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J Korean Dysphagia Soc 2022; 12(1): 64-69

Published online January 30, 2022 https://doi.org/10.34160/jkds.2022.12.1.008

© The Korean Dysphagia Society.

Atypical Dysphagia in an Anti-Hu Positive Non-Small-Cell Lung Cancer Patient

Inah Kim, M.D.1, Jeana Kim, M.D., Ph.D.2, Hee Yeon Lee, M.D., Ph.D.3, Geun Young Park, M.D., Ph.D.4, Sang Ah Jeong, M.D.4, Hyemi Hwang, M.D.4, Sun Im, M.D., Ph.D.4

1Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Hospital Pathology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 3Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 4Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to:Sun Im, Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon 14647, Korea
Tel: +82-32-340-2170, Fax: +82-32-340-2173, E-mail: lafolia@catholic.ac.kr

Received: June 15, 2021; Revised: June 16, 2021; Accepted: August 19, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Anti-Hu antibodies usually present in small cell lung cancer are associated with encephalomyelitis, encephalitis, cerebellitis, and neuropathies. However, to our knowledge, non-small-cell lung cancer (NSCLC) related anti-Hu syndrome presenting acute exacerbation of dysphagia has not been reported. Herein, we report a rare case of atypical dysphagia in an anti-Hu positive NSCLC patient resulting in a fatal outcome. A 73-year-old Korean male went through surgical interventions for recurrent tongue cancer and NSCLC. After the surgery, he resumed full oral feeding with a regular diet. However, four weeks later, he developed a sudden difficulty in swallowing. Neck computed tomography angiography, brain magnetic resonance imaging, brain positron emission tomography, computed tomography and electromyography all showed nonspecific findings. A paraneoplastic antibody test was positive for anti- Hu antibodies. His dysphagia worsened and eventually, he expired due to malignant pleural effusion. Our case shows that anti-Hu antibodies can be expressed in NSCLC and when associated with dysphagia, the outcome can be fatal.

Keywords: Deglutition disorders, Paraneoplastic syndromes, Carcinoma, Non-small-cell lung

Anti-Hu antibody is frequently detected in multiple cancers, especially in small cell lung cancer (SCLC) and cause neurological paraneoplastic syndromes, inclu-ding cerebellar ataxia, limbic encephalitis, Lambert–Ea-ton syndrome, polyradiculopathy, opsoclonus-myo-clo-nus syndrome, and most commonly, paraneoplastic sen-so-ry neuropathy1. Expression of Hu antigen in non- small-cell lung cancer (NSCLC) is rarely reported and cases associated with dysphagia has not been reported. In this case report, we report a rare case of anti-Hu paraneoplastic syndrome in NSCLC that manifested as rapidly progressive dysphagia. In this study, information pertinent to patient’s personal identification were not included. This case report was waived for informed consent due to the retrospective nature of the case.

A 73-year-old male was referred to the department of rehabilitation medicine for the evaluation of dysphagia. He had multiple medical comorbidities including hypertension, dyslipidemia, coronary artery disease and atrial flutter. Two years prior, he had been diagnosed with squamous cell carcinoma of the tongue and had gone through right partial glossec-tomy, followed by radiation therapy. At that time, he had not experienced any major swallowing difficulties as an aftereffect. Five months prior to our visit, he underwent near total glossectomy due to recurrence of tongue cancer. After the operation the patient resumed regular diet. However, 4 weeks after opera-tion, aspiration symptoms suddenly developed. Aspi-ration pneumonia occurred and consequently he received percutaneous endoscopic gastrostomy. At the same time, lung cancer in positron emission tomography-computed tomography (PET-CT) was found with biopsy results indicating a double primary cancer of poorly differentiated squamous cell carci-noma in left upper lobe of lung, which is one of the main subtypes of NSCLC.(Fig. 1) In the fiberoptic endoscopic evaluation of swallowing with ice chip and liquid protocol, premature spillage of liquid into the vallecular space was noted. Also, no laryngeal elevation motion was detected. Despite the patient’s effort to initiate swallowing, no pharyngeal trigger was observed. Aspiration with weak coughing was shown.(Fig. 2) His videofluoroscopic swallowing study (VFSS) confirmed pharyngoesophageal passage diffi-culty, very poor pharyngeal stripping waves and im-paired pharyngeal wall contraction.(Fig. 3) Laryngeal motion was significantly impaired and overflow aspiration without coughing reflex was observed. These findings did not correlate with the surgical procedures that mainly involved the oral cavities. Head and neck computed tomography angiography, brain magnetic resonance imaging and PET-CT all showed no evidence of occult brain or head and neck lesions that may explain for patient’s swallowing difficulty.(Fig. 4, 5) Results of nerve conduction study/needle electromyography showed no evidence of peripheral neuropathy, myopathy or neuromuscular junction disorder. Serum study of paraneoplastic antibody was positive for anti-Hu antibodies with borderline positive titer between 7 and 14. Despite swallowing rehabilitation, the patient showed pro-gressive rapid deterioration of dysphagia in two months in following instrumental swallowing tests. A follow-up titer showed further elevation of anti-Hu antibodies. Soon after, his medical condition rapidly deteriorated with chest computed tomography showing increased size of lung mass. The patient expired nine months later due to aspiration pneumonia and com-plications related to malignant pleural effusion.

Figure 1. Hematoxylin and eosin stained lung biopsy shows poorly differentiated squamous cell carcinoma in left upper lobe (asterisk). (A) Magnification ×20. (B) Magni-fication ×100.

Figure 2. Fiberoptic endoscopic evaluation of swallowing with ice chip and liquid protocol shows saliva pooling of moderate degree with saliva aspiration past glottis.

Figure 3. Videofluoroscopic swallowing study confirmed pharyngoesophageal passage difficulty, very poor pharyngeal stripping waves and impaired pharyngeal wall contraction. Laryngeal motion was significantly impaired and overflow aspiration without coughing reflex was observed. 

Figure 4. T2-weighted brain magnetic resonance images in the axial view (A, B) show no acute lesion or neurodegenerative change.

Figure 5. Brain dopamine transporter (DAT) imaging with positron emission computed tomography shows normal DAT activity in bilateral striata.

We experienced an unusual case of anti-Hu paraneoplastic syndrome related to NSCLC; poorly differentiated squamous cell carcinoma; presenting as atypical dysphagia. The Hu antigens are a family of nuclear proteins normally expressed in all neurons of the central/peripheral nervous system. The presence of antibodies against Hu proteins in paraneoplastic syndromes is associated with destruction of parts of the nervous system and with relative control of growth of the underlying tumor2. Hu antigen is almost exclusively present in neuronal tissue, but may ectopically be expressed by cancer cells, especially in small-cell lung cancer3. Expression of Hu antigen by the tumor triggers an immune response that is misdirected against similar proteins expressed in brain4.

The exact mechanism on how anti-Hu syndrome may lead to swallowing difficulty is unknown. Fujimoto, et al. reported a case of SCLC with high titer of anti-Hu antibodies who developed a tonic left pupil and multiple cranial nerve palsies, including palsies of the left fifth through tenth nerves and both twelfth nerves presenting dysphagia5. Saiz, et al. reported that among 22 patients with positive anti-Hu antibodies, definite paraneoplastic sensory neurono-pathy, clinical presentation compatible with brainstem involvement and tumor diagnosis, a medullary syndrome was seen in 11 patients and 7 of them presented with dysphagia, dysarthria and central hypoventilation6. It could be presumed that anti-Hu antibody that attacks proteins similar to Hu antigen expressed in cranial nerve IX or X, may have caused dysphagia in our patient. This is in accordance to the VFSS features that showed functional impairment of the pharyngeal stages.

Anti-Hu antigen is known to be selectively expressed in SCLC. In SCLC, anti-Hu antibody may rarely result in dysphagia but the prognosis is reported to be favorable1. There are two unusual presentations of our case that deserves attention, first; anti-Hu antibodies was related to NSCLC and not to SCLC, second; as dysphagia aggravated, medical condition deteriorated with worsened dyspnea with an increase in titer of anti-Hu antibody. This is in sharp contrast to the protective roles suggested in some studies1. Ni, et al. reported that patients with SCLC and positive anti-Hu antibodies showed tendency to respond better to therapy and live longer than cancer patients who did not possess anti-Hu antibodies1,11,13,14. Furthermore, SCLC patients with anti-Hu antibody-associated para-neoplastic sensory neuropathy showed extraordinary long-term survival1,11,14.

In our case, we concluded that the fast deterio-rating nature of dysphagia might have been related to a rare presentation of anti-Hu paraneoplastic syndrome, since other possible causes were excluded. In general, dysphagia associated with cancer often results from direct invasion or metastasis of tumor into the brain. In our case, a structural lesion of the pharyngeal area that may affect airway protection and pharyngeal passage was excluded. Moreover, atypical features of dysphagia in our case could not be explained by post-operative changes alone. The patient had resumed oral diet immediately after the operation. Also, the operation site only involved the oral structure with sparing of the pharyngeal structures. Sudden aggravation 4 weeks after the glossectomy and increased titer of anti-Hu antibody as the deterioration of swallowing progressed were supplying arguments. In fact, Rihani, et al. reported that tongue atrophy occurs in patients who underwent total glossectomy with reconstruction, leading to gradual decrease in swallowing function over time10. This is quite different from the dysphagia patterns of our patient. Also, the patient did not have any swallowing problems after the first and the second glossectomy. Therefore, one may cautiously postulate that the rapid aggravation of dysphagia may have been related to paraneoplastic syndrome related to anti-Hu antibody. Until now, only limited studies have shown dysphagia to present in anti-Hu syndrome6,7 and this is the first case report to show its relation to NSCLC.

Some limiting factors need to be considered in this study. First, it took several weeks for the final results to be confirmed and unfamiliarity of anti-Hu para-neoplastic syndrome led to a delay in diagnosis. Even though atypical features of dysphagia that did not match with patient’s surgical site were detected in swallowing tests, the paraneoplastic antibody studies were performed only after exclusion of other causes, such as stroke or movement disorder. Second, our case did not show any evidence of neuronopathy, one of the typical symptoms of anti-Hu syndrome. However, this does not draw doubts about anti-Hu syndrome in our case, since there are cases when anti-Hu antibody was present and yet no evidence of neuropathy. Some reports have shown that 13% of these Anti-Hu could present with no neuropathy8. According to Kazarian, et al., 16-25% of SCLC pa-tients without paraneoplastic neurological autoim-mune syndromes have detectable titers of anti-Hu antibodies in their serum9. In fact, the involvement of the cranial nerve can be confirmed through laryngeal electromyography. Nevertheless, it was not testable in our patient due to severe medical deterioration. However, the involvement of the cranial nerves was suspected in this patient by the absence of laryngeal elevation and pharyngeal trigger in fiberoptic endoscopic evaluation of swallowing. Lastly, radiation therapies might have had a delayed effect on dysphagia. However, the first radiotherapy was confined to the tumor bed (60 Gy/30 Fxs), and the second one was confined to the flap area and IV-Vb lymphatics in the left neck (50 Gy/28 Fxs). The radiation dosage and extent may have been too limited to have involved the posterior pharyngeal muscles or hyoid muscles. In fact, it is known that the risk of fibrosis increases with irradiation dose, particularly after total doses exceeding 70 Gy12. Moreover, our patient did not show definite passage difficulty due to stricture in pharyngeal or esophageal phases, which is commonly found in radiotherapy-induced dysphagia. Also, radiation-induced dysphagia manifests with insidious onset with a more chronic clinical course. Despite the accumulation effects of the radiation therapies cannot be completely ruled out, it is unlikely to have been the main cause of swallowing dysfunction considering the acute deteriorating nature as seen in this case. According to our knowledge, our case is one of the few rare cases of anti-Hu positive paraneoplastic syndrome related to NSCLC presen-ting as atypical dysphagia.

In conclusion, our case suggests that anti-Hu antibody related paraneoplastic syndrome in NSCLC may be related to fatal dysphagia. In contrast to the protective roles seen in SCLC, the contrasting detrimental effects in NSCLC should alert clinicians to its aggressive clinical course. To better understand and manage these medically complex patients, more research is warranted on the exact mechanism of Hu antigen and its role in NSCLC leading to dysphagia.


No potential conflict of interest relevant to this article was reported.


Conceptualization: Kim IA, Im S.

Writing-original draft: Kim IA, Kim JA, Im S.

Writing-review & editing: Kim IA, Im S, Lee HY, Jeong SA, Park GY, Hwang HM.

Approval of final manuscript: All authors.

  1. Ni J, Weng L, Liu M, Yang H, Wang Y. Small Cell Lung Cancer Accompanied by Tonsillar Metastasis and Anti-Hu Antibody-Associated Paraneoplastic Neuropathy: A Rare Case Report With Long-Term Survival. Medicine (Baltimore). 2015;94:e2291.
    Pubmed KoreaMed CrossRef
  2. Hammam T, McFadzean RM, Ironside JW. Anti-hu paraneoplastic syndrome presenting as bilateral sixth cranial nerve palsies. J Neuroophthalmol. 2005;25:101-104.
    Pubmed CrossRef
  3. Raskin J, Masrori P, Cant A, Snoeckx A, Hiddinga B, Kohl S, et al. Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody. Lung Cancer. 2017;109:74-77.
    Pubmed CrossRef
  4. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol. 1992;141:881-886.
    Pubmed KoreaMed
  5. Fujimoto S, Kumamoto T, Ito T, Sannomiya K, Inuzuka T, Tsuda T. A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies. Clin Neurol Neurosurg. 2002;104:98-102.
    Pubmed CrossRef
  6. Saiz A, Bruna J, Stourac P, Vigliani MC, Giometto B, Grisold W, et al. Anti-Hu-associated brainstem encephalitis. J Neurol Neurosurg Psychiatry. 2009;80:404-407.
    Pubmed CrossRef
  7. Yeung JC, Pringle CE, Sekhon HS, Kilty SJ, Macdonald K. Bilateral Vocal Cord Paralysis and Cervicolumbar Radi-culopathy as the Presenting Paraneoplastic Manifesta-tions of Small Cell Lung Cancer: A Case Report and Literature Review. Case Rep Otolaryngol. 2016;2016:2868190.
    Pubmed KoreaMed CrossRef
  8. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-- associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore). 1992;71:59-72.
    Pubmed CrossRef
  9. Kazarian M, Laird-Offringa IA. Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer. 2011;10:33.
    Pubmed KoreaMed CrossRef
  10. Rihani J, Lee T, Ducic Y. Secondary onlay free flap reconstruction of glossectomy defects following initial successful flap restoration. Otolaryngol Head Neck Surg. 2013;149:232-234.
    Pubmed CrossRef
  11. Ni J, Weng L, Liu M, Yang H, Wang Y. Small Cell Lung Cancer Accompanied by Tonsillar Metastasis and Anti- Hu Antibody-Associated Paraneoplastic Neuropathy: A Rare Case Report With Long-Term Survival. Medicine (Baltimore). 2015;94:e2291.
    Pubmed KoreaMed CrossRef
  12. Jacques B, Harry K, Henk S, Augustinus H, Joop D, Joos L, et al. Dose and volume effects on fibrosis after breast conservation therapy. Int J Radiation Oncology biol Phys. 1994;30:1073-1081.
    Pubmed CrossRef
  13. Graus F, Dalmou J, Ren˜e' R, et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol. 1997;15:2866-2872.
    Pubmed CrossRef
  14. Poepel A, Jarius S, Heukamp LC, et al. Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome. J Neurol Sci. 2007;263:145-148.
    Pubmed CrossRef

Article

Case Report

J Korean Dysphagia Soc 2022; 12(1): 64-69

Published online January 30, 2022 https://doi.org/10.34160/jkds.2022.12.1.008

Copyright © The Korean Dysphagia Society.

Atypical Dysphagia in an Anti-Hu Positive Non-Small-Cell Lung Cancer Patient

Inah Kim, M.D.1, Jeana Kim, M.D., Ph.D.2, Hee Yeon Lee, M.D., Ph.D.3, Geun Young Park, M.D., Ph.D.4, Sang Ah Jeong, M.D.4, Hyemi Hwang, M.D.4, Sun Im, M.D., Ph.D.4

1Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Hospital Pathology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 3Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 4Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to:Sun Im, Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon 14647, Korea
Tel: +82-32-340-2170, Fax: +82-32-340-2173, E-mail: lafolia@catholic.ac.kr

Received: June 15, 2021; Revised: June 16, 2021; Accepted: August 19, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Anti-Hu antibodies usually present in small cell lung cancer are associated with encephalomyelitis, encephalitis, cerebellitis, and neuropathies. However, to our knowledge, non-small-cell lung cancer (NSCLC) related anti-Hu syndrome presenting acute exacerbation of dysphagia has not been reported. Herein, we report a rare case of atypical dysphagia in an anti-Hu positive NSCLC patient resulting in a fatal outcome. A 73-year-old Korean male went through surgical interventions for recurrent tongue cancer and NSCLC. After the surgery, he resumed full oral feeding with a regular diet. However, four weeks later, he developed a sudden difficulty in swallowing. Neck computed tomography angiography, brain magnetic resonance imaging, brain positron emission tomography, computed tomography and electromyography all showed nonspecific findings. A paraneoplastic antibody test was positive for anti- Hu antibodies. His dysphagia worsened and eventually, he expired due to malignant pleural effusion. Our case shows that anti-Hu antibodies can be expressed in NSCLC and when associated with dysphagia, the outcome can be fatal.

Keywords: Deglutition disorders, Paraneoplastic syndromes, Carcinoma, Non-small-cell lung

INTRODUCTION

Anti-Hu antibody is frequently detected in multiple cancers, especially in small cell lung cancer (SCLC) and cause neurological paraneoplastic syndromes, inclu-ding cerebellar ataxia, limbic encephalitis, Lambert–Ea-ton syndrome, polyradiculopathy, opsoclonus-myo-clo-nus syndrome, and most commonly, paraneoplastic sen-so-ry neuropathy1. Expression of Hu antigen in non- small-cell lung cancer (NSCLC) is rarely reported and cases associated with dysphagia has not been reported. In this case report, we report a rare case of anti-Hu paraneoplastic syndrome in NSCLC that manifested as rapidly progressive dysphagia. In this study, information pertinent to patient’s personal identification were not included. This case report was waived for informed consent due to the retrospective nature of the case.

CASE REPORT

A 73-year-old male was referred to the department of rehabilitation medicine for the evaluation of dysphagia. He had multiple medical comorbidities including hypertension, dyslipidemia, coronary artery disease and atrial flutter. Two years prior, he had been diagnosed with squamous cell carcinoma of the tongue and had gone through right partial glossec-tomy, followed by radiation therapy. At that time, he had not experienced any major swallowing difficulties as an aftereffect. Five months prior to our visit, he underwent near total glossectomy due to recurrence of tongue cancer. After the operation the patient resumed regular diet. However, 4 weeks after opera-tion, aspiration symptoms suddenly developed. Aspi-ration pneumonia occurred and consequently he received percutaneous endoscopic gastrostomy. At the same time, lung cancer in positron emission tomography-computed tomography (PET-CT) was found with biopsy results indicating a double primary cancer of poorly differentiated squamous cell carci-noma in left upper lobe of lung, which is one of the main subtypes of NSCLC.(Fig. 1) In the fiberoptic endoscopic evaluation of swallowing with ice chip and liquid protocol, premature spillage of liquid into the vallecular space was noted. Also, no laryngeal elevation motion was detected. Despite the patient’s effort to initiate swallowing, no pharyngeal trigger was observed. Aspiration with weak coughing was shown.(Fig. 2) His videofluoroscopic swallowing study (VFSS) confirmed pharyngoesophageal passage diffi-culty, very poor pharyngeal stripping waves and im-paired pharyngeal wall contraction.(Fig. 3) Laryngeal motion was significantly impaired and overflow aspiration without coughing reflex was observed. These findings did not correlate with the surgical procedures that mainly involved the oral cavities. Head and neck computed tomography angiography, brain magnetic resonance imaging and PET-CT all showed no evidence of occult brain or head and neck lesions that may explain for patient’s swallowing difficulty.(Fig. 4, 5) Results of nerve conduction study/needle electromyography showed no evidence of peripheral neuropathy, myopathy or neuromuscular junction disorder. Serum study of paraneoplastic antibody was positive for anti-Hu antibodies with borderline positive titer between 7 and 14. Despite swallowing rehabilitation, the patient showed pro-gressive rapid deterioration of dysphagia in two months in following instrumental swallowing tests. A follow-up titer showed further elevation of anti-Hu antibodies. Soon after, his medical condition rapidly deteriorated with chest computed tomography showing increased size of lung mass. The patient expired nine months later due to aspiration pneumonia and com-plications related to malignant pleural effusion.

Figure 1. Hematoxylin and eosin stained lung biopsy shows poorly differentiated squamous cell carcinoma in left upper lobe (asterisk). (A) Magnification ×20. (B) Magni-fication ×100.

Figure 2. Fiberoptic endoscopic evaluation of swallowing with ice chip and liquid protocol shows saliva pooling of moderate degree with saliva aspiration past glottis.

Figure 3. Videofluoroscopic swallowing study confirmed pharyngoesophageal passage difficulty, very poor pharyngeal stripping waves and impaired pharyngeal wall contraction. Laryngeal motion was significantly impaired and overflow aspiration without coughing reflex was observed. 

Figure 4. T2-weighted brain magnetic resonance images in the axial view (A, B) show no acute lesion or neurodegenerative change.

Figure 5. Brain dopamine transporter (DAT) imaging with positron emission computed tomography shows normal DAT activity in bilateral striata.

DISCUSSION

We experienced an unusual case of anti-Hu paraneoplastic syndrome related to NSCLC; poorly differentiated squamous cell carcinoma; presenting as atypical dysphagia. The Hu antigens are a family of nuclear proteins normally expressed in all neurons of the central/peripheral nervous system. The presence of antibodies against Hu proteins in paraneoplastic syndromes is associated with destruction of parts of the nervous system and with relative control of growth of the underlying tumor2. Hu antigen is almost exclusively present in neuronal tissue, but may ectopically be expressed by cancer cells, especially in small-cell lung cancer3. Expression of Hu antigen by the tumor triggers an immune response that is misdirected against similar proteins expressed in brain4.

The exact mechanism on how anti-Hu syndrome may lead to swallowing difficulty is unknown. Fujimoto, et al. reported a case of SCLC with high titer of anti-Hu antibodies who developed a tonic left pupil and multiple cranial nerve palsies, including palsies of the left fifth through tenth nerves and both twelfth nerves presenting dysphagia5. Saiz, et al. reported that among 22 patients with positive anti-Hu antibodies, definite paraneoplastic sensory neurono-pathy, clinical presentation compatible with brainstem involvement and tumor diagnosis, a medullary syndrome was seen in 11 patients and 7 of them presented with dysphagia, dysarthria and central hypoventilation6. It could be presumed that anti-Hu antibody that attacks proteins similar to Hu antigen expressed in cranial nerve IX or X, may have caused dysphagia in our patient. This is in accordance to the VFSS features that showed functional impairment of the pharyngeal stages.

Anti-Hu antigen is known to be selectively expressed in SCLC. In SCLC, anti-Hu antibody may rarely result in dysphagia but the prognosis is reported to be favorable1. There are two unusual presentations of our case that deserves attention, first; anti-Hu antibodies was related to NSCLC and not to SCLC, second; as dysphagia aggravated, medical condition deteriorated with worsened dyspnea with an increase in titer of anti-Hu antibody. This is in sharp contrast to the protective roles suggested in some studies1. Ni, et al. reported that patients with SCLC and positive anti-Hu antibodies showed tendency to respond better to therapy and live longer than cancer patients who did not possess anti-Hu antibodies1,11,13,14. Furthermore, SCLC patients with anti-Hu antibody-associated para-neoplastic sensory neuropathy showed extraordinary long-term survival1,11,14.

In our case, we concluded that the fast deterio-rating nature of dysphagia might have been related to a rare presentation of anti-Hu paraneoplastic syndrome, since other possible causes were excluded. In general, dysphagia associated with cancer often results from direct invasion or metastasis of tumor into the brain. In our case, a structural lesion of the pharyngeal area that may affect airway protection and pharyngeal passage was excluded. Moreover, atypical features of dysphagia in our case could not be explained by post-operative changes alone. The patient had resumed oral diet immediately after the operation. Also, the operation site only involved the oral structure with sparing of the pharyngeal structures. Sudden aggravation 4 weeks after the glossectomy and increased titer of anti-Hu antibody as the deterioration of swallowing progressed were supplying arguments. In fact, Rihani, et al. reported that tongue atrophy occurs in patients who underwent total glossectomy with reconstruction, leading to gradual decrease in swallowing function over time10. This is quite different from the dysphagia patterns of our patient. Also, the patient did not have any swallowing problems after the first and the second glossectomy. Therefore, one may cautiously postulate that the rapid aggravation of dysphagia may have been related to paraneoplastic syndrome related to anti-Hu antibody. Until now, only limited studies have shown dysphagia to present in anti-Hu syndrome6,7 and this is the first case report to show its relation to NSCLC.

Some limiting factors need to be considered in this study. First, it took several weeks for the final results to be confirmed and unfamiliarity of anti-Hu para-neoplastic syndrome led to a delay in diagnosis. Even though atypical features of dysphagia that did not match with patient’s surgical site were detected in swallowing tests, the paraneoplastic antibody studies were performed only after exclusion of other causes, such as stroke or movement disorder. Second, our case did not show any evidence of neuronopathy, one of the typical symptoms of anti-Hu syndrome. However, this does not draw doubts about anti-Hu syndrome in our case, since there are cases when anti-Hu antibody was present and yet no evidence of neuropathy. Some reports have shown that 13% of these Anti-Hu could present with no neuropathy8. According to Kazarian, et al., 16-25% of SCLC pa-tients without paraneoplastic neurological autoim-mune syndromes have detectable titers of anti-Hu antibodies in their serum9. In fact, the involvement of the cranial nerve can be confirmed through laryngeal electromyography. Nevertheless, it was not testable in our patient due to severe medical deterioration. However, the involvement of the cranial nerves was suspected in this patient by the absence of laryngeal elevation and pharyngeal trigger in fiberoptic endoscopic evaluation of swallowing. Lastly, radiation therapies might have had a delayed effect on dysphagia. However, the first radiotherapy was confined to the tumor bed (60 Gy/30 Fxs), and the second one was confined to the flap area and IV-Vb lymphatics in the left neck (50 Gy/28 Fxs). The radiation dosage and extent may have been too limited to have involved the posterior pharyngeal muscles or hyoid muscles. In fact, it is known that the risk of fibrosis increases with irradiation dose, particularly after total doses exceeding 70 Gy12. Moreover, our patient did not show definite passage difficulty due to stricture in pharyngeal or esophageal phases, which is commonly found in radiotherapy-induced dysphagia. Also, radiation-induced dysphagia manifests with insidious onset with a more chronic clinical course. Despite the accumulation effects of the radiation therapies cannot be completely ruled out, it is unlikely to have been the main cause of swallowing dysfunction considering the acute deteriorating nature as seen in this case. According to our knowledge, our case is one of the few rare cases of anti-Hu positive paraneoplastic syndrome related to NSCLC presen-ting as atypical dysphagia.

In conclusion, our case suggests that anti-Hu antibody related paraneoplastic syndrome in NSCLC may be related to fatal dysphagia. In contrast to the protective roles seen in SCLC, the contrasting detrimental effects in NSCLC should alert clinicians to its aggressive clinical course. To better understand and manage these medically complex patients, more research is warranted on the exact mechanism of Hu antigen and its role in NSCLC leading to dysphagia.

CONFLICT OF INTEREST


No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS


Conceptualization: Kim IA, Im S.

Writing-original draft: Kim IA, Kim JA, Im S.

Writing-review & editing: Kim IA, Im S, Lee HY, Jeong SA, Park GY, Hwang HM.

Approval of final manuscript: All authors.

Fig 1.

Figure 1.Hematoxylin and eosin stained lung biopsy shows poorly differentiated squamous cell carcinoma in left upper lobe (asterisk). (A) Magnification ×20. (B) Magni-fication ×100.
Journal of the Korean Dysphagia Society 2022; 12: 64-69https://doi.org/10.34160/jkds.2022.12.1.008

Fig 2.

Figure 2.Fiberoptic endoscopic evaluation of swallowing with ice chip and liquid protocol shows saliva pooling of moderate degree with saliva aspiration past glottis.
Journal of the Korean Dysphagia Society 2022; 12: 64-69https://doi.org/10.34160/jkds.2022.12.1.008

Fig 3.

Figure 3.Videofluoroscopic swallowing study confirmed pharyngoesophageal passage difficulty, very poor pharyngeal stripping waves and impaired pharyngeal wall contraction. Laryngeal motion was significantly impaired and overflow aspiration without coughing reflex was observed. 
Journal of the Korean Dysphagia Society 2022; 12: 64-69https://doi.org/10.34160/jkds.2022.12.1.008

Fig 4.

Figure 4.T2-weighted brain magnetic resonance images in the axial view (A, B) show no acute lesion or neurodegenerative change.
Journal of the Korean Dysphagia Society 2022; 12: 64-69https://doi.org/10.34160/jkds.2022.12.1.008

Fig 5.

Figure 5.Brain dopamine transporter (DAT) imaging with positron emission computed tomography shows normal DAT activity in bilateral striata.
Journal of the Korean Dysphagia Society 2022; 12: 64-69https://doi.org/10.34160/jkds.2022.12.1.008

References

  1. Ni J, Weng L, Liu M, Yang H, Wang Y. Small Cell Lung Cancer Accompanied by Tonsillar Metastasis and Anti-Hu Antibody-Associated Paraneoplastic Neuropathy: A Rare Case Report With Long-Term Survival. Medicine (Baltimore). 2015;94:e2291.
    Pubmed KoreaMed CrossRef
  2. Hammam T, McFadzean RM, Ironside JW. Anti-hu paraneoplastic syndrome presenting as bilateral sixth cranial nerve palsies. J Neuroophthalmol. 2005;25:101-104.
    Pubmed CrossRef
  3. Raskin J, Masrori P, Cant A, Snoeckx A, Hiddinga B, Kohl S, et al. Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody. Lung Cancer. 2017;109:74-77.
    Pubmed CrossRef
  4. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol. 1992;141:881-886.
    Pubmed KoreaMed
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