Article information

Korean J Otorhinolaryngol-Head Neck Surg. 2024;.kjorl-hns.2024.00241

Publication date (electronic) : 2024 October 16

doi : https://doi.org/10.3342/kjorl-hns.2024.00241

Hyeop Oh¹, Su Mi Seong¹, Eo Jin Kim^,2, Bo Hae Kim^,1,3

¹Department of Otorhinolaryngology-Head and Neck Surgery, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, Goyang, Korea

²Department of Pathology, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, Goyang, Korea

³Sensory Organ Research Institute, College of Medicine, Dongguk University, Gyeongju, Korea

오협¹, 성수미¹, 김어진^,2, 김보해^,1,3

¹동국대학교 의과대학 일산병원 이비인후-두경부외과학교실

²동국대학교 의과대학 일산병원 병리학교실

³동국대학교 의과대학 감각기관연구소

Address for correspondence Bo Hae Kim, MD, PhD Department of Otorhinolaryngology-Head and Neck Surgery, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University 27 Dongguk-ro, Ilsandong-gu, Goyang 10326, Korea Tel +82-31-961-7438 Fax +82-31-961-7437 E-mail bohae111@naver.com

Eo Jin Kim, MD, PhD Department of Pathology, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University 27 Dongguk-ro, Ilsandong-gu, Goyang 10326, Korea Tel +82-31-961-7930 Fax +82-31-961-7939 E-mail pathejk@hanmail.net

Received 2024 May 1; Revised 2024 June 12; Accepted 2024 June 17.

Trans Abstract

Introduction

Multiple cranial neuropathies (MCN) can stem from various etiologies such as autoimmune diseases, neurovascular diseases, tumors, or infections [1]. Detailed history taking and physical examination facilitate the localization of the cranial nerves affected by the disease and provide insights of the underlying cause. Among the various etiologies of MCN, malignant lymphoma considered as a major contributor [2]. A biopsy with a sufficient specimen for immunohistochemical staining is required to diagnose lymphoma and classify its subtypes [3]. However, obtaining such specimen becomes challenging when the lymphoma affects the cranial nerve [4]. Given the extreme rarity of primary central nervous system (CNS) lymphoma without nodal involvement, detailed physical examinations and appropriate imaging tests provide crucial clinical indicators for determining excisional biopsy sites beyond the CNS, thereby leading to early diagnosis of lymphoma [5].

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-ALCL) is defined as a CD30+T-cell non-Hodgkin lymphoma, consisting of neoplastic lymphoid cells typically exhibiting large size, abundant cytoplasm and pleomorphic nuclei often horseshoe- or kidney-shaped [6,7]. While morphologically similar to anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, ALK-ALCL is categorized separately due to its distinct pathogenesis and clinical course [8]. Although ALCL commonly involves extranodal structures, including the skin, bone, soft tissues, lungs, and liver, gastrointestinal (GI) tract involvement is rare [6,7,9]. Therefore, an initial suspicion of stomach involvement in ALCL is difficult. ALK-ALCL accounts for only 2%-3% of all non-Hodgkin lymphomas and rarely involves head and neck structures, with the exception of lymph nodes [10]. Although anthracycline-based chemotherapy is recommended for first-line treatment, approximately 50% of patients experience recurrence after chemotherapy [10]. Furthermore, CNS involvement of ALK-ALCL is significant factor indicating the poor prognosis. However, due to the rarity of ALK-ALCL, a clear understanding of its long-term prognosis remains elusive. In addition, it is sometimes difficult to distinguish ALCL from undifferentiated carcinomas and other malignancies in head and neck region [6]. These characteristics of ALCL result in a relatively delayed diagnosis compared to other types of lymphoma [11].

We diagnosed ALK-ALCL simultaneously involving multiple cranial nerves, bilateral submandibular glands (SMGs), and the stomach within a considerably short time based on strong suspicion of lymphoma arising from initial physical examination findings. We report our experience in diagnosing ALK-ALCL in a patient with MCN, along with a literature review.

Case

A 54-year-old male with no underlying diseases visited our clinic with a voice change 3 days prior to presentation. He simultaneously complained of difficulty in deglutition and bilateral cheek numbness. There were no additional neurological symptoms such as vertigo, dysarthria, or weakness of the extremities. Laryngoscopy revealed no obstructive lesions in the laryngopharyngeal structure, and both vocal folds were mobile. The tongue and shoulder movements were also intact. However, during phonation, the asymmetrical elevation of soft palate was identified (Fig. 1). Additionally, although sensation in both cheeks was symmetric, there were notable differences in sensation between the bilateral mandibular (V3 dermatome) area and the cheek (V2 dermatome), with decreased cheek sensation upon touch. Incidentally, we discovered firm and symmetrically enlarged SMGs that the patient did not notice previously. Consequently, we strongly suspected that certain diseases, such as lymphoma or metastatic malignancy of the cranial nerves, could be responsible for MCN with multiple organ involvement.

Fig. 1.

Asymmetrical elevation of soft palate during phonation. Resting (A), during phonation (B).

Evaluations to identify the etiology of MCN were conducted in a hospital setting. General laboratory tests and cerebrospinal fluid (CSF) analyses revealed normal findings on the day of admission. Contrast magnetic resonance imaging (MRI) was performed to evaluate the status of the involved cranial nerves. The MRI revealed a mass lesion with low-to-intermediate signal intensity on both T1 and T2 weighted images in the left jugular fossa, combined with pachymeningeal enhancement at the adjacent cerebellar convexity and internal auditory canal (Fig. 2A). Homogenous enhancement extended not only around the mass lesion, but also to both sides of the pterygopalatine fossa, retromaxillary fat pad, trigeminal nerve V2, and the pterygoid canal (Fig. 2C). Furthermore, enhancement of the left V3 route with a prominent left trigeminal nerve ganglion was observed (Fig. 2A). These MRI findings were consistent with the clinical symptoms and suggested the presence of a malignant tumor in the CNS [12]. Since the abnormality of bilateral SMGs on physical examination was concurrently accompanied by MCN, lymphoma was the initial candidate for MCN etiology rather than metastatic cancer.

Fig. 2.

MRI and PET-CT images. (A) Abnormal enhancement in left jugular fossa with max standard uptake value of 3.4 (white arrow head) and (B) left V3 with prominent trigeminal nerve ganglion of value of 3.4 (yellow arrowhead) were observed on MRI and PET-CT. (C) Abnormal enhancement in both pteryopalatine fossa, both retromaxillary fat pad, and both pterygoid canal (D) with max standard uptake value of 3.4 (white arrows) were observed on MRI and PET. (E) Hypermetabolic lesions on both SMG (maxSUV=9.7) and right cervical lymph nodes (maxSUV=5.5) respectively. (F) Hypermetablic lesions were observed in the upper body greater curvature of stomach (maxSUV=2.3) and left axillary lymph nodes (yellow arrow). SMG, submandibular gland; maxSUV, maximum standard uptake value.

Brain and whole-body positron emission tomography-computed tomography (PET-CT) were conducted and revealed hypermetabolic lesions with a maximum standard uptake value (maxSUV) of 3.4 in the left jugular fossa, both sides of foramen ovale and pterygopalatine fossa, which were consistent with the abnormal enhancement detected on MRI (Fig. 2B and D). In addition, hypermetabolic lesions on bilateral SMGs with a maxSUV of 9.7 and adjacent right cervical lymph nodes with a maxSUV of 5.5 were also observed (Fig. 2E). Incidentally, hypermetabolic lesions were also detected in the upper body greater curvature of the stomach (maxSUV of 2.3) (Fig. 3B) and left axillary lymph nodes (maxSUV 2.3) (Fig. 2F). As the stomach is commonly involved in lymphoma, esophagogastroduodenoscopy (EGD) was immediately performed within the preparation period for SMG resection for biopsy [13]. On EGD, multiple erythematous patches were observed in the greater curvature of the stomach, which were consistent with the hypermetabolic lesions observed on PET, and punch biopsies were performed at that site (Fig. 3A). The following day, an excisional biopsy of the right SMG and neck lymph nodes was performed. During surgery, a firmly palpated SMG was found to be severely adhered to the surrounding tissue.

Fig. 3.

Esophagogastroduodenoscopy (EGD) and PET-CT images. A: Multiple erythematous patches were observed on EGD in the consistent location where abnormal findings were observed in PET and punch biopsy was done (arrowhead). B: Hypermetabolic lesion of stomach greater curvature was observed on PET-CT (arrow).

On hospital day 15, microscopic examination of the gastric specimen revealed diffuse infiltration of atypical tumor cells with pleomorphic nuclei, which disrupted the normal architecture of the gastric glands. The tumor cells were medium-to-large-sized with basophilic cytoplasm and irregular pleomorphic nuclei containing distinct nucleoli. Immunohistochemically, the tumor cells were positive for CD3 (Agilent Technologies, ApS, Glostrup, Denmark) but negative for CD20 (Agilent Technologies, ApS) and pan-cytokeratin (Agilent Technologies, Inc., Santa Clara, CA, USA). These findings were consistent with a diagnosis of T-cell lymphoma. In addition, the histological features of some tumor cells that showed lobulated, horseshoe-, or kidney-shaped nuclei suggested the possibility of ALCL (Fig. 4A). Due to the limited number of gastric tissue specimens and insufficient tumor cell burden, further evaluation of ALCL was conducted using consecutive excisional biopsy specimens from the right SMG. On microscopic examination of the SMG specimens, the histological findings were similar to those of the gastric specimens (Fig. 4B), and the tumor cells showed strong immunoreactivity for CD30 (Agilent Technologies, ApS) (Fig. 4C), epithelial membrane antigen (EMA) (Agilent Technologies, ApS), and CD5 (Leica Biosystems, Newcastle, UK). In addition to the histological finding of the presence of the so-called hallmark cells with horseshoe- or kidney-shaped nuclei, the immunohistochemical findings of the SMG specimen were compatible with the diagnosis of ALCL. Additional immunohistochemical staining for ALK and multiple polymerase chain reaction fragment analysis for monoclonality of the T-cell receptor gene confirmed the diagnosis of ALK-ALCL on hospital day 29. A bone marrow biopsy was performed on the iliac crest for staging. Histopathological examination showed no definite T-cell involvement in the bone marrow.

Fig. 4.

Microscopic findings. A: Medium to large-sized cells (white arrow) with multinucleated (white arrowhead) or horseshoe-shaped (yellow arrowhead) nuclei are observed in the gastric specimen (H&E, ×400). B: The same histopathologic findings are also observed in submandibular gland specimen (H&E, ×400). C: Immunohistochemical staining for CD30 reveals strong membranous and cytoplasmic staining in atypical cells (×400). H&E, hematoxylin and eosin.

Discussion

We diagnosed ALK-ALCL originating from T-cells, which has aggressive features and poor prognosis when involving the CNS [11]. The diagnosis of ALK-ALCL takes a relatively longer time, average of 40.5 days, when compared with other types of lymphoma, owing to its rarity [11]. However, the diagnostic period of ALK-ALCL could be shortened with detailed physical examinations at initial presentation, early imaging tests followed by biopsy, and meticulous histopathological review by an experienced pathologist.

Various etiologies, including autoimmune diseases, vascular diseases, neoplasms, and infections, can lead to MCN [1]. CSF analysis and MRI are usually recommended as initial tests to determine the etiology of MCN [1]. CSF analysis, which measures chemicals in the CSF using component analysis, cytology, immunohistochemistry, and flow cytometry, provides significant information for estimating the cause of MCN [14]. MRI is also instrumental in identifying abnormal structures in the CNS and assessing the extent of the disease [5]. CSF analysis results were normal in this patient. Therefore, various etiologies, including infection, autoimmune diseases, and hemorrhage could be ruled out [1]. Abnormal MRI findings, including abnormal mass lesions of the left jugular fossa with extensive enhancement of multiple structures, indicated CNS malignancy [15]. Simultaneous enlargement of the bilateral SMGs is a crucial clue for suspecting lymphoma as the etiology of MCN in this patient [16].

Evaluation of the metabolic status of CNS masses is important for estimating the possibility of malignancy, including lymphoma [15]. In addition, whole-body PET-CT provides significant information regarding the presence of abnormal hypermetabolic lesions in other parts of the body, which is essential for the staging work-up of malignancy [15]. Since CNS biopsy poses technical difficulties and can cause serious morbidity, biopsy at the extracranial site is safer and easier to perform, if possible [15]. Concomitant brain and whole-body PET-CT were crucial in determining the biopsy site, such as the SMG, in this patient. Furthermore, SMG resection, which is safer than CNS biopsy, provided sufficient specimens for diagnosis of the lymphoma subtype. In the process of lymphoma staging, attention to hypermetabolic lesions in the stomach is crucial because lymphoma most commonly involves the GI tract [13,15].

Consultation with an experienced pathologist is also important for rapid diagnosis of ALK-ALCL [3]. To the best of our knowledge, this is the first report of ALK-ALCL simultaneously involving the CNS, SMGs, and stomach. The initial suspicion of ALK-ALCL as a lymphoma subtype is difficult because of its rarity [11]. However, a strong suspicion of lymphoma based on physical examinations and imaging tests, coupled with active consultation with experienced pathologists can lead to the rapid identification of characteristic cells with horseshoe- or kidney-shaped nuclei in both specimens obtained from the stomach and SMG, resulting in a relatively early diagnosis of ALK-ALCL.

Although there are several reports of ALK-ALCL involving the CNS, only one case reporting lower cranial nerve paralysis caused by ALK-ALCL was identified in our literature review [11]. Additionally, there is only one case reporting ALK-ALCL arising from the salivary gland (parotid gland) [17]. Since this is the first report of simultaneous involvements of multiple cranial nerves, bilateral SMGs, and the stomach. However, when a variety of non-specific physical findings caused by ALK-ALCL are observed in the head and neck region, as in this patient, it is crucial to consider lymphoma as the primary etiology for an early diagnosis. In addition, detailed pathologic review with an experienced pathologist facilitates shortening the time for diagnosis.

In cases presenting with an atypical manifestation of MCN, lymphoma should be considered the primary etiology. ALK-ALCL is a very rare form of T-cell lymphoma, with no previous reports of the simultaneous involvement of the CNS, SMG, and stomach. We diagnosed ALK-ALCL, which usually takes a longer time to diagnose than other types of lymphomas, in a relatively short time through detailed physical examination, early imaging tests followed by biopsy, and meticulous histopathological review by experienced pathologists.

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