Evaluation of Non-infectious Pulmonary Complications in Hematological Malignancies on MDCT: Decoding Imaging Markers

Abstract

Patients with hematological malignancies are at risk of developing of various infectious and non-infectious pulmonary complications. Common non-infectious pulmonary complications include pulmonary edema, leukostasis, diffuse alveolar haemorrhage (DAH) and differentiation syndrome. The overlapping imaging features pose diagnostic dilemma. We retrospectively analysed the CT findings in identifying differentiating imaging markers and developing an algorithm. 46 diagnosed patients of non-infectious pulmonary complications who underwent CT chest between February 2017 to March 2020 were included. The CT findings were recorded as parenchymal (GGO, consolidation, septal thickening, peribronchovascular interstitial thickening, and nodules), pleural effusion, and mediastinal lymphadenopathy. We categorized non-infectious pulmonary complications as: differentiation syndrome (Group1, n = 6), DAH (Group 2, n = 8), leukostasis (Group 3, n = 14),leukemic infiltrate (Group 4, n = 5), and pulmonary edema(Group 5, n = 13). Chi-square or Fisher exact test were used with p value $<$0.05 as statistically significant.Absence of diffuse GGO in Group 4, interlobular septal thickening in Group 2 and Group 3, nodules in Group 5, and peribronchovascular interstitial thickening in Group 2 were statistically significant. Presence of interlobular septal thickening in Group 5, nodules in Group 4, and peribronchovascular interstitial thickening in Group 5 were statistically significant. Based on the results, an algorithm was developed which may suggest a possible diagnosis in an appropriate clinical scenario.

Introduction

Hematological malignancies are a diverse group of disorders and includes; mature B cell, T cell, and NK cell neoplasm; myeloproliferative, myelodysplastic neoplasms, acute myeloid leukemia and several other neoplasms. These patients are at a risk of multitude of acute pulmonary complications because of immunocompromised state, treatment regimen, direct tissue invasion or altered coagulation profile by the disease. Broadly, they are categorized into infectious and non-infectious complications.Common non-infectious pulmonary complications include pulmonary edema, leukostasis, diffuse alveolar haemorrhage (DAH), and differentiation syndrome [1]. The overlapping imaging features in many instances pose diagnostic enigma.An early diagnosis is essential to prompt early treatment and to reduce mortality. Multidetector computed tomography (MDCT) is a technique in which images are acquired rapidly and thin section high resolution CT (HRCT) images are reconstructed. Multiplanar reformations (MPRs) as well as other post processing applications such as maximum/minimum intensity projection images can also be done in evaluation of lung/airway diseases.

In this study, we retrospectively analysed the imaging findings to identify differentiating imaging markers; and developing an algorithmic approach in differentiating amongst common non-infectious pulmonary complications.

Materials and Methods

After institute ethical committee approval, all diagnosed patients of non-infectious pulmonary complications based on clinical details, laboratory, and/or pathological findings who underwent CT chest between February 2017 to March 2020 were included. Patients with diagnosis of more than one non-infectious pulmonary complications were excluded from the study. CT images were reviewed and recorded in a predesigned proforma by two experienced chest radiologists who were blinded to the clinical details and diagnosis. The findings were recorded as parenchymal, pleural, and mediastinal with detailed evaluation as following:

Parenchymal

1. Ground Glass opacity (GGO): apical/basal/diffuse distribution; central/peripheral/both distribution; peribronchial location/around the nodules; confluent/patchy lobular; sparing of apices/costophrenic angles/subpleural regions; crazypaving

2. Consolidation: apical/basal/diffuse distribution; central/peripheral/both distribution; peribronchial location; cavitation

3. Septal thickening: smooth/nodular/irregular; upper lobe/lower lobe/both distribution

4. Nodules: well defined; perilymphatic/random/centrilobular; apical/basal/both distribution; cavitation. Ground glass appearing nodules were noted as GGO.

5. Peribronchovascular interstitial thickening: smooth/nodular; apical/basal/parahilar distribution

Pleural effusionUnilateral/bilateral; free/loculated/septated

Mediastinum Lymph nodes

We categorized these complications into groups in this manner: differentiation syndrome (Group1), DAH (Group 2), leukostasis(Group 3), pulmonary leukemic infiltrate (Group 4), and pulmonary edema(Group 5).

Comparison between the CT findings and different groups were made using Chi-square or Fisher exact test as appropriate. p-value of $<$0.05 was considered statistically significant. All statistical analysis was performed using STATA/SE v 14.2 (STATA Corp LP, College Station, TX) software.

Based on statistically significant imaging findings (either present or absent) of a group compared with others, an algorithmic approach was proposed.

Results

A total of 46 patients were reviewed (32males and14 females). The age range was 4 years to 70 years.Hematological malignancies encountered were acute myeloid leukemia (20/46, 43.4%), acute promyelocytic leukemia (8/46,17.3%), acute lymphoblastic leukemia (8/46, 17.3%), and others (22%). Among the divergent groups of non-infectious pulmonary complications, leukostasis was the commonest (14/46,30.4%); followed by pulmonary edema (13/46,28.2%) and DAH (8/46,17.4%).

Overall, GGO was the most frequent findings and was seen in all cases of differentiation syndrome and DAH (Fig. 1a).Lower lobe predominance (5/13) was seen in the pulmonary edema. Both central and peripheral involvement (6/8) with sparing of apices/costophrenic angles/ sub pleural region (4/8) was noted in DAH (Fig. 1b). Confluent lobular pattern (4/8) was seen in DAH. Patchy and geographic pattern (4/11) was common in pulmonary edema.Peribronchial distribution (5/10) was seen in leukostasis (Fig. 1c). In pulmonary leukemic infiltrate, GGO was seen surrounding the nodules (Fig. 1d). Crazy paving was seen in two cases of pulmonary edema.

Fig. 1.

CT findings in various non-infectious pulmonary complications in hematological malignancies. a to c are complications predominantly presenting with ground glass opacities (GGOs), d to g shows those showing septal thickening and nodules. a. Differentiation syndrome—diffuse GGO (white arrows) with peribronchial interstitial thickening (black arrow); b. Diffuse alveolar hemorrhage—diffuse GGO (white arrow) with subpleural sparing (black arrow); c. Leukostasis - multifocal GGO predominantly in peribronchial distribution; d. Leukemic infiltration—randomly distributed nodules with surrounding GGO in a case of leukemic infiltration (arrows); e. Pulmonary edema—diffuse GGO (white arrow), smooth interlobular septal thickening (black arrow) and smooth peribronchial interstitial thickening (red arrow); f. Leukostasis—Multiple tiny nodules (black arrows) with subtle GGO, peribronchial interstitial thickening (red arrow) and nodular septal thickening (white arrows); g. Leukemic infiltration—Irregular and nodular peribronchial thickening (arrows)

Sepal thickening was seen more frequently in pulmonary edema. Smooth interlobular septal thickening with upper lobe predominance was seen in pulmonary edema (Fig. 1e). Smooth peribronchovascular interstitial thickening with parahilar distribution was common findings in pulmonary edema. Peribronchovascular interstitial thickening was also seen in 7 cases of leukostasis and 4 of them showed nodular thickening (Fig. 1f, g).

Nodule was common finding in leukostasis and pulmonary leukemic infiltrate (Fig. 1d, f). Perilymphatic distribution was predominant finding.

Pleural effusion was the second common finding and seen predominantly in pulmonary edema (12/13).It was seen bilaterally and was free. Unilateral pleural effusion was seen in one case of DAH and in two cases of leukostasis.

Consolidation and mediastinal lymphadenopathy were infrequently seen and their proportion among different groups was not statistically significant.

Absence of diffuse GGO in Group 4, interlobular septal thickening in Group 2 and Group 3, nodules in Group 5, and peribronchovascular interstitial thickening in Group 2 were statistically significant. Presence of interlobular septal thickening in Group 5, nodules in Group 4, and peribronchovascular interstitial thickening in Group 5 were statistically significant (Table 1).

Table 1.

Distribution of imaging findings amongst common Noninfectious pulmonary complications and statistics

Imaging findings	Total no of patients (n = 46)	DS${}^{\ast }$ Group1 (n = 6)	DAH${}^{\#}$ Group2 (n = 8)	Leukostasis Group3 (n = 14)	Pulmonary Leukemic infiltration Group 4 (n = 5)	Pulmonary edema Group5 (n = 13)	Group1 versus 2$+$3$+$4$+$5 p-value	Group2 versus 1$+$3$+$4$+$5 p-value	Group3 versus 1$+$2$+$4$+$5 p-value	Group4 versus 1$+$2$+$3$+$5 p-value	Group5 versus 1$+$2$+$3$+$4 p-value
GGO	35	6 (100%)	8 (100%)	10 (71.4%)	0 (0%)	11 (84.6%)	0.3	0.1	0.7	<0.001	0.4
Consolidation	7	0 (0%)	2 (25%)	3 (21.4%)	0 (0%)	2 (15.4%)	0.5	0.5	0.6	0.9	0.9
Interlobular sepal thickening	17	2 (33.3%)	0 (0%)	1 (7.1%)	2 (40.0%)	12 (92.3%)	0.9	0.01	0.007	0.9	<0.001
Nodules	12	1 (16.7%)	0 (0%)	6 (42.9%)	5 (100%)	0 (0%)	0.9	0.09	0.1	0.001	0.01
Peribronchovascular interstitial thickening	20	1 (16.7%)	0 (0%)	7 (50%)	1 (20%)	11 (84.6%)	0.2	0.006	0.7	0.3	0.001
Pleural effusion	29	2 (33.3%)	5 (62.5%)	9 (64.3%)	1 (20%)	12 (92.3%)	0.1	0.9	0.9	0.05	0.01
Mediastinal lymphadenopathy	8	0 (0%)	2 (25%)	2 (14.3%)	2 (40.0%)	2 (15.4%)	0.5	0.6	0.9	0.2	0.9

DS differentiation syndrome, DAH diffuse alveolar hemorrhage

Bold values indicated statistically significant findings

Based on the aforementioned statistical results, an algorithm was developed (Fig. 2).

Fig. 2.

An algorithmic approach to the diagnosis of common non-infectious pulmonary complications in patients with hematological malignancies

Discussion

In this study, we intended to detect specific imaging findings on chest CT favouring the diagnosis of one of the non-infectious pulmonary complications amongst common non-infectious pulmonary complications and developed algorithmic approach for interpreting imaging findings. This study did not focus on the imaging patterns of infectious complications; and only included non-infectious complications. Most of the common infections (bacterial/fungal) on imaging show a pattern of nodules or focal consolidations. The non-infectious complications, on the other hand, mostly present with diffuse lung involvement predominantly of a ground glass pattern. Further, amongst infections, the viral pneumonias give rise to such an imaging appearance. Viral pneumonias are relatively less frequent in the studied subject population. In addition, infections were excluded on the basis of clinical details, laboratory findings and other investigations as well.

Step 1. Presence and distribution of GGO

Patchy or diffuse GGO involving bilateral lungs should suggest possibility of pulmonary edema, DAH, leukostatsis, and differentiation syndrome. However, if it is absent or seen surrounding nodules, should point towards the diagnosis of pulmonary leukemic infiltrate. This is inconcordance with previous study by Heyneman et al [2], in which GGO were associated with consolidation which was secondary to infiltration of the leukemic cell in the air space. Additionally, pulmonary leukemic infiltration is characterized by the presence of nodules (as seen in all our cases), interlobular septal and peribronchovascularinterterstial thickening (seen in two and one case in our study respectively) reflecting predilection of leukemic cells forperilymphatic distribution [3].

Step 2. Presence of interlobular septal thickening

Presence of interlobular septal and peribronchovascular interstitial thickening (predominantly in parahilar regions) along with absence of nodules favour pulmonary edema [4, 5]. Absence of septal thickening in acute stage accompanied with absence of nodules and peribronchovascular interstitial thickening suggest DAH [6, 7]. Interlobular septal thickening may or may not be seen in differentiation syndrome and leukostatsis.

In our study, absence of interlobular septal thickening in leukostasis was statistically significant; in contrast to the study by Stefanski et al in which interlobular septal thickening was the most common findings [8].

Step 3. Presence of peribronchovascular interstitial thickening

In our study, absence or presence of peribronchovascular interstitial thickening was inconclusive in differentiating leukostasis from differentiation syndrome. However, absence of interlobular septal thickening in leukostasis was statistically significant. There are limited literature describing the CT features of differentiation syndrome and leukostatsis. Davis et al [9] had reported small irregular peripheral nodules, GGO and pneumothorax as imaging findings seen on CT in differentiation syndrome. Previous study on chest radiographs had showed increase in vascular pedicle width, cardiothoracic ratio, peribronchial cuffing, GGO, pleural effusion as predominant imaging finding in differentiation syndrome [10]. Nodules and peribronchovascular interstitial thickening in leukostasis are likely due to leukemic cell infiltration in interstitium representing continuum of same disease [11].

There are few limitations in our study such as small and variable sample size among different groups and being a retrospective study. Therefore, there is a need for a study with larger sample size for future implication in imaging evaluation.

Conclusion

An algorithmic approach to CT findings such as GGO, septal thickening, nodules, and peribronchovascular interstitial thickening may suggest possible diagnosis in an appropriate clinical scenario in the evaluation of common non infectious pulmonary complications in patients with hematological malignancies.

Author Contributions

Conceptualization: Rashmi Singh, Priyanka Naranje, Ashu Seith Bhalla, Smita Manchanda

Methodology, Analysis and Investigation: Rashmi Singh, Priyanka Naranje, Ashu Seith Bhalla

Draft Preparation: Rashmi Singh, Priyanka Naranje, Ashu Seith Bhalla

Manuscript review and editing: Priyanka Naranje, Ashu Seith Bhalla, Smita Manchanda, Manoranjan Mahapatra

Funding Information

None

Code availability

STATA/SE v 14.2 (STATA Corp LP, College Station, TX) software

Conflict of interest

The authors declare that they have no conflict of interest.