The Dual Threat: Navigating the Concurrence of Granulomatosis with Polyangiitis and Squamous Cell Carcinoma – A Diagnostic and Therapeutic Conundrum

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 Keywords: GRANULOMATOSIS WITH POLYANGIITIS, SQUAMOUS CELL CARCINOMA, ANCA-VASCULITIS, LUNG CANCER, DIAGNOSTIC CHALLENGE, PULMONARY VASCULITIS, COEXISTENCE

The simultaneous presentation of a systemic autoimmune disease and a malignancy represents one of the most demanding diagnostic and therapeutic challenges in clinical medicine. Granulomatosis with polyangiitis (GPA), a severe form of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), rarely coexists with primary lung malignancies such as Squamous Cell Carcinoma (SCC). This complexity is amplified by the fact that both conditions can present with remarkably similar clinical and radiological features, often delaying a definitive diagnosis and complicating life-saving treatment strategies.

We analyze a critical case of a 78-year-old male presenting with this dual pathology and delve into the pathophysiology, epidemiology, clinical presentation, imaging, diagnosis, treatment, and prognosis of this sinister association, drawing upon the latest global medical consensus.

Case Presentation Summary

A 78-year-old male presented with a four-week history of a severe cough, intermittent hemoptysis, and epistaxis. His medical history was notable for hypertension and a history of treated tuberculosis infection; he was also an ex-smoker. Initial evaluation with a Chest P-A radiograph revealed a 3.5 cm infiltrative mass in the right lower lobe.


 Figure 1: Chest P-A Radiograph Caption: A posteroanterior chest radiograph demonstrates a prominent, infiltrative mass measuring approximately 3.5 cm, located in the right lower lung field, raising immediate suspicion of both infectious and malignant etiologies.

Further investigation with a Computed Tomography (CT) scan was necessary. The CT confirmed a dominant 5 cm cavitating mass in the right lower lobe, accompanied by multiple smaller cavitating nodules located bilaterally.

Figure 2: Axial Lung Window CT (Upper Section) Caption: Axial CT image (lung window) showing a large, thick-walled cavitating mass (labeled 'a' in the original case) within the right lower lobe, a finding highly characteristic of both lung malignancy (SCC) and Granulomatosis with polyangiitis (GPA).


Figure 3: Axial Lung Window CT (Lower Section) Caption: Axial CT image (lung window) demonstrating additional small, bilateral cavitating nodules (labeled 'b' in the original case), a pattern that strongly favors a systemic vasculitis such as GPA, though differential diagnosis remains wide.

Serological testing showed a positive ANCA titer (1/20) with an elevated Proteinase 3 (PR3) level (14.6 IU/mL). A required tissue biopsy ultimately confirmed the coexistent diagnoses of Granulomatosis with polyangiitis (GPA) and Squamous Cell Carcinoma (SCC).

Pathophysiology and Epidemiology

Granulomatosis with Polyangiitis (GPA)

GPA, formerly known as Wegener’s granulomatosis, is an uncommon systemic necrotizing vasculitis of small-to-medium-sized vessels. The hallmark of GPA is the presence of ANCA, specifically directed against Proteinase 3 (PR3-ANCA) in up to 80% of European patients. Pathologically, it is defined by necrotizing granulomatous inflammation primarily affecting the upper and lower respiratory tracts, along with necrotizing glomerulonephritis. The pathogenesis involves a complex interaction between genetic predisposition, environmental triggers (e.g., infections), and an autoimmune response where ANCA directly activates neutrophils, leading to degranulation, vascular damage, and granuloma formation. The annual incidence is approximately 7.7 to 15.4 per million adults in European countries, most commonly affecting individuals in their fifth to seventh decades of life.

Squamous Cell Carcinoma (SCC)

SCC is a type of non-small cell lung carcinoma (NSCLC) characterized by the malignant proliferation of epithelial cells exhibiting squamous differentiation. The strongest risk factor is a heavy smoking history. SCC typically arises centrally in the large bronchi, but can also occur peripherally. A critical pathological feature is its propensity to undergo central necrosis, leading to cavitation within the tumor—a finding that directly overlaps with GPA.

The Coexistence Connection

The co-occurrence of AAV and malignancy is increasingly recognized. Data suggests a standardized incidence ratio (SIR) of cancer in AAV patients of 1.6–2.0 compared to the general population. The reasons are multi-faceted:

  1. Immunosuppression: Long-term exposure to immunosuppressive agents like cyclophosphamide used to treat GPA is a well-documented risk factor for various malignancies, including urothelial cancer, leukemia, and, critically, lung cancer.

  2. Impaired Immunosurveillance: Chronic systemic inflammation and the underlying immune dysregulation in GPA may impair the body’s ability to detect and eradicate nascent cancer cells.

  3. Shared Pathways: There is speculation regarding common pathological pathways or the tumor itself acting as an antigenic trigger for the ANCA-driven vasculitis (paraneoplastic syndrome).

Clinical Presentation and Imaging Features

Clinical Presentation

The clinical manifestations of GPA are highly variable, often preceded by non-specific constitutional symptoms such as fatigue, fever, and weight loss for weeks or months. The classic organ triad is:

  • Upper Respiratory Tract (70–92%): Persistent rhinitis, nasal crusting, sinusitis, epistaxis (as seen in the patient), saddle nose deformity, and subglottic stenosis.

  • Pulmonary (45–87%): Cough, dyspnea, and hemoptysis (as seen in the patient).

  • Renal (20–85%): Rapidly progressive glomerulonephritis, which can lead to kidney failure.

SCC presents with symptoms of mass effect or tissue destruction, commonly including persistent cough, hemoptysis (as seen in the patient), chest pain, and constitutional symptoms like weight loss.

Imaging Features: The Diagnostic Mimic

Pulmonary involvement in GPA is most frequently characterized by pulmonary nodules, which may be multiple, bilateral, and often cavitating (40–70% of cases). The presence of bilateral, small cavitating nodules (Figure 3) is a strong pointer towards a systemic vasculitis like GPA.

In contrast, SCC often presents as a single, large mass, commonly demonstrating cavitation due to necrosis.

The critical diagnostic dilemma lies in cases, like the one presented, where a single, dominant cavitating mass (Figure 2) suggestive of cancer is found alongside smaller, bilateral cavitating nodules, which are highly suggestive of GPA. Cavitating lung lesions, whether solitary or multiple, force a wide differential diagnosis that includes infection (Tuberculosis, Aspergillosis), GPA, and malignancy (SCC).

Differential Diagnosis and Definitive Diagnosis

The differential diagnosis for a patient with upper respiratory, pulmonary symptoms, and cavitating lung masses must be broad:

  • Infection: Tuberculosis (especially given the patient's history), fungal infections (Aspergillosis, Histoplasmosis).

  • Malignancy: Primary lung cancer (SCC, Adenocarcinoma), or metastases.

  • Systemic Diseases: Granulomatosis with polyangiitis, Sarcoidosis, Rheumatoid Nodules.

Definitive diagnosis requires a multi-modality approach:

  1. Clinical Suspicion: Recognition of the constellation of upper respiratory, pulmonary, and systemic symptoms.

  2. Serology: Confirmation of a positive ANCA, typically PR3-ANCA, is highly suggestive of GPA.

  3. Histopathology: Biopsy is mandatory. The definitive diagnosis of GPA requires demonstrating necrotizing vasculitis, necrotizing granulomatous inflammation, and necrosis. In cases of coexisting pathology, the biopsy is vital to confirm the presence of both the characteristic GPA features and the malignant cells (SCC), often within the same lesion. In this patient, the biopsy successfully identified the simultaneous presence of both GPA and SCC.

Treatment and Prognosis

The management of coexistent GPA and SCC is exceedingly complex, requiring a delicate balance between treating the life-threatening autoimmune disorder and aggressively managing the malignancy.

GPA Treatment

Standard induction therapy for severe, organ-threatening GPA involves a combination of high-dose corticosteroids (e.g., prednisone) and a cytotoxic agent like cyclophosphamide or the anti-CD20 monoclonal antibody, Rituximab. This approach is highly effective, inducing remission in over 88% of patients within nine months.

SCC Treatment

Treatment for SCC is dictated by the cancer stage and generally involves surgery, radiation therapy, chemotherapy, and/or immunotherapy.

The Therapeutic Conundrum

The central dilemma is the management of GPA in a patient with a known malignancy. Cyclophosphamide, a highly effective GPA induction agent, is a known carcinogen, and its use significantly increases the risk of subsequent cancers.

In the case presented, the patient showed a short-lived response to GPA treatment (likely cyclophosphamide and corticosteroids) before the malignancy progressed. This rapid progression, despite initial treatment, supported the conclusion that the aggressive nature of the SCC, rather than resistant vasculitis or therapy-induced cancer, was the primary cause of clinical deterioration. The patient was then urgently referred to the lung cancer multidisciplinary team for staging and management of the T4N2M0 SCC.

The prognosis is heavily influenced by renal involvement in GPA and the stage of the malignancy. The 10-year survival rate for GPA without kidney involvement is 60-70%, dropping to 40% with renal involvement. The presence of advanced-stage SCC significantly darkens the overall prognosis, making close collaboration between rheumatology, oncology, and pulmonary medicine essential for patient care.

Quiz

Question 1: Initial Management

Based on the patient's presenting symptoms (cough, hemoptysis, epistaxis) and the Chest P-A radiograph (Figure 1) showing a right lower lobe mass, what is the most appropriate initial management strategy?

A. Immediate start of high-dose oral corticosteroids for presumed vasculitis. 

B. Previous image verification and immediate empiric anti-tuberculosis therapy. 

C. CT scan request, referral to a respiratory specialist, and urgent ANCA serology. 

D. Bronchoscopy with Transbronchial Needle Aspiration (TBNA) as the first step. 

E. Reassurance and symptomatic management for presumed chronic sinusitis.

Answer: C, Explanation: While a mass in a patient with hemoptysis necessitates an urgent work-up for cancer, the coexistent epistaxis and PR3-ANCA history strongly suggest a systemic vasculitis like GPA. The initial Chest X-ray is insufficient. The most appropriate step is a rapid, multi-faceted investigation, including a definitive chest CT for detailed imaging, ANCA serology, and prompt referral to a specialist to coordinate the differential diagnosis (Infection vs. Vasculitis vs. Malignancy). Options A, B, and E are insufficient or potentially harmful. D is premature without further imaging.

Question 2: Imaging Feature for Differential Diagnosis

The CT scan revealed a large cavitating mass in the right lower lobe and multiple smaller cavitating nodules bilaterally (Figures 2 and 3). Which of the following is the most characteristic pulmonary imaging feature of Granulomatosis with Polyangiitis (GPA) that frequently overlaps with a differential diagnosis like Squamous Cell Carcinoma?

A. Diffuse interstitial lung disease with honeycombing. 

B. Perilymphatic nodules with a "beaded" fissural appearance. 

C. Thick-walled, multiple or solitary cavitating pulmonary nodules/masses. 

D. Hilar and mediastinal lymphadenopathy. 

E. Ground-glass opacities with a crazy-paving pattern.

Answer: C. Explanation: Cavitating pulmonary nodules or masses are the most common and classic pulmonary manifestation of GPA, occurring in up to 70% of patients. This feature, however, is a major source of diagnostic confusion as it is also typical for Squamous Cell Carcinoma (due to central necrosis) and various infections (Tuberculosis, Aspergillosis).

Question 3: Therapeutic Challenge in Coexistence

In the long-term management of a patient with GPA and co-existing SCC, what is the major iatrogenic risk associated with a highly effective GPA induction treatment that must be carefully considered against the background of a solid tumor malignancy?

A. Development of drug-induced lupus erythematosus from Rituximab. 

B. Increased risk of non-melanoma skin cancer from corticosteroid use. 

C. Increased risk of hematologic malignancies (e.g., leukemia) and urothelial cancer from Cyclophosphamide use. 

D. Acute kidney injury requiring dialysis due to Methotrexate. 

E. Cardiac toxicity from Azathioprine.

Answer: C. Explanation: Cyclophosphamide is a highly effective cytotoxic agent used for GPA induction therapy. However, its long-term use is a well-established and serious risk factor for secondary malignancies, including urothelial carcinoma and hematologic malignancies. The decision to use cyclophosphamide in a patient with a known malignancy, especially one like lung cancer (whose risk is also increased by cyclophosphamide use), is a complex risk-benefit calculation.

References

  1. Stone, J. H., Merkel, P. A., et al. (2010). Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. The New England Journal of Medicine, 363(3), 221-232.

  2. Jennette, J. C., Falk, R. J., et al. (2017). 2017 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis & Rheumatology, 69(8), 1541-1551.

  3. Comarmond, C., & Cacoub, P. (2014). Granulomatosis with polyangiitis (Wegener): clinical aspects and treatment. Autoimmunity Reviews, 13(11), 1121-1125.

  4. Gómez-Puerta, J. A., et al. (2019). ANCA-associated vasculitis and cancer risk: A systematic review and meta-analysis of observational studies. Seminars in Arthritis and Rheumatism, 48(4), 711-717.

  5. Lee, T. W., et al. (2016). Concurrent granulomatous polyangiitis and squamous cell carcinoma of the lung: a case of balancing treatment. BMJ Case Reports, 2016. (Similar case reporting the difficulty of treatment balance).

  6. Chung, S. A., et al. (2023). International consensus on the nomenclature and classification of vasculitis. Annals of the Rheumatic Diseases, 82(2), 224-234.

  7. Polverosi, R., et al. (2019). A hidden lung cancer in a patient with granulomatosis with polyangiitis. BJR Case Reports, 5(2). (The specific case study discussed, highlighting the diagnostic mimicry and treatment dilemma).

  8. Sy, A., et al. (2022). Granulomatosis with polyangiitis: current clinical characteristics and updates in diagnosis. Frontiers in Medicine, 9, 1369233.

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