MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia

Discussion

Plasma markers are currently used to screen patients at risk of NPC, including asymptomatic subjects from regional populations and family screening programs as well as symptomatic patients with nonspecific symptoms such as epistaxis. In this setting, MR imaging is also used to detect clinically occult early stage NPC in patients with abnormal blood test results but normal endoscopic results. Unfortunately, it is common to encounter patients who have both false-positive NPC plasma markers and BH of the nasopharyngeal walls and adenoid. In these patients, the challenge is not only to detect stage T1 NPC confined to the nasopharynx using MR imaging but also to discriminate these cancers from benign disease and thus reduce the number of unnecessary nasopharyngeal biopsies.

Although detailed MR imaging patterns of the local spread of NPCs have been well-described in the literature,^9⇓–11 there is a paucity of data related to stage T1 NPC confined to the nasopharynx, despite its importance for NPC screening. In this study, we found that stage T1 NPCs varied considerably in size, from small tumors localized at a single site to large exophytic tumors involving all sites and filling the nasopharyngeal cavity. Most NPCs arose laterally to cause size and signal asymmetries between the nasopharyngeal halves, whereas less than a third were diffuse or located centrally in the roof or posterior wall. The deep mucosal white line along the deep tumor margin was almost universally present among stage T1 cancers. This deep mucosal white line of greater contrast enhancement in the deep relative to the superficial layer has received scant attention in the literature. We believe that this line represents contrast enhancement in the dense fibrous tissue containing submucosal blood vessels. In most NPCs (84%), the deep mucosal white line exhibited focal discontinuity on at least 1 imaging slice. Although the integrity of this line has not been previously assessed in NPC, we believe that discontinuity might represent the earliest sign of impending extranasopharyngeal invasion. A loss or distortion of the normal contrast-enhancing adenoidal septa was an additional feature observed in stage T1 NPC. Although this feature has been described in NPC, its incidence has not been reported.^1,2,8 In the present study, all stage T1 NPCs exhibited this complete absence or distortion of the adenoidal septa, regardless of whether the tumor arose from within the adenoid or spread into the hypertrophied adenoid from adjacent walls.

The MR imaging features of stage T1 NPC differed significantly from those of BH. Compared with all cases of BH, stage T1 NPC confined to the nasopharynx had a greater volume, size asymmetry, and signal asymmetry; of these, size asymmetry was the most accurate criterion for NPC identification. This is not surprising because most stage T1 NPCs were centered laterally, whereas BH is a diffuse process. Although this study quantified differences in size between the 2 sides of the nasopharynx, in routine practice, this feature can usually be easily assessed subjectively. However, although most stage T1 NPCs could be detected via size asymmetry, a minority (11.9%) of early cancers were symmetric, especially those that were diffuse or centrally located. These early cancers were difficult to detect by MR imaging because they were not accompanied by the deep tumor invasion associated with higher T-stage tumors, which was used in previous studies that achieved NPC detection sensitivities of 97%–100%.^2,12

Differences in signal intensity (ie, NPC had a lower and higher contrast enhancement relative to BH1 and BH2, respectively) helped to identify focal tumors, though overall signal intensity alone was a poor discriminator. We found that stage T1 NPCs exhibited variable contrast enhancement both within heterogeneous tumors and among different tumors. BH is also known to exhibit a range of MR imaging appearances.^{2,13⇓⇓⇓–17} Notably, there were no differences between NPC and BH in this study when the signal intensities of BH1 and BH2 were combined. The range of NPC contrast-enhancement levels and the overlap with BH are of concern regarding symmetric NPCs, which can exhibit higher contrast enhancement and thus appear like BH1 (Figs 3A and 4A) or lower contrast enhancement and thus appear like BH2 (Figs 3B and 4C). Signal intensity was also assessed on the basis of the asymmetry in signal intensity between the 2 sides of the nasopharynx. Although this criterion was highly accurate for NPC, the positive predictive value was low, especially in symmetric NPCs (positive predictive value, 42%). Volume was the poorest discriminator among all criteria, even for symmetric NPCs, because the volumes of both NPC and BH ranged widely. Therefore, the use of volume to determine NPC would have led to a high number of nasopharyngeal biopsies for benign disease.

The 2 remaining MR imaging criteria related to the adenoidal septa (adenoid) and the deep mucosal white line (walls) exhibited greater promise for NPC detection. These 2 criteria detected NPC with a high level of accuracy, including symmetric tumors that may otherwise have been missed by MR imaging. Regarding the first criterion, distortion, disruption, or a complete loss of the adenoidal septa was significantly more likely to appear in NPC compared with adenoidal BH. However, the adenoidal septa should be assessed carefully because distortion caused by cysts or a single central column of lymphoid hyperplasia could be mistaken for NPC.¹⁵ Accordingly, vestigial adenoids and those comprising mainly cysts were not assessed in this study. Moreover, some previous MR imaging studies reported a higher rate of absent adenoidal septa in cases of adenoidal BH.¹⁷ Therefore, we suggest that an hypertrophied adenoid with absent or distorted septa should only be biopsied in a patient who is at a high risk of NPC and has undergone an MR imaging examination dedicated to the nasopharynx. However, the previously reported high negative predictive value of this sign suggests that nasopharyngeal biopsy can be avoided if the adenoidal septa are symmetric and separated by hyperplastic columns of low contrast enhancement (ie, striped appearance).² Regarding the second criterion, a focal loss of the deep mucosal white line was found to be significantly more common in NPC than in BH2. However, any assessment of the loss of this deep mucosal white line should be mindful of the fact that this line is not seen in the BH1 pattern. The BH1 and BH2 patterns often coexist in the nasopharynx; therefore, a focal loss of this line should only be determined on a slice through the nasopharynx where the line is present but focally disrupted.

Despite the use of new criteria, the ability of MR imaging to discriminate NPC from BH remains hindered by the false-positive findings of NPC, which are caused by asymmetric BH. The presence of a focal area of BH2 (Fig 7) is of special concern because the deep mucosal white line and superficial band of low contrast enhancement show a striking similarity to some small-stage T1 NPCs (Fig 1A). Accordingly, we have continued to follow these subjects. We believe that the diffuse BH2 pattern might be a response to stimulants such as Epstein-Barr virus infection, which cause a greater abundance of lymphoid cells in the lymphoid stroma and epithelium and may cause the appearance of a band of low contrast enhancement in the superficial layer of the nasopharyngeal mucosa, as well as in the columns of the hypertrophied adenoid. Differential rates of resolution might explain the asymmetry and why a minority of BH2 cases are focal by the time the MR imaging examination is performed. These focal sites of BH2 might act as a chronic reservoir of infection and become the MR imaging precursors of NPC. Furthermore, recruitment of vessels by the growing tumor might result in areas of greater enhancement like those observed in BH1and explain the heterogeneous enhancement pattern of early T-stage NPC. Although currently this scenario is only conjecture, the BH2 pattern is interesting and we believe it deserves future study.

Size asymmetry was the best overall criterion for detecting stage T1 NPC; however, size asymmetry included not only subjects with a focal mass but also those with asymmetry in an otherwise diffuse lymphoid hyperplasia pattern. Our previous NPC detection study with long-term follow-up³ showed that asymmetry in a diffuse benign hyperplasia pattern without a focal mass had a low specificity for NPC; therefore, to keep nasopharyngeal biopsies of healthy subjects to a minimum, we did not use this criterion to indicate NPC in a recent population screening study.⁷ Taking into consideration the new criteria in this study and recent research, we have updated our proposed MR imaging grading system (Table 4): The grades for normal (grade 1) and probably benign (grade 2) are unchanged; asymmetry in thickness of an otherwise benign hyperplasia pattern is now graded as indeterminate (grade 3); the new signs (asymmetry in signal, focal loss of the white line, or absence/distortion of adenoidal septa) together with a focal mass are graded as suspicious (grade 4); and extension outside the nasopharynx is graded as probably malignant (grade 5). Future studies are required to validate this proposed MR imaging grading system, but we hope it will provide a framework for further refinement and inclusion of new indicators of malignancy such as the presence of metastatic retropharyngeal nodes.

This study had several limitations. First, the signal intensity in an NPC may be influenced by the subjective choice of the representative ROI and possibly by postbiopsy effects that are not obvious on the images. Differences in magnet strengths and between manufacturers must also be considered as potential limitations when comparing signal ratios. Given these potential limitations, we only used the signal intensity data to illustrate the main differences among the 3 groups (NPC, BH1, and BH2) and not to identify diagnostic thresholds. In addition, a subgroup analysis of cases performed on the same scanner yielded results similar to those of the overall analysis, except for the difference in T2 signal intensity ratios between NPC and BH1, which showed the same trend but no longer reached statistical significance. Second, our results may not be applicable to MR imaging examinations that are not dedicated to the nasopharynx, such as examinations of the brain, which often include sections through the nasopharyngeal roof. Finally, we did not examine the role of diffusion-weighted imaging, which remains in the early stages of development for small nasopharyngeal lesions, or the combined performance of MR imaging and nasopharyngeal endoscopy and plasma levels of Epstein-Barr virus DNA.