Manuscript: reported that patients with CLL have varied causes




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lymphocytic leukemia (CLL) is the most common adult leukemia in the world. It
is a B-cell disorder that mainly affects older adults with a median age at
diagnosis of 70 years. CLL accounts for nearly one-quarter of all newly
diagnosed leukemia cases. The clinical course of CLL patients is heterogeneous
and several genetic aberrations such as deletions of 11q or 17p or leukemic
cell expressions of ZAP-70, CD38 or unmutated immunoglobulin heavy chain (IgVH)
variable gene regions are associated with a poorer clinical outcome and have
proved useful in identifying patients who may have more aggressive disease and
thus a higher likelihood of requiring treatment 1-3.


The approach to management
of CLL is changing. In recent years, the treatment has focused on the use of
targeted novel agents such as venetoclax, ibrutinib, ofatumumab, obinatuzumab
and idelalisib 1. With these new treatment options,
patients with CLL are living longer, but are also exposed to more drugs and
their possible adverse effects 4. Consequently, an increasing number of CLL
patients are presenting with pulmonary infiltrates that do not respond to
antibiotic therapy. We previously reported that patients with CLL have varied
causes for these respiratory symptoms including leukemic infiltration of lungs
signifying worsening, or progressive disease 5. However, it has not been determined
whether the genetic markers correspond to likelihood or severity of pulmonary


We report 98
patients with CLL and pulmonary infiltrates who had an invasive diagnostic
procedure after completing a course of antibiotics and describe the pathologic
findings in patients diagnosed with bronchopulmonary leukemic infiltrates




Materials and Methods


This study was
part of a retrospective chart review that was approved by the Institutional
Review Board at Hofstra Northwell Health System (IRB #10-188A). The medical
records of patients with CLL who were hospitalized at Long Island Jewish
Medical Center, a tertiary care CLL referral center, with a respiratory illness
between January 2000 and June 2016 were reviewed. These records were identified
using International Classification of Diseases (ICD) codes for respiratory
diseases and CLL. Charts were then analyzed for patients who had completed
antibiotics and subsequently had an invasive thoracic procedure performed for
diagnostic purposes.


The biopsy
specimens were then sent to the department of pathology at Long Island Jewish
Medical Center. All pathology specimens were reviewed by two pathologists ME
& NG. In some cases there was more than one pathological finding from a
single biopsy specimen. BPLI was diagnosed by the presence of a monomorphous
population of small to intermediate sized atypical lymphoid cells. It was
further classified into a specific type of lymphoma based on
immunohistochemical studies and/or flow cytometry. Immunohistochemical stains
used 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 Acid
fast bacilli (AFB) for mycobacteria and Gomori methenamine silver (GMS) for
fungal organisms. Gram stain was used to look for bacterial infections.






A total of ninety-eight
patients with CLL, respiratory complaints and pulmonary infiltrates on
radiography underwent 111 invasive diagnostic procedures. There were 72
bronchoscopies, 29 surgical lung biopsies and 10 transthoracic biopsies. In 82
patients these procedures yielded 85 diagnoses that guided clinical management (Figure
1). In 16 patients the pathologic, histologic and microbiologic findings were
unremarkable. Patient characteristics are shown in Table 1. The median age of
patients was 69 years (range 48-88) and 71were male (72.4%). A high-stage Rai
classification was seen in 75.5% (74/98) of the patients and 79.6% (78/98)
patients had received prior CLL treatment. Diagnoses included bronchopulmonary
leukemic infiltrates (BPLI) in 32/85 patients (37.6%), organizing pneumonia in
11/85 patients (12.9%), primary lung cancer in 9/85 (10.6%) and the remaining
33/85 patients (38.8%) were diagnosed as pneumonia with an identified causative


Leukemic Infiltrates (BPLI)


BPLI were
identified in 32/85 (37.6%) biopsy results. Fifteen of these were found on
surgical biopsy, 15 on bronchoscopic biopsy and 2 by transthoracic biopsy. Of
the 15 patients in whom BPLI was diagnosed by surgical biopsy, 6 had a prior
non-diagnostic parenchymal biopsy: 4 bronchoscopic and 2 transthoracic. Of the
patients with BPLI, 71% were of a high Rai classification and 86% had received
prior chemotherapy. In 27/32 (85%) cases the biopsies returned with only BPLI
due to CLL (without inflammation). BPLI was noted to be associated with acute
or chronic inflammation in 5/32 (15%) cases.


Among the
patients 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 had
Zap70. Additionally, 20/32 patients were receiving IVIg as part of their
treatment strategies.




Morphologically, biopsies
of pure CLL/SLL BPLI without inflammation showed a monomorphous population of
small to intermediate sized atypical lymphoid cells with clumped nuclear
chromatin and inconspicuous nucleoli Figure 2. No atypical mitoses or atypia
was seen. One of the cases showed some large atypical cells interspersed with
the small lymphoid cells, consistent with large cell transformation/Richter’s
transformation. Similarly, another case showed focal large lymphoid cells on
pathologic review. Flow cytometry studies showed monoclonal B-cells, positive
for either kappa or lambda, CD19, CD20, CD23, CD5; negative for FMC7, and CD10.
Immunohistochemical stains revealed the neoplastic lymphoid cells to be
positive 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. Reactive
T-cells in the background showed positivity for CD3, CD5 and BCL2. Ki-67 was
usually low.


Five cases
demonstrated BPLI with associated acute and/or chronic inflammation Figure 4.
Acute inflammation consisted of
neutrophils and necrotic debris with few lymphocytes or histiocytes separate
from the neoplastic process. Cases of organizing pneumonia showed a mixed
population of lymphocytes and macrophages dispersed diffusely or forming
aggregates with areas of fibrin exudates, and necrosis. One case had areas of
both diffuse monotonous neoplastic lymphoid cell population within the
interstitium consistent with CLL coexisting with areas of organizing fibrin
exudates, histiocytic infiltration and fibroblastic proliferation , consistent
with organizing pneumonia. Some areas of the lung parenchyma also showed
necrotizing inflammation containing acutely branching thin fungal hyphae. These
GMS positive fungal hyphae were most consistent with aspergillus.


In cases of
inflammation without BPLI, no monotonous population of lymphoid cells was identified.
Corresponding BAL or bronchial washings showed predominantly inflammatory
nuclear debris containing degenerated macrophages, bronchial cells, squamous
metaplastic cells and bacterial colonization.