of the cortex. In these areas, average plasma cell count was 100 cells/hpf with 45 cells/hpf positive for IgG4. The IgG4:IgG ratio was 1:2.2. Sinuses were unremarkable [Figure 3]. On immunohistochemistry, these plasma cells were positive for kappa and lambda (polyclonal) and negative for leukocyte common antigen (LCA), and B-cell markers (CD20, CD19, and Bcl-2).
Biopsy from the left upper lid mass showed ductular destruction and extensive areas of periductal concentric fibrosis [Figure 4]. A moderate to dense lymphoplasmacytic infiltrate was noted in the periductal areas, averaging 50 plasma cells/hpf, which were strongly positive (3+) for IgG4 on immunohistochemistry (IgG4 positive plasma cells = 22/hpf) [Figure 4] and [Figure 5]. The IgG4:IgG ratio was 1:2.2. The few collections of foamy macrophages were also seen. Obliterative phlebitis was not seen. The histomorphological and clinical features were suggestive of a multisystemic inflammatory/autoimmune disorder with a possibility of IgG4 related disease and multicentric Castleman's disease. To confirm this, serum IgG4 levels were 3.4 g/L (by particle-enhanced immunonephelometry, normal range 0.03–1.5 g/L). Serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were within normal limits. Therefore, a final diagnosis of multisystemic IgG4 related disease was suggested. The patient was started on oral Wysolone (prednisolone) 40 mg OD. Repeat CT after 8 weeks of treatment revealed 50% reduction in paraspinal, orbital and renal mass, and the patient is relieved of pressure symptoms. Significant reduction in serum IgG4 levels (2.2 g/L) after 8 weeks was noted as well.
IgG4 disease clinically presents with multifocal tumor-like masses which create an obvious confusion with malignancy. Clinicoradiological diagnosis of lymphoma in our case is an example of the deceptive clinical features of this disease. It is important to recognize IgG4 disease at an early stage as timely diagnosis can prevent extensive organ destruction and fibrosis.,
The differential diagnosis of IgG4-RD depends on the involved organs and clinical presentation. Pathological features of IgG4-RD of salivary glands and lacrimal glands overlap with autoimmune disorders such as Sjogren's syndrome (SS) and pseudolymphoma. Both the conditions show an extensive lymphoplasmacytic infiltrate. IgG4 disease commonly affects middle-aged men. Although the age and sex were favorable of SS in our case, however, lack of dryness of eyes, xerostomia, the presence of large, deep-seated bilateral orbital masses, and the multisystemic involvement excluded the possibility of SS.,
Sections from the lymph node showed the effacement of lymph node architecture by sheets of plasmacytoid cells, based on which, multicentric Castleman's disease, plasma cell dyscrasia, and marginal zone lymphoma qualify for differential diagnoses. Monoclonality of lymphoid cells for light chain (kappa or lambda), positivity for LCA, CD20, CD19, and Bcl-2 favor the diagnosis of marginal zone lymphoma, which was not the scenario in our case. Younger patient age, unusual sites of involvement such as kidney, salivary gland, and eyelid and polyclonality of plasma cells excluded the possibility of plasma cell dyscrasia. Although the histopathological features were strikingly similar to Castleman's disease related lymphadenopathy, the multisystemic tumor-like masses with orbital involvement, IgG4 immunopositivity in plasma cells, and elevated serum levels of IgG4, coupled with normal IL-6, and CRP levels helped in favoring a diagnosis of systemic IgG4 disease over multicentric Castleman's disease.
Five patterns of lymph node involvement have been described in IgG4 related disease; namely, multicentric Castleman's disease-like (Type I), follicular hyperplasia (Type II), Interfollicular expansion (Type III), progressive transformation of germinal center-like (Type IV), nodal inflammatory pseudotumor-like (Type V). In our case, there was interfollicular expansion by sheets of plasma cells (Type III).
Bilateral orbital involvement in IgG4 disease is fairly common., Patients with lacrimal gland involvement often have concurrent salivary gland involvement, which was not seen in our case. Associated lymphadenopathy, most commonly axillary or mediastinal is seen in 14% of these cases. Multiple organs are involved in 60%–90% of patients with IgG4 related disease. However, such a diverse multisystemic involvement including bilateral lacrimal glands, lymph nodes, kidney, and multiple paraspinal masses, masquerading a disseminated malignant entity has not been reported before, which makes this case unique and unusual.
As per the diagnostic criteria, the combination of characteristic organ involvement, serum IgG4 levels >1.35 g/L, along with the presence of >10 IgG4 positive cells, and IgG4:IgG positive cell ratio of more than 0.4 implies a definite diagnosis of IgG4-related disease. Confirmation of the diagnosis by biopsy is important for the exclusion of malignancy and other disorders that may mimic IgG4-RD. Since in our case, the clinicopathological features were compatible with the diagnosis of IgG4 related disease and the patient responded well to corticosteroids, further biopsy from renal and paraspinal masses was deemed unnecessary. In a retrospective study on ocular adnexal IgG4-RD, recurrence was seen in 45% of patients, requiring repeat steroids and adjunctive treatment. Furthermore, lower serum IgG4 and low IgG4:IgG implied poor prognosis.
Confirmation of IgG4 disease requires characteristic histomorphological features, IgG4 immunopositivity, and elevated serum IgG4 levels. The awareness of this rare entity can help in making a timely diagnosis and prevention of the sequelae. Although such a multisystemic presentation is extremely rare in a young woman, the possibility of IgG4-related disease should always be kept in mind.
Declaration of patient consent
The authors certify that appropriate patient consent was obtained.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]