Imaging Characteristics of Primary Non-Hodgkin's Lymphoma of The Larynx

Purpose This study aimed to report the computed tomography (CT) and magnetic resonance imaging (MRI)characteristics of primary Non-Hodgkin's Lymphoma (NHL) of the larynx. methods The radiographic examinations of ve patients (2 men, 3 women; median age, 68years) with histopathologically proven NHL of the larynx were retrospectively reviewed. CT and MRI images were analyzed qualitatively (Tumor distribution, Local tumor invasion, Tumor appearance, Cervical lymphadenopathy of NHL). Results CT and MRI images showed no obvious signs of vascular and laryngeal cartilage invasion. Three cases (1 MALT, 2 diffuse large B-cell lymphomas (DLBCL)) were centered in the supraglottic region involved the glottis (3/3) and subglottic (1/3). Two cases (MALT) were centered in the glottis involved the subglottic. The laryngeal tumors involved the true cords (5 cases), aryepiglottic folds (3 cases), ventricles and false cords (3 cases), anterior commissure (2 cases). On MRI (4 cases), all NHL presenting as homogeneous intermediate T1-weighted, heterogeneous slightly high T2-weighted mass with homogeneous moderate to evident enhancement. The mucosa with more obvious enhancement and smooth surface could be seen. On CT (1 plain and 3 contrast-enhanced), all tumors were homogeneous moderate density, and no necrosis or calcications were seen. Lymphadenopathy was presented in two patients of DLBCL without necrosis.


Introduction
Primary laryngeal non-Hodgkin's lymphoma (NHL) accounts for less than 1% of laryngeal malignant tumors, while more than 90% of laryngeal malignancies are squamous cell carcinoma [1]. Some cases of NHL of the larynx have been reported in the literature, but a few for the imaging characteristics. Improving the diagnostic and evaluation accuracy of laryngeal NHL can effectively reduce unnecessary tracheotomy and help clinical doctors choosing appropriate treatment strategies, because lymphoma is mostly treated by radiotherapy and chemotherapy rather than surgery [2].
Our purpose is to provide and identify more imaging characteristics of NHL of the larynx through CT and MRI images of another ve additional patients, so as to help to distinguish them from other laryngeal malignant tumors, and help clinicians to correctly diagnose this rare tumor and choose appropriate treatment in the early stage. In the end, it can help patients avoid unnecessary surgery and obtain more long-term bene ts.

General information
The imaging data of ve patients with NHL (two males, three females) proved by immunohistochemistry in our hospital from January 2010 to January 2020 were retrospectively reviewed. One case was consulted by UCLA. All patients signed informed consent before receiving imaging examination. The average age of these patients was 68 years old (range, 53-83 years). All 5 cases came to the hospital with hoarseness.

CT/MRI Examination and Parameters
Four cases underwent 64-row spiral CT scanning, and the axial image thickness was 1 mm. Coronal and sagittal images were reconstructed by multiplanar reconstruction (MPR). Contrast-enhanced CT imaging (three cases) was obtained after intravenous injection of contrast media at a dose of 1.0ml/kg. All MR imaging (four patients) was performed on 1.5T or 3.0T unit to produce transverse T2-weighted sequences with fat suppression and T1-weighted sequences before enhancement. After injection of Gd-DTPA with a dose of 0.2mmol/kg, axial, coronal and sagittal enhanced T1-weighted images (thickness = 4mm) were obtained.
CT/MRI assessment All images were analyzed by two experienced radiologists (with 8 years and 23 years of imaging diagnosis experience) working in consensus using a picture archiving and communication system (PACS) workstation. MR and CT images were assessed for distribution, appearance, local extension, and cervical lymphadenopathy. Besides, the clinical manifestations, histological features and prognosis were analyzed retrospectively also.

Clinical Features and Pathological types
None of the patients had a history of HIV and EB virus infection and had no B symptoms (i.e. unexplained fever > 38 C; night sweating; weight loss > 10%). Two patients con rmed by pathology as MALTlymphoma suffered from laryngeal obstruction (3 degrees [one case] and 2 degrees [one case]) and underwent emergency tracheotomy. The last one of the 3 cases of MALT-lymphoma involved not only the larynx but also the orbit. The other 2 cases were diffuse large B-cell lymphoma (DLBCL). Both cases of diffuse large B-cell lymphoma (DLBCL) were older than 80 years old (Table 1).

CT and MR Features
Tumor distribution. All the tumors were based in the submucosa and mucosa,One case of MALTlymphoma showed no invasion of blood vessels and mucosal epithelium. In the remaining four patients, the blood vessels and mucosal epithelium was not speci ed on pathology reports. CT and MRI images showed no obvious signs of vascular invasion. Three cases, including one MALT-lymphoma, two diffuse large B-cell lymphomas (DLBCL), were centered in the supraglottic region but also involved the glottis (3/3) and subglottic (1/3). The other two cases of MALT-lymphoma were centered in the glottis but also involved the subglottic. In the ve cases, all tumors invaded the true cords. Other involved location included the ventricles and false cords (three cases), aryepiglottic folds (three cases), and anterior commissure (two cases). Among them, all three cases of MALT-lymphoma grew across the midline ( Fig. 1-3). No laryngeal vestibule was involved in all cases.
Local tumor invasion. NHL extended outside the larynx to involve the hypopharynx and oropharynx in one patient (Fig. 4), and the invasion sites included ipsilateral tonsils, pyriform fossa, posterior pharyngeal wall, epiglottic valley, paralaryngeal fat space and extralaryngeal muscles. In another case of lymphoma, multiple thyroid nodules were seen, while Color Doppler ow imaging (CDFI) demonstrated that blood ow signals were not abundant. Unfortunately, thyroid lesions have no pathological results. The pathological type of the above two cases were both diffuse large B-cell lymphoma (DLBCL). A case of laryngeal MALT-lymphoma accompanied with concomitant Wechsler's ring and ocular MALT-lymphoma also. It is noteworthy that no obvious invasion or destruction of laryngeal cartilage was observed in all cases.
Tumor appearance. Four contrast-enhanced MR imaging, one plain CT and three contrast-enhanced CT studies were reviewed. MR imaging demonstrated homogeneous moderate signal intensity on T1WI, heterogeneous slightly high signal intensity on fat suppressed T2WI, with homogeneous moderate to evident contrast enhancement characteristics. In addition, the surface mucosa with more obvious enhancement and smooth surface could be seen (Fig. 1). CT images revealed that all tumors were homogeneous moderate density similar to muscle tissue, with moderate to obvious contrast enhancement. In all cases, the enhancement degree of MALT-lymphoma centered in subglottic region was more obvious in two cases. CT examination showed no clear signs of calci cation and necrosis.
Cervical lymphadenopathy. Lymphadenopathy was present in two patients of diffuse large B-cell lymphoma (DLBCL). Diffuse large B-cell lymphoma (DLBCL) had bilateral lymphadenopathy, one involved from level II to IV zone, the other one involved from level II to VII zone, without obvious necrosis. In the remaining three cases of MALT-lymphoma, small lymph nodes were found on both sides of the neck, but the short diameter was less than 8 mm.  gland and orbit. The larynx is a very rare site for NHL, and its incidence rate is less than 1% in all laryngeal tumors [6,7]. The diffuse large B-cell lymphoma (DLBCL) and the MALT-lymphoma are the most common primary tumors of larynx originating from hematopoietic system [8,9].
The presenting symptoms and signs of laryngeal lymphoma varied from site to site. The most common symptom was hoarseness (70.2%), followed by throat pain (26.3%), dyspnea (17.5%), and dysphagia (17.5%). B-symptoms (including night sweats, weight loss and fever) were rare (14.0%) [1]. In this study, all patients developed hoarseness without B symptoms. Indirect laryngoscopy often shows a polypoid submucosal mass without ulcer or other particular diagnostic characteristics. Two-thirds of the tumors tend to invade supraglottic regions, especially the epiglottis and aryepiglottic folds [10]. This is because the lesions mostly originate from the mucosa associated follicular lymphoid tissue in the lamina propria of the supraglottic region. NHL is speculated to originated from two parts of the larynx: 1) the special lymphoid tissue aggregates in submucosa, mainly B-cell line, or 2) mucosa-associated lymphoid tissues (MALT), mainly originated from the epiglottis and aryepiglottic folds [11].
Laryngeal lymphoma is usually characterized by submucosal mass in the supraglottic region, resulting in narrowing of the laryngeal cavity. The lesions may involve the glottic and subglottic areas downward, and the pharyngeal lymph ring may also be involved upward. In our series of study, imaging ndings revealed that all the patients with laryngeal diffuse large B-cell lymphoma (DLBCL) had supraglottic and glottis involvement. The tumor most involved the false cords, aryepiglottic folds and true cords. In our other three cases of MALT-lymphoma, two cases were centered in the subglottic, involving the glottic region, resulting in laryngeal obstruction. One case was centered in the supraglottic region and involved the glottic region at the same time. This is not consistent with the imaging ndings previously reported by Takayama et al and King et al that laryngeal lymphoma rarely originated from subglottic region [10,12]. It may be because there were too few MALT-lymphomas in their cases of study. It was not surprising that NHL of larynx were not restricted to the glottis in our cases, because lymphatis were very scarce in the true vocal cords. As showed in our cases of study, glottic tumors were often secondary to the spread of tumor tissues in adjacent areas. Among the seven reported cases of B-cell lymphomas causing laryngeal stenosis, ve cases were MALT-lymphoma located in the subglottic region [13][14][15][16][17][18][19]. This is consistent with the results of our study, which may indicate that most of the NHL located in the subglottic region and causing laryngeal stenosis are MALT-lymphoma.
Compared with the pathological classi cation and image morphological characteristics, diffuse large Bcell lymphoma (DBLCL) and MALT-lymphoma showed mass formation at corresponding sites. One case of diffuse large B-cell lymphoma (DBLCL) extended to the hypopharynx, and one case of MALTlymphoma had the same type of lesions in the orbit, and this extensive involvement should raise the suspicion of lymphoma. Because of its submucosal origin, the surface of the lesions is mostly smooth [7,12,20]. In all of our enhanced MRI images, the smooth surface of the tumor was observed with more obvious linear enhancement of the mucosa. On CT plain scan, the lesions showed homogeneous and medium density similar to muscle tissue, and moderate homogeneous enhancement was found on contrast-enhanced scan. No obvious cystic degeneration, necrosis, calci cation and cartilage destruction were the typical features. The results showed that the high signal intensity of laryngeal NHL on T1WI was homogeneous or slightly lower than that of muscle, while on T2WI it was inhomogeneous and slightly hyperintense. The mucosal layer with high signal intensity on enhanced T1WI was clearly displayed and continuously smoothed, indicating that the lesion originated from submucosa [10]. In this study, diffuse large B-cell lymphoma (DBLCL) was more prone to had cervical lymphadenopathy than MALT-lymphoma.
The density, signal intensity and enhancement of the enlarged lymph nodes were consistent with those of the primary lesions, which were also con rmed in the literatures of NHL in other parts of the head and neck [20,21].
The imaging ndings of laryngeal NHL are easy to be confused with other laryngeal lesions. Due to the lack of research on imaging manifestations of this disease, all the above ve cases were misdiagnosed as squamous cell carcinoma at the initial diagnosis, and the diagnostic coincidence rate was low. Laryngeal squamous cell carcinoma (LSCC) originated from the mucous layer. The surface of the lesion was not smooth. It showed uneven moderate or signi cant enhancement on enhanced scan. It was easy to invade laryngeal cartilage. The primary lesion and enlarged lymph nodes were mostly accompanied with necrosis and showed ring enhancement [22]. Besides lymphoma and squamous cell carcinoma, it is also necessary to differentiate them from other laryngeal masses located in the mucosal or submucosal with homogeneous enhancement [12]. Neuroendocrine tumor-atipical carcinoid, paraganglioma, schwannoma, adenoid cystic carcinoma and other minor salivary tumors, sarcoma, tuberculoma, tumorlike lesions (Brown tumor and in ammatory myo broblastic tumor), and in ammatory lesions should all be considered [23].
With the progress of MRI technology, DWI, ADC and dynamic contrast-enhanced MRI (DCE-MRI) are more and more used in the diagnosis and differential diagnosis of head and neck lymphoma [24,25]. Based on the principle of different attenuation coe cient of the same material under different X-ray energy, Dual-Energy CT (DECT) collect data at the same time with high and low energy scanning scheme, and obtains iodine based image, water-based image, energy spectrum curve and virtual plain scan image by postprocessing methods such as material separation and reconstruction technology. In addition, the parameters such as iodine concentration, overlay value and slope of energy spectrum curve obtained can provide additional information for disease identi cation. Seidler  Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable Authors' contributions Pingding Kuang, Qiaoling Ding, Zijian Wang analyzed and interpreted the patients' images, Xinyi Chen consulted relevant materials, and was a major contributor in writing the manuscript. All authors read and approved the nal manuscript. Biao Jiang is the corresponding author.    An 80-year-old man with diffuse large B-cell lymphoma of the larynx. A, Axial CT scan shows moderate uniform enhancement mass (asterisk ) in the right supraglottic region, involving the right aryepiglottic fold, the right piriform fossa (black arrow), the right false vocal cord and the true vocal cord, in ltrating into the subglottic area. The normal shape of the right aryepiglottic fold is not visible, while the normal con guration of the left aryepiglottic fold remained (white arrow). B, Enhanced coronal T1-weighted MR image demonstrates the supraglottic mass (asterisk) extending to the oropharynx (white arrow).