Prognostic Nomogram Incorporating Radiological Features for Predicting Overall Survival in Patients with AIDS-Related Non-Hodgkin Lymphoma
Acquired immune deficiency syndrome (AIDS)-related non-Hodgkin lymphoma (AR-NHL) is a significant cause of morbidity and mortality among patients with AIDS. Despite the advent of highly active antiretroviral therapy (HAART), which has reduced the incidence of AIDS-related tumors, the occurrence rate of AR-NHL has not declined as expected. This study aimed to identify prognostic factors associated with overall survival (OS) in AR-NHL patients and to develop a prognostic nomogram incorporating computed tomography (CT) imaging features to predict survival outcomes.
The study retrospectively reviewed 121 AR-NHL patients from July 2012 to November 2019. Clinical and radiological independent predictors of OS were identified using multivariable Cox analysis. A prognostic nomogram was constructed based on these factors, and its predictive accuracy was assessed using the Harrell C-statistic. Kaplan–Meier survival analysis was used to determine median OS, and the prognostic value of adjuvant therapy was evaluated in different subgroups.
Multivariate Cox regression analysis revealed that involvement of mediastinal or hilar lymph nodes, liver involvement, necrosis in the lesions, treatment with chemotherapy, and CD4 count ≤100 cells/mL were independent risk factors for poor OS. The predictive nomogram demonstrated good discrimination (Harrell C-index = 0.716) and calibration (Hosmer–Lemeshow test, P = 0.620). Notably, only patients in the high-risk group who received adjuvant chemotherapy had significantly better survival outcomes.
The study concluded that the developed nomogram is effective in assessing the survival outcomes of AR-NHL patients. Decision-making regarding chemotherapy regimens and more frequent follow-up should be considered for patients in the high-risk group as determined by this model.
AR-NHL is a high-risk factor for morbidity and mortality in AIDS patients. Although HAART has reduced the incidence of AIDS-related tumors, the occurrence rate of AR-NHL has not declined as expected. Adjuvant chemotherapy can improve patient tolerance and remission rates, but inappropriate therapy may induce adverse effects, including myelosuppression, tissue necrosis, and liver dysfunction. The application of chemotherapy and chemoradiotherapy remains controversial due to the difficulty in selecting suitable AR-NHL patients.
Previous studies have identified CD4+ count, HIV RNA levels, Ann Arbor stage, lactate dehydrogenase (LDH) levels, international prognostic index (IPI) score, and age as key predictors for survival in AR-NHL patients. However, few studies have investigated the significance of imaging characteristics for predicting prognosis and survival. Advanced imaging techniques such as CT, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT play an increasingly essential role in detecting lesions and evaluating disease. CT can detect enlarged lymph nodes, guide biopsy, and observe early relapse through follow-up. However, MRI and PET/CT are limited in some developing countries due to economic and social factors. Therefore, a widely applicable nomogram based on clinical and CT characteristics is needed to predict prognosis in AR-NHL patients accurately.
This study integrated clinical and CT-related factors to create a novel nomogram to stratify patients into low- and high-risk groups. The study aimed to determine the prognostic factors associated with overall survival and to develop a prognostic nomogram incorporating clinical and CT imaging features in AR-NHL patients.
The study was conducted under approval by the Institutional Review Board of You’an Hospital Affiliated with Capital Medical University. The consent to participate was waived due to the retrospective nature of the study. Information from 181 patients with AIDS-related lymphoma from three tertiary infectious disease hospitals was retrospectively reviewed, and their clinical and imaging data were analyzed between July 2012 and November 2019. The diagnosis of HIV infection was based on the standards of the Centers for Disease Control and Prevention of the USA. The diagnosis of lymphoma was based on puncture biopsy, endoscopic biopsy, and operation specimens. All interventions and treatments were processed according to National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: non-Hodgkin lymphomas. Patients were followed up once every 3 months in the first year, once every 6 months in the second year, once every year in the third year, and so on. Overall survival (OS) was selected as the endpoint, measured from the lymphoma diagnosis until the last follow-up or death from any cause. Follow-up was continued until November 2020.
Patients eligible for this study were aged >18 years, had a history of HIV infection, had pathologically confirmed diffuse large B-cell lymphoma (DLBCL) or Burkitt lymphoma (BL), and had available clinical and CT imaging data before any clinical intervention. Patients with Hodgkin lymphoma, indolent B-cell non-Hodgkin lymphoma (NHL), and T-cell NHL or lacking a specific pathological type were excluded. Patients younger than 18 years of age, those with severe artifacts in the CT images, and those lost during follow-up were also excluded.
All examinations were imaged with Philips CT 256. Thirty-nine patients accepted contrast-enhanced CT scans via intravenous contrast materials. The CT protocols included tube voltage, 120 kV; automatic tube current, 30 to 300 mA; rotation time, 0.75 s; collimation, 0.625 mm; pitch, 0.945; matrix, 512 × 512; section thickness, 5 mm; breath-hold at full inspiration. The images were transmitted to the workstation and picture achieving and communication systems for multiplanar reconstruction and post-processing. All images were reviewed by three radiologists blinded to clinical and laboratory data. Three statisticians assessed the CT features independently. Any divergences were resolved by discussion or consultation from a specialist in infectious imaging.
Baseline data included age, sex, pathology, time of finding HIV, time of finding mass, HAART administration, chemotherapy administration, systemic symptoms, CD4 count, white blood cell count, neutrophil percentage, lymphocyte percentage, Ann Arbor stage, and involvement of various lymph nodes and organs.
The imaging findings were tested for agreement using the Kappa test. Continuous variables were tested for normal distribution using the Kolmogorov–Smirnov method. The chi-square test and Fisher exact test were used to compare categorical variables. Univariate analysis of a Kaplan–Meier (K–M) analysis model was fitted to determine significant prognostic factors for OS. Factors with P values <0.050 were tested in a multivariate Cox proportional hazard model for the independence of association. A predictive model was developed for AR-NHL using Cox regression and illustrated by nomogram. The accuracy of predictions was assessed by estimating the nomogram discrimination measured by Harrell concordance index (C-index). The calibration of the nomogram was evaluated by the Hosmer–Lemeshow test. K–M estimates were used to determine median OS by Log-rank methods.
The median follow-up of the entire cohort was 12 months. On univariable analysis, factors associated with poor OS included CD4 ≤100 cells/mL, involvement of mediastinal or hilar lymph nodes, liver, gastrointestinal tract, presence of extracapsular infiltration, necrosis inside the lesions, and treatment without chemotherapy. On multivariable Cox analysis, involvement of mediastinal or hilar lymph nodes, liver, necrosis in the lesions, CD4 ≤100 cells/mL, and treatment without chemotherapy were independent risk factors for short OS.
The predictive models were based on Cox regression and illustrated by nomogram, indicating the probability of 1-, 2-, and 3-year OS in patients with AR-NHL. Harrell C-index was 0.716, suggesting relatively good discrimination. The Hosmer–Lemeshow test demonstrated a P = 0.620 > 0.050, indicating no departure from a good fit. The probability of survival at 1, 2, and 3 years was obtained by drawing a vertical line from the “total points” axis straight down to the outcome axes. The total number of points for each patient was obtained by summing the points for each of the individual factors in the nomogram. In the predictive model, treated with chemotherapy can increase 100 points for total points, followed by liver involved free (add 82 points), CD4 counts >100 cells/mL (add 69 points), mediastinal or hilar lymph nodes involved free (add 58 points), and without necrosis (add 50 points).
Compared with patients with CD4 <100 cells/mL, patients with CD4 over 100 cells/mL had a good prognosis. K–M analysis and the log-rank test showed that patients who did not receive chemotherapy had poor survival outcomes than those receiving chemotherapy. Patients with involvement of mediastinal or hilar lymph nodes or involvement of the liver, or the lesions with necrosis had a worse prognosis. Patients in the high-risk group could benefit from chemotherapy treatment.
To the best of our knowledge, this is the largest study from triple institutions in Asia to evaluate prognostic factors in patients with AR-NHL. The study developed a nomogram based on patients’ demographics, CT imaging features, and laboratory data, which can effectively stratify patients into low- and high-risk groups. Involvement of mediastinal or hilar lymph nodes, liver, necrosis in lesions, CD4 ≤100 cells/mL, and treatment without chemotherapy were independent risk factors for shorter OS. Notably, only patients in the high-risk group in our study were found to be significantly benefited from chemotherapy, so we strongly recommend patients in the high-risk group as candidates for chemotherapy.
Imaging plays an important role in the detection and evaluation of AR-NHL lesions. CT of the head and neck, chest, abdomen, and pelvis is a critical staging modality recommended by the NCCN guidelines. The potential mechanism of necrosis in lymphoma is the occlusion of the supplying hilar artery by the tumor (compression or invasion) in addition to lymphatic flow obstruction. A previous study reported that HIV (−) NHL patients with necrosis had significantly higher Ann Arbor stages, greater IPI, and higher serum LDH levels than those without necrosis. However, in their K–M survival analysis, no statistically significant difference was noted for necrosis. Our study focused on patients with AR-NHL, and necrosis in the lesions was an independent risk factor for shorter OS. Necrosis of the lesion indicated the aggressive behavior of the tumor and the tendency for treatment resistance. The presence of extracapsular infiltration is also correlated with the OS in the current study. The invasion of tumor cells may be a potential mechanism of extracapsular infiltration and may correlate with a poor prognosis. Natural killer (NK) cells play an important role in the growth and infiltration of lymphoma cells and activated NK cells could be a promising immunotherapeutic tool against lymphoma cells either alone or in combination with conventional therapy.
AR-NHLs are usually B-cell, high-grade, and poorly differentiated lymphomas. Extranodal sites involvement is common. The liver is the second most common site with an incidence ranging from 26% to 45%. HIV (+) patients have a higher incidence of NHL than HIV (−) patients. A previous study indicated that primary mediastinal large B-cell lymphoma (PMBCL), representing 10% of all DLBCL, was predictive of poor OS and progression-free survival. Compared with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, rituximab and its use with intensified chemotherapy such as R-Hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone and R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) might improve the response rate and survival outcome for patients with mediastinal NHL, especially for PMBCL.
Although Guech-Ongey et al found acquired immune deficiency syndrome-related Burkitt lymphoma incidence declined at low CD4 counts, suggesting functional CD4 lymphocytes may be required for BL to develop, we consider lower CD4 counts to reflect more severe immunodeficiency, which is likely to cause opportunistic infections and other malignant tumors for patients with AR-NHL.
For patients who have factors correlated with shorter OS time, intensive chemotherapy should be considered. Intensive chemotherapy is relatively safe and effective in AR-NHL. Notably, only patients in the high-risk group in our study were found to be significantly benefited from chemotherapy, so we strongly recommend patients in the high-risk group as candidates for chemotherapy. Chemotherapy and concomitant HAART for AR-NHL does not cause prolonged suppression of lymphocyte subsets. On the contrary, chemotherapy can increase the counts of CD4, CD8, CD19, and CD56 cell populations, which provide reassurance regarding the long-term consequences of chemotherapy in these individuals. While for patients in the lower-risk group, the survival difference was not statistically significant, so HAART alone and regular examination are recommended, because adverse characteristics, such as severe bone marrow toxicity chemotherapy, should be considered.
There are several limitations to the current study. First, it is a retrospective study with a limited number of patients, and patients were diagnosed in different hospitals. Therefore, the quality of chemotherapy and the methods employed by pathologists for diagnosing metastatic lymph nodes were uniform, which might bias our results. Second, although univariate analysis showed that pathology classifications (acquired immune deficiency syndrome-related diffuse large B-cell lymphoma and acquired immune deficiency syndrome-related Burkitt lymphoma) were not an independent prognostic factor for patients, other studies have reported that pathology classifications correspond to a different OS. Prospective investigations with larger samples focus on certain pathological types should be designed to find more predictive factors for prognoses of AR-NHL patients. Importantly, external validation of the proposed staging system in an independent cohort is required to determine whether it can be generalized to other institutions. Despite the current limitations, our study still has a high value because CT lesions necrosis characteristics and organ involvement in clinical work have a high degree of recognition.
In conclusion, a survival-predicting nomogram integrating CT features was developed in this study, which was promising for assessing the survival outcomes of patients with AR-NHL. Notably, decision-making of chemotherapy regimens and more frequent follow-up should be considered in the high-risk group determined by this model.
doi.org/10.1097/CM9.0000000000001785
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