Integrating Metabolic Imaging with Metabolic Intervention - Unfolding the Mystery of Rare Isolated Pulmonary IgG4-related Disease Masquerading as Lung Tumor

Introduction

IgG4-related disease (IgG4-RD) was first identified in Japan and later on predominantly in the Asian subcontinent. It is a multisystemic infiltrative disorder characterized by infiltration of plasma cells positive for IgG4 and sclerosis of involved organs. Involvement of the pancreas, lacrimal glands, salivary glands, bile ducts, retroperitoneal tissues, lung, kidney, prostate, pituitary gland, thyroid, and uterus is widely reported.[1] Hence, it can involve almost any organ in the body, which is why it often shows up in many different ways. Some of the most common presentations include autoimmune pancreatitis (type 1), swelling of the salivary and lacrimal glands, retroperitoneal fibrosis, kidney involvement, enlarged lymph nodes, and lung-related symptoms.[2]

We present a case wherein the patient presented with a lung mass. Malignancy is considered as first differential diagnosis for an elderly smoker with hemoptysis and a lung mass with features of heterogeneous enhancement, spiculations, necrosis, and infiltration into adjacent structures. However, in this case, final diagnosis turned out to be IgG4-RD. We highlight this case due to the rarity of this disease and even more rare presentation, manifesting as an isolated lung involvement. Initial evaluation with CECT scan and CT-guided biopsy failed to reveal the diagnosis. Whereas, metabolic imaging with FDG PET-CT and subsequent PET-guided biopsy confirmed the benign etiology of the mass and revealed features of IgG4-RD. Immunohistochemistry was done, which showed immunopositivity for IgG4. Identifying this rare disease is crucial because its management varies considerably, and the prognosis is favorable.

Case Report

A 72-year-old male, ex-smoker (Smoking Index – 200) presented with complaints of breathlessness, hemoptysis, cough with scanty mucoid expectoration, loss of appetite, and weight for 5 months. The patient initially presented to the primary care hospital, where the patient was diagnosed as having chronic obstructive pulmonary disease with pneumonia and was initiated on antibiotics and inhalers. CT thorax was done in which a heterogeneously enhancing solid lesion/consolidatory area with spiculated margins and internal necrotic area was noted in the right lower lobe and is abutting the pleura on the posterior aspect with mediastinal lymphadenopathy. CT-guided biopsy was done under high suspicion of malignancy; histopathology was suggestive of the chronic inflammatory process. Microbiological testing was done to rule out infections. CBNAAT, Gram stain, Ziehl–Nielson stain, KOH mount, aerobic culture, and fungal culture were all inconclusive.

In view of the above findings, the patient was referred for an FDG PET-CT scan to characterize the metabolic nature of the lung lesion and also to see other sites of involvement elsewhere in the body. It showed FDG avid heterogeneously enhancing irregular mass (5.7 cm × 5.5 cm × 5.0 cm, maximum Standardised uptake value [SUVmax] – 6.8) with spiculated margins, air bronchogram, pleural tags, and areas of necrosis within, involving the posterolateral segment of the lower lobe of the right lung [Figure 1a-c]. Few perilesional nodules (largest 1.6 cm × 1.5 cm SUVmax – 5.6) with heterogeneous FDG uptake were noted in the lateral basal segment of the right lower lobe. Mildly FDG avid variable-sized right lower paratracheal, AP window, subcarinal (1.8 cm × 1.5 cm, SUVmax – 4.8), and right hilar (largest measuring 1.2 cm × 1.3 cm, SUVmax – 4.5) lymph nodes were noted. No other metabolically active lesions were noted in the rest of the body. In view of the failed CT-guided biopsy, an FDG PET-CT-guided metabolic biopsy was planned. The most metabolically active region that was easily assessable was targeted with the help of a robotic arm. Tissue samples were taken from the planned region [Figure 1d] under local anesthesia. The Histopathology examination (HPE) exhibited morphological features of IgG4-RD with areas of fibrosis in a storiform fashion. There was no evidence of granuloma or atypia. On immunohistochemistry, the plasma cells are immunopositive for IgG4 – >30/high power field (% of IgG4+ cells are nearly 35% in focal areas) [Figure 2]. Serum IgG4 levels were within the normal range. He was subsequently initiated on oral prednisolone at 0.6 mg/kg/day. The patient improved symptomatically, hemoptysis resolved, and cough decreased in frequency and intensity. The patient is kept under close monitoring to evaluate resolution and steroid response.

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Figure 1 (a) Maximum intensity projection FDG PET image showing FDG avid lesion in the right lung lower lobe region (black arrow). (b) Fused image of the transaxial section of FDG PET-computed tomography (CT) showing an FDG avid heterogeneously enhancing irregular mass lesion involving the right lung lower lobe. (c) Transaxial section of contrast-enhanced computed tomography showing heterogeneous enhancement in the mass lesion involving the right lung lower lobe. (d) FDG PET-CT guided biopsy image showing the posterior approach for the biopsy. The biopsy needle was directed toward the highest metabolic activity area of the right lung mass, to increase the likelihood of obtaining pathologic/neoplastic tissue for histopathologic analysis (in this case, results revealed IgG4-related disease)

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Figure 2 (a) Photomicrograph shows a large area of plasma cell predominant mixed inflammatory infiltrate (H and E, ×100). (b) Interspersed eosinophils (red arrow) are also noted in the infiltrate (H and E oil immersion). (c) CD38 highlights the plasma cell population, and storiform fibrosis is seen in the background (immunohistochemistry [IHC] ×100). (d) The plasma cells also show IgG4 positivity (>30/hpf; IHC ×400)

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We also counseled our patient regarding cancer screening for at least 5 years after treatment completion. IgG4-RD involving the lung has an intriguing character where it is often found associated with malignancy at the time of diagnosis or in future.

Discussion

IgG4-RD was primarily identified in a population of patients presenting with autoimmune pancreatitis. IgG4 disease was identified to involve multiple organ systems. Virtually, any organ can be involved,[3] but pancreatic involvement is reportedly most common.[4] Usually, at the time of diagnosis, it is found to involve multiple organ systems. Thoracic involvement in IgG4-RD ranges from 14% to 35% of patients.[5] Isolated presentation in the thorax is extremely rare; fewer than 20 cases are reported worldwide for isolated lung involvement.[6] On FDG PET-CT, IgG4-related lung disease (IgG4-RLD) can manifest into four primary subtypes: solid nodules or masses in the lung parenchyma, with or without enlarged lymph nodes in the hilar or mediastinal regions showing high 18F-FDG uptake; multiple ground-glass opacities; thickening of the alveolar interstitium; and thickening of the bronchovascular bundle.[7] IgG4-RLD has overlapping radiologic features and can resemble various other diseases, and in particular, the solid nodular type of IgG4-RLD is difficult to distinguish from carcinoma lung.[8] Another common characteristic between IgG4-RLD and carcinoma lung is increased SUV on FGD PET-CT scans. However, SUV levels in IgG4-RLD are generally lower than those in carcinoma lung and tend to decrease as the inflammatory process resolves.[9] Although histopathology is highly recommended to rule out malignancies and other conditions, imaging with FDG PET-CT has proven effective in assessing organ involvement, guiding biopsies, and monitoring the disease response. In IgG4-RD, hypermetabolic parenchymal disease or hypermetabolic pleural thickening-like manifestations of thoracic involvement have been described on FDG PET-CT.[10] In our case, there was isolated pulmonary involvement. FDG PET-CT revealed a metabolically active solitary lesion with mediastinal lymphadenopathy. The imaging findings mostly mimicked lung carcinoma. Further CT-guided biopsy did not provide a definitive diagnosis, so for a histological confirmation of the disease, a PET-guided metabolic biopsy was planned, which finally confirmed the IgG4-RD. Immunosuppression is the mainstay treatment strategy. Cyclophosphamide, azathioprine, mycophenolate mofetil, and rituximab have been used in steroid-resistant or those relapses on steroid withdrawal cases.[11] This is a unique case scenario which highlights the importance of integrating metabolic imaging with metabolic intervention in the accurate detection of a rare isolated pulmonary IgG4-RD, which was clinicoradiologically mimicking lung carcinoma. The use of these combined metabolic studies ensured timely and accurate management, thereby avoiding unnecessary invasive procedures and complications.