- Broad evaluation of altered mental status (optional, ~10 min)
- Recognize the sensitivity/specificity of CT guided biopsy in the evaluation of lung nodules
1. Work-up of altered mental status (~10 extra min) under the “what is your differential…?” question. The differential table under that question contains this patient’s full set of lab result in the right-most column.
2. Additional diagnoses associated with the finding of granulomas on pathology (~ 5 extra min)
Click on any blue text for a more detailed history/work-up.
For a quick refresher on the clinical manifestations of GPA and its diagnosis, the “what is it?” and “how is it diagnosed?” sections can be combined into a quick 5-10 min talk.
70 yo M with no known PMH who was brought in for 5 weeks of progressive malaise, anorexia and confusion. He was seen at urgent care 2 weeks ago for a nonproductive cough that has been ongoing for ~ a month and was treated with oseltamivir without improvement in symptoms. He has been slightly disoriented over the past few weeks but was significant worse over the past 2 days and was found at home to be incomprehensibe on the day of presentation. He otherwise has not seen a health care provider in decades and has no known PMH and takes no medications. He does not drink, smoke, or use illicits.
On exam, he is afebrile, VS are notable for HR in the 100-110s, RR 20s, BPs 130/70s, saturating in the mid 90s% on RA. He is thin, in no distress. He is oriented to self only and makes nonsensical statements when asked questions but otherwise has no motor deficits. Cardiopulmonary exam is unremarkable except for tachycardia.
His initial labs are notable for Na 129, K 3.8, Cl 98, HCO3 21, Cr 3.1 (no baseline), WBC elevated at 20.99 (PMN predominant), hct 38, plts 315.
What additional work-up would you want for this patient? (~10 min)
He has undifferentiated altered mental status (AMS) but appears without any focal neurologic deficits on exam, which might point to a toxic metabolic cause. His leukocytosis also points to a potential infectious or inflammatory cause.
A mnemonic for altered mental status is MOVE STUPID.
- EKG showed the following: Sinus tachycardia without evidence of ischemia, right heart strain.
- CT Head: microvascular changes and maxillary, frontal, and ethmoid sinusitis
- CT C/A/P (full CT findings) was notable only for multiple spiculated lung nodules:
Work-up above revealed possible UTI (though urine culture ultimately negative) and sinusitis on head CT. He was empirically treated with ceftriaxone without improvement in his mental status. His chest CT showed a left upper lobe spiculated mass suspicious for primary lung cancer, which can be associated with brain metastases, but no obvious masses were seen on head CT.
Neurology was consulted for AMS and recommended a brain MRI which showed multiple areas of diffusion restriction that were concerning for embolic strokes versus metastatic foci.
How does this change your differential? Do you want any additional work-up?
The spiculated lung mass was concerning for cancer and the brain lesions could be consistent with metastatic foci, though Neurology felt the location of these lesions did not explain his persistent altered mentation. Lung cancer can be associated with paraneoplastic syndromes can present with confusion (e.g. limbic encephalitis) so a paraneoplastic panel was sent off that was ultimately negative. He underwent a CT guided biopsy of the largest lung lesion (left upper lobe).
Given the constellation of clinical finding – possible embolic phenomena, sinusitis, and lung mass – there was a question of vasculitis. Further rheumatologic work-up (full rheumatologic labs) which was notable for elevated ESR, CRP, positive ANCA panel and high levels of anti-PR3.
At even higher magnification, evaluation of the areas of necrosis reveal a multinucleated giant cell, suggesting granulomatous inflammation. Click the picture to see multinucleated giant cell.
What other diseases are associated with this pathology? (~3-5 min)
- Infections accounted for the vast majority of necrotizing granulomas without evident diagnoses on initial histologic exam4
- Endemic fungi: Histoplasma, Coccidiomycosis
- Tuberculous and non-tuberculous mycobacterium
- Noninfectious causes include4:
- Rheumatoid nodules (though no clinical evidence of prior or currently active arthritis)
- Chronic granulomatous disease
Fungal stain ultimately negative
TB stain ultimately negative
He was started on rituximab and steroids.
What is it?
GPA is an autoimmune small vessel vasculitis previously known as Wegener’s granulomatosis. It typically presents in older adults with peak age of onset ~ 65 – 70 years old1. Inflammation and destruction of the small vessels of the body results in multiorgan involvement, most commonly lungs and kidneys:
Additional organ systems: Heme – hypercoagulability
How is it diagnosed?
- American College of Rheumatology classification includes clinical signs/symptoms and pathologic confirmation
- Positive ANCA is not required for diagnosis, but is very sensitive (96%) and specific (98.5%)1
- 88% of GPA patients are c-ANCA positive1
- ANCA positivity without the right clinical context should prompt evaluation for vasculitis mimics (e.g., sepsis/infections, myositis)
- Granulomatous inflammation
- Necrosis, specifically serpiginous necrosis
All of his initial evaluation and presentation seemed to point towards malignancy. How good is a negative CT-guided core biopsy for excluding malignancy?
- In Quint, et al., 2006, the negative predictive value of CT guided biopsy was 76% for “benign nonspecific” biopsy results which included histologic findings of scar and inflammation. However, the above mentioned study also included a “benign specific” group that had 100% NPV for malignancy – these included diagnoses such as fungus, hamartoma and schwannoma2.
- Patients with GPA are at increased risk of malignancy (most commonly bladder, non-melanoma skin cancer, and lymphomas3.
- Patients with GPA have ~ 1.6 – 2x risk of developing a malignancy compared to normal population3.
- Effect is mostly attributed to treatments (e.g., cyclophosphamide, TNF-alpha inhibitors)3
- In a patient where there is high clinical suspicion for GPA, we felt that the pathology showing evidence of granulomas is reliable at ruling
TAKE HOME POINTS:
- GPA is a small vessel vasculitis, commonly associated with c-ANCA (anti-PR3) positivity. GPA has multisystem involvement – classically sinus, pulmonary (which can manifest as lung nodules, diffuse infiltrates or cavitating lesions), and renal (glomerulonephritis). However, it can also involve the CNS in the form of cerebral vasculitis or CVAs.
- ANCA is not required for diagnosis but has high sensitivity and specificity in the right clinical context.
- CT guided biopsy of a lung nodule is very effective at ruling out malignancy if pathology points to an alternative diagnosis. If the pathology is benign but non-specific, it is not effective at ruling out malignancy.
- Lutalo, P & Cruz, D. “Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis)” 2014. Journal of Autoimmunity. 48-49: 94-99.
- Quint, et al. “CT guided thoracic core biopsies: value of a negative result?” 2006. Cancer Imaging. 6(1): 163 – 167
- Mahr, A, et al. “ANCA-associated vasculitis and malignancy: Current evidence for cause and consequential relationships.” 2013. Best Practice and Research Clinical Rheumatology. 27(1): 45-56.
- Mukhopadhyay, et al. “Pulmonary necrotizing granulomas of unknown cause: clinical and pathologic analysis of 131 patients with completely resected nodules.” 2013. CHEST. 144(3): 813-24.