|Year : 2018 | Volume
| Issue : 3 | Page : 232-235
IgG4 related disease (IgG4-RD) as a costochondral mass: A rare presentation
Ajoy Oommen John1, Ajay Kumar Mishra1, Anne Jennifer2, Ronald Albert Benton Carey1
1 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||17-Jul-2018|
Ajoy Oommen John
Department of Medicine Unit 3, Christian Medical College, Ida Scudder Road, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
A 39-year-old female came for evaluation for progressive lower costochondral pain and swelling with no associated systemic or constitutional symptoms and no evidence of the involvement of any other organ system. Diagnostic thoracotomy with excision of involved rib and costochondral junction showed plasma cell-rich chronic inflammation with foci of fibrosis with no definite storiform fibrosis or obliterative phlebitis. Immunohistochemistry showed 30%–40% immunoglobulin G4 (IgG4)-positive cells/hpf with an IgG:IgG4 ratio of 30% with sterile cultures and no elevation of serum IgG4 levels. With a presumptive diagnosis of IgG4-related disease, she was started on steroids with which she had complete symptom relief and resolution of the lesion. This case highlights the importance of considering the diagnosis of IgG4 disease even in the absence of typical histopathological findings and elevated serum IgG4 levels. The authors have not found any prior reports in the English literature of IgG4 disease of the ribs and costochondral junction.
Keywords: Costochondral mass, immunoglobulin G4 disease, storiform fibrosis
|How to cite this article:|
John AO, Mishra AK, Jennifer A, Benton Carey RA. IgG4 related disease (IgG4-RD) as a costochondral mass: A rare presentation. CHRISMED J Health Res 2018;5:232-5
|How to cite this URL:|
John AO, Mishra AK, Jennifer A, Benton Carey RA. IgG4 related disease (IgG4-RD) as a costochondral mass: A rare presentation. CHRISMED J Health Res [serial online] 2018 [cited 2020 Feb 24];5:232-5. Available from: http://www.cjhr.org/text.asp?2018/5/3/232/236900
| Introduction|| |
Immunoglobulin G4-related disease (IgG4-RD) is a multisystem disorder of unknown etiology characterized by dense lymphoplasmacytic infiltration into tissues which is rich in IgG4-positive plasma cells, tumefactive lesions, and storiform fibrosis. They are also often associated with elevated serum IgG4 levels. IgG4 RD of the bone is rare and may not fulfill the traditional diagnostic criteria. Skeletal involvement in IgG4 RD has been reported before although these seem to be restricted to the involvement of the paranasal sinuses., As far as the authors are aware, this is the first report of IgG4 RD involving the costal cartilage with rib destruction.
| Case Report|| |
A 39-year-old homemaker presented with insidious onset right subcostal pain for 3 months. The pain was moderate in intensity, persistent and was not radiating. She had no other systemic symptoms. A biopsy done elsewhere had revealed nonspecific inflammatory changes and she had been treated with nonsteroidal anti-inflammatory agents, with minimal relief. On examination, she was afebrile and vital signs were normal. She had localized tenderness over the right lower costochondral junction but no other significant findings were present. There was no other localized bony tenderness, and remaining systemic examination was also normal. Her hemogram was normal (hemoglobin of 11.3 g/dl, total leukocyte count of 14,600/cumm, and platelet counts of 219,000/cumm). Renal function test, liver function tests, and serum electrolytes were normal except for a mildly elevated alkaline phosphate (144 U/ml). Erythrocyte sedimentation rate was 49 mm. Chest radiograph and electrocardiogram were normal. Computed tomography (CT) imaging of her thorax [Figure 1] showed soft-tissue thickening and fat stranding around the lower anterior costochondral junctions bilaterally. The lesion was not amenable to guided biopsies owing to its small size.
|Figure 1: Computed tomography thorax showing soft-tissue thickening with fat stranding in bilateral lower costochondral junctions|
Click here to view
The differentials considered were localized infectious osteochondritis of either bacterial or tuberculous etiology, malignancy – either primary neoplasms of the bone or secondary, and Paget's disease of the bone. Sputum smears for acid-fast bacilli, bacterial, mycobacterial and fungal cultures, bone marrow aspiration, and histopathology were negative. Ultrasonography of the abdomen was unremarkable. At this point, she was advised to be on close follow-up and was given analgesics for symptomatic relief.
At 3-month follow-up, her pain had worsened, and she had new onset pain on the left side. Examination revealed bilateral lower costochondral tenderness, with an ill-defined mass palpable along the proximal left 7th rib near the costochondral junction and tenderness along the left 7th rib. Repeat CT imaging showed persistent lower costochondral junction swelling, with an increase in the size of the swelling on the left side [Figure 2]. The swelling was also extending to the subcutaneous and surrounding intercostal muscles. Mycobacterial and bacterial cultures remained sterile. A bone scan showed areas of increased tracer uptake at the costochondral junctions and proximal rib. This was most prominent in the right 7th costochondral junction. There were no other areas of increased uptake [Figure 3]. An ultrasound-guided biopsy of the lesion showed plasma cell-rich chronic inflammation with foamy histiocytes and few eosinophils. Since this biopsy was noncontributory, an open thoracotomy and biopsy were done under general anesthesia. Intraoperatively, the 7th costal cartilage was found to be destroyed with surrounding necrotic tissue. The cultures were sterile and the histopathology again showed plasma cell-rich chronic inflammation. There were foci of fibrosis and hyalinization, scattered eosinophils, and few lymphoid follicles. Definite storiform fibrosis or obliterative phlebitis was not noted. However, immunohistochemistry showed 30%–40% IgG4-positive cells/hpf with an IgG: IgG4 ratio of 30% [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d. A serum IgG 4 was done which was not elevated (82.3 mg/dl). There were no abnormal lymphocytes and no morphological features to suggest a lymphoproliferative neoplasm. Hence, further markers such as MYD88 were not performed.
|Figure 2: Computed tomography thorax showing increase in swelling over left costochondral junction and surrounding soft tissue|
Click here to view
|Figure 3: Technetium 99m bone scintigraphy showing increased tracer uptake at bilateral lower costochondral junctions|
Click here to view
|Figure 4: (a) Plasma cell-rich chronic inflammation. (b) Plasma cell-rich chronic inflammation-high power field. (c) Plasma cell-rich inflammation staining for immunoglobulin G4. (d) Plasma cells with chronic inflammation and stain positive for immunoglobulin G4|
Click here to view
We made a diagnosis of probable IgG4 disease since multiple cultures from two different sites had remained sterile and histopathology had persistently shown the same findings. She was started on steroids at 1 mg/kg and gradually tapered over 4 months.
At 4-month follow-up, she was symptom free, and the swelling had resolved both at the operated and the nonoperated site. The slow taper of steroids was continued and she was initiated on azathioprine as a second-line immunosuppressive agent.
At 1 year follow-up, she continued to be symptom free and a repeat CT scan showed complete resolution of the lesion [Figure 5]. Her steroids were stopped and azathioprine was continued.
|Figure 5: Follow-up computed tomography thorax at 1 year showing complete resolution|
Click here to view
| Discussion|| |
IgG4 RD is a rare multisystem, immune-mediated, fibro-inflammatory disorder with characteristic histopathological findings. The organ involvement can be sequential or multiple organs can be found to be involved at the time of presentation. In Japan, the estimated incidence of this disease is 0.2–1/100,000. As the definition and understanding of this disease evolves, this number is likely to change.
Diagnosis of immunoglobulin G4-related disease
Kamisawa and Okomoto first proposed that the infiltration of IgG4-positive plasma cells into various organs associated with elevated IgG4 levels is a systemic disorder. Since then, IgG4 RD has expanded to include a diverse variety of diseases that were previously considered to be single organ disorders. As a consequence of this wide disparity in clinical features and manifestations, there arose a need for comprehensive diagnostic criteria for IgG4-RD. Two groups of Japanese investigators across multiple specialties collaborated to propose the following two diagnostic criteria (a) serum IgG4 concentration >135 mg/dl and (b) >40% of IgG4 + plasma cells being IgG4 + and >10 cells/high power field of biopsy sample. This was further refined with the development of a diagnostic algorithm and organ-specific diagnostic criteria.
Role of immunoglobulin G4 in diagnosis
A recent meta-analysis concluded that IgG4 levels are only a modestly effective diagnostic marker for IgG4 RD. At the cutoff value specified above, it had a sensitivity and specificity of 87.2% and 82.6%. It has been noted that serum IgG4 levels are known to be normal in approximately 30% of patients. This has lent further support to the idea that IgG4 levels can only be used as a supportive diagnostic marker in addition to clinical presentation, histology, and imaging findings.
Other reported cases of bone involvement in immunoglobulin G4-related disease
Skeletal involvement with destructive lesions in IgG4 RD has been reported before although these seem to be restricted to the involvement of the paranasal sinuses.,, As far as the authors are aware, this is the first report of an IgG4 RD involving the costal cartilage with rib destruction.
Can a clinical picture be more diagnostic than a diagnostic criteria?
This case does not fulfill the comprehensive diagnostic criteria for IgG4-RD for the following reasons:
1. The presence of elevated serum IgG4 levels is a hallmark of this disease. However, a number of factors appear to influence the IgG4 levels. In a cohort of 125 patients with IgG4 RD, the factors significantly associated with elevated IgG4 levels were older age, low complement levels, high absolute eosinophil counts, number of organs involved, and higher IgE levels. Another study also demonstrated that IgG4 levels correlated with the number of organs involved. Depending on these variables up to 50% of patients with IgG4 RD can have normal IgG4 levels, and hence it has been postulated that the elevated IgG4 levels may identify a subset of patients with more severe disease.
Another important hallmark of this disease is a dense IgG4-positive infiltration of plasma cells. Hence, the ratio of IgG4-positive plasma cells to IgG-positive plasma cells forms an essential feature of the comprehensive diagnostic criteria. To date, only two prior case reports have shown scant IgG4 positive plasma cells in affected organs, with a clinical picture similar to IgG4-RD. The first published by Makiishi et al. described a patient with bilateral submandibular gland enlargement, along with enlargement of multiple cervical and mediastinal lymph nodes with a diffusely enlarged pancreas and kidneys. The histopathology from the submandibular glands described findings similar to sclerosing sialadenitis. The immunohistochemical staining showed multiple IgG-positive cells; the ratio of IgG4 to IgG-positive plasma cells was <2%. The patient had good clinical improvement with steroid therapy. Another recent case report by Hara et al. reports a 74-year-old male with multiple lymph node enlargement and positive emission tomography showing accumulation of fluorodeoxyglucose in parotid and submandibular glands, lymph nodes, lungs, kidneys, pancreas, and prostate. Renal biopsy showed lymphoplasmacytic infiltration and fibrosis similar to IgG4-related TIN. Biopsies from other sites also showed histopathology suggestive of IgG4-RD. However, although immunohistochemistry from all the sites showed IgG-positive plasma cells, the IgG4/IgG-positive plasma cell ratio was <40%. This patient was also treated with steroids, with a gradual taper, and he demonstrated good treatment response and no flare for almost 4 years.
Both the cases described above are similar to our patient in that they have clinical, imaging, and histopathological evidence of an infiltrative disorder with immunohistochemically proven IgG- and IgG4-positive plasma cell infiltration and dramatic steroid response. As mentioned above, our patient demonstrated complete clinical and radiological resolution of the lesions and has remained free of disease through 20 months of follow up.
Our patient, along with the above-described case reports, supports the hypothesis that IgG4 antibodies do not play a primary etiological role in IgG4 RD.
The strengths of our case are that since multiple biopsies including a surgical excision biopsy were performed, the chances of a sampling error are extremely low. In addition, the good steroid response and prolonged disease-free follow up also argue strongly in favor of a correct initial diagnosis.
The limitations are that the diagnosis still remains presumptive and a low-grade lymphoma could still be considered plausible differential, since they also demonstrate steroid responsiveness. However, the many features against a lymphoma are (a) the lack of morphological features and (b) the lack of further disease progression after 20 months of follow up. As elucidated earlier, the failure to fulfill the current diagnostic criteria may be a reflection of a milder form of the disease as well as a lack of sensitivity of the diagnostic criteria as currently constructed.
| Conclusion|| |
We have described a rare case of IgG4-related disease involving the costochondral junction with normal IgG4 levels which required a diagnostic thoracotomy for diagnosis and with good response to glucocorticoids. The case illustrates the following:
- That IgG4 antibodies may not be the primary etiological factor in the disease
- A subset of patients do exist, who do not fulfill the current diagnostic criteria for IgG4 RD. This may reflect a less severe variant of the disease or a need for further refining of the current criteria to account for this discrepancy
- Steroids should be considered as a treatment for these patients, once sufficient efforts have been made to rule out the relevant differentials.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name, and initial will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. The Lancet 2015;385:1460-71.
Stone JH, Zen Y, Deshpande V. IgG4-Related Disease. N
Engl J Med 2012;366:539-51.
Pace C, Ward S. A rare case of igg4-related sclerosing disease of the maxillary sinus associated with bone destruction. J Oral Maxillofac Surg 2010;68:2591-3.
Ikeda R, Awataguchi T, Shoji F, Oshima T. A case of paranasal sinus lesions in IgG4-related sclerosing disease. Otolaryngol - Head Neck Surg 2010;142:458-9.
Palazzo E, Palazzo C, Palazzo M. IgG4-related disease. Jt Bone Spine Rev Rhum 2014;81:27-31.
Kamisawa T, Okamoto A. Autoimmune pancreatitis: Proposal of IgG4-related sclerosing disease. J Gastroenterol 2006;41:613-25.
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al
. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol Jpn Rheum Assoc 2012;22:21-30.
Okazaki K, Uchida K, Ikeura T, Takaoka M. Current concept and diagnosis of IgG4-related disease in the hepato-bilio-pancreatic system. J Gastroenterol 2013;48:303-14.
Hao M, Liu M, Fan G, Yang X, Li J. Diagnostic Value of Serum IgG4 for IgG4-Related Disease: A PRISMA-compliant Systematic Review and Meta-analysis. Medicine (Baltimore) 2016;95:e3785.
Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol 2011;23:108-13.
Sadler R, Chapman RW, Simpson D, Soonawalla ZF, Waldegrave EL, Burden JM, et al
. The diagnostic significance of serum IgG4 levels in patients with autoimmune pancreatitis: A UK study. Eur J Gastroenterol Hepatol 2011;23:139-45.
Kurien R, Babu TR, Rupa V. Unusual cause of maxillary sinus mass with proptosis. BMJ Case Rep 2015;2015:bcr2015210627.
Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al
. High Serum IgG4 Concentrations in Patients with Sclerosing Pancreatitis. N
Engl J Med 2001;344:732-8.
Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al
. IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients. Arthritis Rheumatol Hoboken NJ 2015;67:2466-75.
Zen Y, Nakanuma Y. IgG4-related disease: A cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812-9.
Makiishi T, Shirase T, Hieda N, Maeda S. Immunoglobulin G4-related disease with scant tissue IgG4. BMJ Case Rep 2013;2013.
Hara S, Kawano M, Mizushima I, Yamada K, Fujita K, Harada K, et al
. A condition closely mimicking IgG4-related disease despite the absence of serum IgG4 elevation and IgG4-positive plasma cell infiltration. Mod Rheumatol 2016;26:784-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]