CT findings predict survival of patients with peripheral T cell lymphoma: a preliminary study

Peripheral T-cell lymphoma (PTCL) is an uncommon disease entity more prevalent in Asia than in Western countries and accounts for 5% to 30% of all non-Hodgkin lymphomas (NHL).^{1, 2, 3} It is a heterogeneous group of clinically aggressive lymphomas including PTCL-not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL). PTCL is usually associated with poor outcome compared with B-cell lymphomas.^{4, 5, 6, 7} Thus, PTCL requires prompt diagnosis and vigilant monitoring of progression since it is a life-threatening disease.

The International Prognostic Index (IPI), which was developed for predicting the clinical course of aggressive lymphomas, is commonly used in PTCL. This system is based on age, performance status, lactate dehydrogenase, stage, and extranodal involvement. Establishing the correct diagnosis and accurately evaluating the extent of tumor involvement are important for patients with PTCL because they directly impact the staging and treatment of the tumor. Therefore, accurately describing the characteristics of PTCL (for example, the tumor size and local extension, lymph node metastases, or extranodal involvement, etc.) is fundamental in clinical imaging practice.

Computed tomography (CT) is usually used for evaluation of the patient who has lymphoma, because it offers the advantage of obtaining information about both the nodal and extranodal components of the disease. Hence, it allows for accurate staging of the disease and follow-up of the therapeutic response. Radiologic manifestations about lymphoma have been described in many studies; however, most of them have focused on B-cell lymphoma. Although several reports concerning the imaging characteristics of PTCL have been published^{8, 9, 10}, these studies usually focused on nodal diseases or conducted on this entity only targeting one extranodal site, for example, the head and neck. Furthermore, the prognostic value of the imaging findings was absent in these studies. The purpose of this study was to evaluate the prognostic value of CT findings to predict clinical outcomes in patients with PTCL involving both nodal and extranodal sites.

In the present study, an ill-defined margin with peripheral tissue invasion was identified to be an independent risk factor for clinical outcome of patients with PTCL. This CT sign is considered more indicative of squamous cell carcinomas than of NHL, if there is no history of previous treatment or recent infection. For squamous cell carcinoma, an ill-defined margin with peripheral tissue invasion increases the risk of local failure, distant metastases, and decreased survival.^{10, 12} To our knowledge, there are only a few reports on the prognostic significance of ill-defined margin and local tumor invasion in NHL, perhaps because they have been considered uncommon findings in malignant lymphoma. Zhou et al.¹³ reported that the lesion margin was an independent risk factor for clinical outcome in 59 patients with head and neck NHL. Kim et al.¹⁴ also reported that local tumor invasion as assessed by CT or MR imaging was a more important prognostic factor than IPI in predicting a low probability of complete remission and lower overall and disease-free survival in extranodal lymphoma. The result of our study was in agreement with previous literatures.

For malignant solid tumors, direct invasion may result in the infiltration of tumor cells to surrounding tissues and neighboring organs. Although a lymphoma is not really considered as a solid tumor, it does form a mass. For aggressive lymphoma subtypes, peritumoral/extracapsular infiltration often occurs. In the present study, the local invasion of PTCL, affected the fat, bone, skin or vessel nearby the tumor and gave the tumor an ill-defined margin on CT images. Of primary importance in the prognosis of patients with PTCL is the sequence of events leading to the development of tumor cell invasion. In previous studies, extensive deregulation of genes that control functions typically damaged in malignant cells, such as matrix remodeling, cell adhesion, transcription regulation, proliferation, and apoptosis, was found in T-cell or B-cell lymphomas.^{15, 16, 17, 18, 19} The complexity of these tumors is represented by 25 to 30 up-regulated cancer genes and several down-regulated tumor suppressors that provide a growth advantage and enhance the ability to invade and disseminate. This might explain the mechanisms of local invasion and distant dissemination of PTCL in our study. The course of tumor invasion entails a series of stages that lead to dissemination and the formation of secondary tumors in distant organs and is, largely, responsible for the mortality and morbidity of PTCL.

Concentrating research efforts on identifying and understanding the mechanisms concerned in peritumoral invasion may lead to limiting tumor progression and, as a result, to a reduction in mortality for PTCL patients. In our opinion, when PTCL manifests as an ill-defined margin and peritumoral invasion, no matter the nodal disease or the extranodal lesion, patients are significantly more likely to experience poor outcomes than those with a well-defined lesion without local tumor invasion. And it may suggest the high aggressiveness of the disease, and more aggressive therapy is warranted for such circumstances.

A severely inhomogeneous tumor pattern on CT images was found to be associated with a high malignancy grade in NHL. This CT pattern was also compatible with a poor prognosis in patients treated with chemotherapy.^{10, 20} In this study, inhomogeneous density was another radiological sign that was associated with poor survival outcome in univariate analysis. This result was similar to those of previous studies. Although inhomogeneous density can be noted in other diseases, such as epithelial tumor, soft tissue neoplasia or infection, nearly a half of the patients (about 45%) with PTCL in our study showed this radiological characteristic. Inhomogeneous density may correspond to asymmetric tumor cell density, intralesional hemorrhage, necrosis or cystic change. This heterogeneity of tumor parenchyma always leads to heterogeneous density on CT images. Intratumoral hemorrhage and cystic change are seldom seen in untreated lymphoma. In our opinion, asymmetric tumor cell density and uneven distribution of blood vessel density in PTCL may contribute to inhomogeneous density on CT images, though the corresponding radiological-pathological studies are absent in our study. A previous study showed that tumor cells of T-cell lymphoma grown under an inhomogeneous cell density, especially under a high cell density environment, become better adapted to survival. They are not only superior in their tumorigenic potential, but are also resistant to the antitumor action of multiple anticancer drugs.²¹ Increased intratumoral vascularity has also been described as a negative prognostic factor in diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus chemotherapy.²²

Although intratumoral necrosis was not a common feature of NHL, it was found in nearly 27.5% of patients (14/51) in our study. Three previous studies have investigated the prognostic implications of tumor necrosis at CT or MRI in lymphoma.^{23, 24, 25} Hopper et al.²³ investigated chest CT scans of 76 patients with newly diagnosed Hodgkin lymphoma with mediastinal involvement. Their results showed that the presence of mediastinal necrotic lymph nodes appears to have little prognostic significance in patients with Hodgkin lymphoma. Saito et al.²⁴ evaluated CT and MRI scans of 60 patients with different non-Hodgkin lymphoma subtypes for the presence of necrosis in lymph nodes. They found that lymph node necrosis had no significant influence on patients’ disease-free survival, but may have a prognostic significance in patients with non-Hodgkin lymphomas. Adams et al.²⁵ studied CT scans of 51 patients with DLBCL for the tumor necrosis in lymph nodes as well as extranodal sites. The findings of their study also indicate the prognostic potential of tumor necrosis at CT in newly diagnosed DLBCL. The result of our study was similar to those of Saito et al. and Adams et al. Univariate analysis showed that intratumoral necrosis was associated with poor clinical outcomes. This may indicate that the underlying PTCL has an aggressive tumor growth. Although intratumoral necrosis was not an independent risk factor by multivariate analysis, it may have a prognostic significance in patients with PTCL.

The results of our study showed that PTCL is likely to involve multiple regions and manifest as a generalized disease. Lee et al.⁸ also found that the most common radiologic feature of PTCL was systemic dissemination, including various organ involvement and generalized lymphadenopathy. In addition, in their series of 581 patients with intestinal non-Hodgkin lymphoma, Kim et al.²⁶ identified that B-cell lymphoma mainly presented as localized disease while T-cell lymphoma involved multiple sites. Three subtypes of T-cell lymphoma including PTCL-NOS, EATL and NK/T lymphoma had a relatively lower response rate and a higher recurrence rate. Although multiple site involvement was not an independent risk factor to predict patients’ prognosis in our study, it was associated with poor clinical outcome in univariate analysis. Again, this may suggest that this characteristic is an indicative sign of the aggressive clinical course of PTCL.

In diagnosis, staging, monitoring of treatment and prediction of prognosis in patients with lymphoma, ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET/CT) has proved to be a more effective modality than diagnostic CT.^{27, 28, 29, 30} Jung et al.³¹ investigated the prognostic accuracy of interim PET/CT in PTCL and derived cutoffs for standardized uptake value (SUV) and metabolic tumor volume (MTV) assessments that were significantly predictive for survival. Cottereau et al.³² also reported that higher MTV predicted a poor survival in patients with PTCL. However, in China the limited number of hybrid PET/CT scanners and major financial restrictions also prevent widespread use of this expensive modality. Furthermore, intravenous contrast material administration is usually absent in FDG PET/CT studies and blood vessel invasion by lymphoma may not be clearly depicted. Small disease missed by PET/CT because of the absence of FDG uptake and non-pathological FDG accumulation can also be properly identified by contrast-enhanced CT.

Our study has several limitations, the first of which is its retrospective nature. Second, a detailed pathological study was absent to be correlated to the imaging findings. Therefore, further investigation on large cases with a detailed radiological-pathological correlation study is needed. Third, different CT equipment and techniques were used. CT examinations of 10 patients were performed on a single spiral CT with a section thickness of 10 mm. Compared with the smaller section thickness, it may affect the quality of the CT images and decrease the probability that more tissue of a given lesion will be captured. Fourth, different histological subtypes of PTCL were involved, and each subtype may have different clinical features and treatment response. However, this problem is simply unavoidable due to the limitations of a retrospective study and the rarity of PTCL, and should not have significantly affected the imaging characteristics studied.

In conclusion, multiple site involvement, an ill-defined margin with peritumoral invasion, inhomogeneous density, and intratumoral necrosis are relatively significant CT features of PTCL. An ill-defined margin with peritumoral invasion indicates a high risk of unfavorable survival outcome for PTCL. Nevertheless, the interaction between the different clinical and radiologic parameters is complex, and the imaging-based criteria for the assessment of treatment success and outcome is still the subject of ongoing investigations. To reliably evaluate the survival of patients with PTCL, it is important that the imaging examinations be performed according to unified technology and are interpreted according to standardized rules.