inflammatory, infectious and indeterminate lung nodules · 2019-01-21 · inflammatory, infectious...
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Inflammatory, Infectious and Indeterminate Lung Nodules
Lynette M. Sholl, M.D.Brigham and Women’s Hospital
&Harvard Medical School, Boston, MA
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Disclosures
• Consultant for Foghorn Therapeutics, AstraZeneca, LOXO Oncology
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Objectives:
• Examine the pathologic differential diagnosis of ground glass nodules and other mass lesions worrisome for malignancy
• Recognize features that discriminate between reactive and neoplastic alveolar proliferations
• Define the features of in situ and invasive adenocarcinomas of the lung
• Examine diagnostic reproducibility
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What is a “ground glass nodule”?
“A hazy opacity that does not obscure underlying pulmonary structures on high-res CT.”
Estimated 20% of pure ground glass nodules and 60-90% of GGN with solid component are malignant.
Park et a. RadioGraphics. March-April 2007.
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Clinical and radiographic mimics of pulmonary neoplasia• Ground glass nodule differential
diagnosis:• Tumor
• Lung adenocarcinoma/AIS/MIA• Invasive mucinous
adenocarcinoma• Metastatic carcinoma
• Inflammatory• Organizing pneumonia• Drug reaction
• Infection
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Case 1.
• 70 year old nonsmoking man with systemic amyloidosis with cough and hemoptysis, lower lobe opacity. No resolution following antibiotic therapy.
• Proceeded to surgical resection due to concern for primary malignancy.
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Pulmonary wedge resection:
Diagnosis: Pneumocystis pneumonia
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Fluffy pink proteinaceous debris filling airspacesBlack speckles (organisms) may be evident on H&E
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Clusters of organisms are evidence on silver stain5-8 micron cysts resemble cups, or contact lenses
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Pneumocystis pneumonia:
• Results from infection with Pneumocystis jirovecii• Considered a fungus• Cysts and trophozoites visible in infected tissue
• Cysts- visible on silver stain/5-8 microns• Trophozoites- visible on geimsa stained cytology preparations/1-5 microns
• Most people are exposed by early childhood• Becomes clinically significant in immunosuppressed patients
https://www.cdc.gov/dpdx/pneumocystis/index.html
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Patient follow-up:
• Subsequent testing revealed that the patient was HIV+
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Case 2:
• 38 year old man with Crohn’s disease on TNF-inhibitor
• Tore down a 100 year old farmhouse one month prior
• Two week history of fever/malaise
• CT shows pulmonary GGOs and mediastinal lymphadenopathy
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Lymph node biopsy:
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Disseminated histoplasmosis
• A disease of the immunocompromised
• In immunocompetent hosts, inhaled organisms lead to asymptomatic development of solitary lung/lymph node granuloma
• Slowly enlarged pulmonary granuloma may mimic primary malignancy
• Self-contained pulmonary infection is observed in majority of adults from endemic areas in autopsy series
• Our patient: treated with antifungals and recovered
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accessmedicine.mhmedical.com
Histoplasma capsulatumOhio/Mississippi river valley -
Bird/bat droppings5 micron ovoid yeast formsNarrow-based buddingInvisible when dead(old granulomas)
Basophilic on H&E when aliveAggregate in macrophages
Cryptococcus neoformansUbiquitous - Birds/pigeons4-7 micron round yeasts with surrounding clear spaceNarrow-based buddingAlcian blue/Mucicarmine+ mucinous capsule
Blastomyocosis dermatitidisSouth central US, Great Lakes -soilCan present with acute pneumonia8-15 micron yeast forms, occ. mycelial formsBroad based buddingBasophilic on H&E with refractile cell wall
Coccidioides immitisSouthwestern US- “valley fever” – soil5 to 60 micron spherules containing endosporesSmall immature spherules mimic other yeastsOccasional hyphal formsMay form a cavitary mass- especially in diabetics
Risk of rupture into pleuraNeutrophils or eosinophils may be prominent
Cour
tesy
N. R
ekht
man
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Endemic mycoses
• An important differential diagnosis for granulomatous disease in the lung
• Chronic/resolved infection is a frequent incidental finding immunocompetent hosts in endemic regions
• Endemic regions are not necessarily well-defined, e.g. Histoplasma infection very common in New England; Cocci outbreaks observed in pacific northwest
• May be clinically significant in some patients, especially the immunocompromised host
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Case 3.
70 year old man with metastatic melanoma status post left pneumonectomy now with new right sided consolidation with ground glass components.
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Core needle biopsy performed:
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Diagnosis
• Sarcoid-like granulomatosis of the lung• A recognized sequelae of immune checkpoint blockade therapy in multiple tumor
types
• Usually presents as lymphadenopathy, reported in 5-7% of patients• Patients are usually asymptomatic (distinct from therapy-related pneumonitis)• Holding immune checkpoint therapy leads to clearance of the radiographic
abnormalities
• Reference: Nishino et al. Sarcoid-like granulomatosis of the lung related to immune-checkpoint inhibitors: Distinct clinical and imaging features of a unique immune-related adverse event. Cancer Immunol Res. 2018 Apr 5
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Case 4. 57 year old man with metastatic melanoma, undergoing treatment with PD-1 inhibitor.
March 2017 September 2017 July 2018
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Resected left lower lobe mass:
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Differential diagnosis
• Infection• Mycobacterial (tuberculosis vs. atypical)• Endemic mycosis• Aspergillus• Bacterial
• Treated tumor• Vasculitis
• granulomatosis with polyangiitis
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Special stains performed
• Gram, silver and AFB stains all negative.
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Nocardia/modified AFB stain
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Mycobacterial immunohistochemistry
PCR sequencing sent: Mycobacterium avium complex identified.
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Pulmonary mycobacterial infection
• Reactivation of mycobacteria (including Mycobacterium tuberculosis and atypical species) described in the setting of immune checkpoint blockade.
• Unrestrained T-cell effector responseflorid necrotizing granulomatous inflammation
Special stains for mycobacterium:• Traditional AFB staining is relatively insensitive• Two or more blocks may require staining• Organisms enriched at interface of necrosis and viable tissue• Mycobacterial IHC is more sensitive than AFB- organisms visible at low power
• bright signal, “leaking” of antigen increases the size of the organisms• increased number of organisms stained• Can cross-react with Nocardia and Candida
Barber DL et al. The Journal of Immunology 2010;186:1598–1607.Picchi H et al. Clinical Microbiology and Infection 2018;24:216–218.Solomon IH et al. The American Journal of Surgical Pathology 2017;41:1364–1370.
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Case 5:
• 57 year old man with severe right-sided chest pain• Chest CT scan showed bilateral pulmonary masses• PET/CT showed significant uptake in lung and prostate
• (SUV max 10-11)
• Lung wedge biopsy performed
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CT scan; Lung wedge biopsy obtained.
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Basophilic necrosis
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Obliterative vasculitis Prominent giant cells
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Granulomatosis with polyangiitis (formerly known as Wegener’s)• ANCA associated vasculitis
• Anti-PR3 ANCA positivity (C-ANCA) in 66%• P-ANCA in 24%
• May lead to life-threatening pulmonary hemorrhage or kidney failure• 28% 5-year fatality
• Significant genetic component• Responsive to immune suppression
Lyons PA et al. NEJM 2012. en.wikipedia.org
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Case 6: 55 year old man, incidental lung mass, growing on repeat CT scans over 6 months
At followup #1 Three months later
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Lung core needle biopsy:
• LUNG ADENOCARCINOMA, lepidic pattern in this limited specimen
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Lung lobectomy performed.
• Gross examination reveals 5.4 cm ill-defined mass
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Lung Lobectomy, final diagnosis:
• Organizing pneumonia with atypical alveolar pneumocytes consistent with reactive changes
• The mass was entirely submitted for histologic evaluation.
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Reactive pneumocyte proliferation Atypical adenomatous hyperplasia
Polyclonal populationVariable to high N:C ratioVariable amounts of cytoplasmMay have prominent nucleoliMay have coarse, open chromatin
Clonal populationHigh N:C ratioCytoplasmic vacuolesMultinucleationIntranuclear inclusionsGaps between cells
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Reactive pneumocyte proliferation Adenocarcinoma in situ
Architectural complexityMay have striking interstitial thickeningDistinct boundary
Architectural complexitySubtle interstitial thickeningDifficult-to-define boundaryAssociated inflammation/organization
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A core biopsy overcall leading to unnecessary surgery: How can you avoid this outcome?• Correlate with clinical history (recent infectious pneumonia) and
radiology (radiographic impression of inflammatory vs malignant?) but this exercise is not always helpful.
• Consider the pathologic features of reactive vs neoplastic proliferations – reactive proliferations may be MORE atypical than atypical adenomatous hyperplasia or adenocarcinoma in situ
• On cytology, reactive vs. malignant alveolar proliferations may be nearly impossible to distinguish
• Hedge: “Atypical pneumocyte proliferation” and discuss obtaining additional biopsies if clinically indicated/feasible
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Best practices in pulmonary pathology
• Clinical and radiographic correlation are often essential• Keep an open mind about the infectious and inflammatory differential
in masses resected for suspicion for malignancy
• Stay up to date on the bread and butter and the unusual: • Pulmonary Pathology Society case of the month (coordinated by
Sanjay Mukhopadhyay and Sinchita Roy-Choudhuri)• https://www.pulmonarypath.org/cotm/
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PPS Biennial MeetingJune 26, 27, 28, 2019Dubrovnik, CroatiaRegistration details:www.pulmonarypath.org