Manuscript: reported that patients with CLL have varied causes

Manuscript: Introduction Chroniclymphocytic leukemia (CLL) is the most common adult leukemia in the world. Itis a B-cell disorder that mainly affects older adults with a median age atdiagnosis of 70 years. CLL accounts for nearly one-quarter of all newlydiagnosed leukemia cases. The clinical course of CLL patients is heterogeneousand several genetic aberrations such as deletions of 11q or 17p or leukemiccell expressions of ZAP-70, CD38 or unmutated immunoglobulin heavy chain (IgVH)variable gene regions are associated with a poorer clinical outcome and haveproved useful in identifying patients who may have more aggressive disease andthus a higher likelihood of requiring treatment 1-3.  The approach to managementof CLL is changing. In recent years, the treatment has focused on the use oftargeted novel agents such as venetoclax, ibrutinib, ofatumumab, obinatuzumaband idelalisib 1. With these new treatment options,patients with CLL are living longer, but are also exposed to more drugs andtheir possible adverse effects 4. Consequently, an increasing number of CLLpatients are presenting with pulmonary infiltrates that do not respond toantibiotic therapy.

We previously reported that patients with CLL have variedcauses for these respiratory symptoms including leukemic infiltration of lungssignifying worsening, or progressive disease 5. However, it has not been determinedwhether the genetic markers correspond to likelihood or severity of pulmonaryinfiltration. We report 98patients with CLL and pulmonary infiltrates who had an invasive diagnosticprocedure after completing a course of antibiotics and describe the pathologicfindings in patients diagnosed with bronchopulmonary leukemic infiltrates(BPLI).    Materials and Methods This study waspart of a retrospective chart review that was approved by the InstitutionalReview Board at Hofstra Northwell Health System (IRB #10-188A).

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The medicalrecords of patients with CLL who were hospitalized at Long Island JewishMedical Center, a tertiary care CLL referral center, with a respiratory illnessbetween January 2000 and June 2016 were reviewed. These records were identifiedusing International Classification of Diseases (ICD) codes for respiratorydiseases and CLL. Charts were then analyzed for patients who had completedantibiotics and subsequently had an invasive thoracic procedure performed fordiagnostic purposes. The biopsyspecimens were then sent to the department of pathology at Long Island JewishMedical Center. All pathology specimens were reviewed by two pathologists ME& NG. In some cases there was more than one pathological finding from asingle biopsy specimen. BPLI was diagnosed by the presence of a monomorphouspopulation of small to intermediate sized atypical lymphoid cells.

It wasfurther classified into a specific type of lymphoma based onimmunohistochemical studies and/or flow cytometry. Immunohistochemical stainsused to classify a lymphoma included CD5, CD3, CD20, CD79a, PAX5, CD23, BCL2,BCL6, Ki67, cyclin D1, FMC7, CD43, CD38 and CD10. Special stains used were Acidfast bacilli (AFB) for mycobacteria and Gomori methenamine silver (GMS) forfungal organisms. Gram stain was used to look for bacterial infections.

 Results PatientCharacteristics A total of ninety-eightpatients with CLL, respiratory complaints and pulmonary infiltrates onradiography underwent 111 invasive diagnostic procedures. There were 72bronchoscopies, 29 surgical lung biopsies and 10 transthoracic biopsies. In 82patients these procedures yielded 85 diagnoses that guided clinical management (Figure1). In 16 patients the pathologic, histologic and microbiologic findings wereunremarkable. Patient characteristics are shown in Table 1. The median age ofpatients was 69 years (range 48-88) and 71were male (72.

4%). A high-stage Raiclassification was seen in 75.5% (74/98) of the patients and 79.

6% (78/98)patients had received prior CLL treatment. Diagnoses included bronchopulmonaryleukemic infiltrates (BPLI) in 32/85 patients (37.6%), organizing pneumonia in11/85 patients (12.9%), primary lung cancer in 9/85 (10.6%) and the remaining33/85 patients (38.

8%) were diagnosed as pneumonia with an identified causativeorganism. BronchopulmonaryLeukemic Infiltrates (BPLI) BPLI wereidentified in 32/85 (37.6%) biopsy results. Fifteen of these were found onsurgical biopsy, 15 on bronchoscopic biopsy and 2 by transthoracic biopsy. Ofthe 15 patients in whom BPLI was diagnosed by surgical biopsy, 6 had a priornon-diagnostic parenchymal biopsy: 4 bronchoscopic and 2 transthoracic.

Of thepatients with BPLI, 71% were of a high Rai classification and 86% had receivedprior chemotherapy. In 27/32 (85%) cases the biopsies returned with only BPLIdue to CLL (without inflammation). BPLI was noted to be associated with acuteor chronic inflammation in 5/32 (15%) cases. Among thepatients with BPLI 24/32 (75%) had an unmutated IgVH, 16/32 (50%) had CD 38,12/32 had Trisomy 12, 11/32 had 13q deletion, 4/32 had 1p deletion and 1/32 hadZap70. Additionally, 20/32 patients were receiving IVIg as part of theirtreatment strategies. Pathologicalfindings Morphologically, biopsiesof pure CLL/SLL BPLI without inflammation showed a monomorphous population ofsmall to intermediate sized atypical lymphoid cells with clumped nuclearchromatin and inconspicuous nucleoli Figure 2.

No atypical mitoses or atypiawas seen. One of the cases showed some large atypical cells interspersed withthe small lymphoid cells, consistent with large cell transformation/Richter’stransformation. Similarly, another case showed focal large lymphoid cells onpathologic review.

Flow cytometry studies showed monoclonal B-cells, positivefor either kappa or lambda, CD19, CD20, CD23, CD5; negative for FMC7, and CD10.Immunohistochemical stains revealed the neoplastic lymphoid cells to bepositive for CD5, CD23, CD20, CD79a, PAX5, BCL-2; negative for CD3, cyclin D1,BCL-6, and CD10 Figure 3. These findings were consistent with CLL/SLL. ReactiveT-cells in the background showed positivity for CD3, CD5 and BCL2. Ki-67 wasusually low.

 Five casesdemonstrated BPLI with associated acute and/or chronic inflammation Figure 4.Acute inflammation consisted ofneutrophils and necrotic debris with few lymphocytes or histiocytes separatefrom the neoplastic process. Cases of organizing pneumonia showed a mixedpopulation of lymphocytes and macrophages dispersed diffusely or formingaggregates with areas of fibrin exudates, and necrosis. One case had areas ofboth diffuse monotonous neoplastic lymphoid cell population within theinterstitium consistent with CLL coexisting with areas of organizing fibrinexudates, histiocytic infiltration and fibroblastic proliferation , consistentwith organizing pneumonia. Some areas of the lung parenchyma also showednecrotizing inflammation containing acutely branching thin fungal hyphae. TheseGMS positive fungal hyphae were most consistent with aspergillus.  In cases ofinflammation without BPLI, no monotonous population of lymphoid cells was identified.

Corresponding BAL or bronchial washings showed predominantly inflammatorynuclear debris containing degenerated macrophages, bronchial cells, squamousmetaplastic cells and bacterial colonization.