Clinical relevance of hyponatraemia in olfactory neuroblastoma

Sir,

Olfactory neuroblastoma (ONB) is a rare malignant tumour of the nose and paranasal sinuses1. Majority of the affected patients typically present with gradually progressive nasal obstruction with or without epistaxis. Rarely, ONB secretes aberrant peptides, leading to corresponding paraneoplastic manifestations, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH) that produces severe hyponatraemia2. The estimated prevalence rate of SIADH in ONB is around two per cent, although the true prevalence is likely to be more2. As per several reports, in around 50 per cent of ONB cases that had SIADH, the diagnosis of SIADH preceded the diagnosis of ONB by several months to few years, and the cause for SIADH in those cases who had no sinonasal symptoms was attributed to other conditions or was considered idiopathic until the manifestations and the diagnosis of ONB2,3. The practical implication of this observation is that in any case of SIADH without an attributable cause, the treating physician might have to consider cross-sectional imaging of the nose and paranasal sinuses to rule out ONB4-6. Furthermore, in a diagnosed case of ONB with SIADH, the serum sodium levels could play a role in predicting the disease clearance surgically, and could be used as a marker of the disease status during the post-therapeutic surveillance2,7. However, so far the evaluation of the association between ONB and SIADH for the above-discussed clinical applications is limited. Besides, to our knowledge, no research has analyzed the relationship between the SIADH (in ONB) and the patient-related or disease-related clinicopathological predictors. Hence, this study was aimed to explore the association of SIADH in ONB cases, and to understand the clinical relevance of SIADH in predicting disease clearance (and its role in post-therapy surveillance).

This was a retrospective study conducted at the division of Head and Neck Surgery, department of Otorhinolaryngology, Kasturba Medical College, Manipal, a tertiary care hospital and cancer centre located in southern part of India. After obtaining approval from the Institute Ethical Committee (IEC-852/2020), the medical records of ONB cases presented at our institute between September 2017 and August 2020 were retrieved. The study was carried out between December 2020 and May 2021.

A total of seven patients were presented to our department during the study period. Their demographical characteristics, clinical manifestations and management details are summarized in Table I, and the serial serum sodium levels of all these cases are tabulated temporally in the Figure. Of the seven patients included in this study, four had hyponatraemia at the time of diagnosis of ONB. In all these cases, the hyponatraemia was non-responsive to conventional corrective measures such as fluid restriction, hypertonic saline and pharmacotherapy. Moreover, in one of these cases with a significant intracranial extension and raised intracranial tension, the hyponatraemia was severe, affecting the patient’s higher mental functions. However, only one of the four SIADH patients received curative-intent treatment at our hospital in the form of radical excision by craniofacial surgery, followed by radiotherapy. One of the other patient underwent complete treatment elsewhere but was available for follow up. The serum levels improved immediately after the surgery in both these patients and remained within the normal limit during subsequent follow up.

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Figure

Line diagram showing the serum sodium values at the time of diagnosis and subsequent follow up.

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On analyzing the association of pre-treatment hyponatraemia with the clinicopathological factors descriptively, a positive trend was apparent with respect to the age of the patient at the time of diagnosis and the duration of symptoms before the diagnosis, but not with the gender and the stage of the disease. Of the four patients with hyponatraemia, three were below 40 years of age (75%), and only one was in the seventh decade of life. Except for the latter, all other patients in this series who were aged more than 40 yr had normal sodium levels. As for the duration of illness, all four cases who had pre-treatment hyponatraemia had the symptoms for four or more months before being diagnosed with ONB (100%), and all those with a shorter symptomatic period had no hyponatraemia. Despite the absence of statistical support, these peculiar observations imply that the paraneoplastic manifestation of ONB in the form of SIADH is common among young patients and in those with long standing diseases.

To further validate our findings, we reviewed the literature in Pubmed, for all published cases of SIADH associated with ONB over the past 10 yr (Jan 2012 - May 2021), and the findings from these studies are tabulated in Table II. Interestingly, except for a case published by Gabbay et al2, none of the other reports published in this decade reported a patient aged above 40 yr, supporting our hypothesis that the association of SIADH in ONB is mostly prevalent among young patients. With respect to the duration of symptomology, in several of these published reports, the symptom of SIADH preceded the diagnosis of ONB by several years, suggesting the long duration of association between SIADH and ONB6,8.

Another important finding in the current study was that the SIADH secondary to secretary ONB was non-responsive to conventional corrective measures, and could only be corrected by an adequate disease clearance in the form of an appropriate locoregional surgery. As depicted in Table II, the reviewed literature also aligned with this observation, as the resolution of hyponatraemia (that was otherwise resistant to conventional therapeutic measures) was observed only after a successful excision of the ONB in those published cases. Interestingly, in all those reports, and in two of our patients who underwent a curative intent treatment, the cessation of natriuresis and normalization of serum osmolality and serum sodium levels were quite dramatic and occured immediately after the complete excision of tumour, way before the adjuvant treatment could even be initiated (Table II). The persistence of hyponatraemia post-surgery could be attributed to the continued production of hormonal peptides from the residual tumour cells, and accordingly, it has to be interpreted as a probable sign of incomplete clearance of malignant disease2,7. In other words, the post-operative sodium level could serve as a reliable marker of surgical efficacy in ONB cases associated with SIADH. In such cases with persisting hyponatraemia postoperatively, the treating team can contemplate re-imaging, and possibly re-surgery whenever applicable. Furthermore, in patients who had SIADH secondary to ONB, the post-surgery serum sodium levels could aid in decision-making regarding the appropriate adjuvant treatment. While the adjuvant treatment in the form of radiotherapy is known to prolong the overall survival in ONB, and should be offered to all those eligible patients irrespective of the serum sodium levels, it may be clinically appropriate to consider chemotherapy in addition to the adjuvant radiotherapy in those with persisting hyponatraemia post surgery15.

Finally, in two of the patients who underwent curative surgery in the present study, the serum sodium levels were within the normal limits during the subsequent follow up, corresponding to the absence of locoregional disease on clinic-radiological evaluation. In one another patient who was put on palliative treatment, the hyponatraemia persisted with the progression of the disease. In line with our results, all of those previous studies (Table II) that had measured serum sodium levels during the post-treatment surveillance also reported a positive correlation between the serum sodium levels and disease state. These findings suggest a simple and reliable alternative for disease surveillance after surgery in the form of serum sodium levels, rather than protocols such as serial radiology that not only add to the financial burden but could also expose the patients to a significant dose of radiation unnecessarily3,12. In general, during the follow up of an already treated case of ONB with resolved SIADH, a new onset hyponatraemia is a likely sign of recurrence of the disease, and such a case should be worked up accordingly, with appropriate radiological investigations. Interestingly, the utility of serum sodium levels for the post therapeutic surveillance of ONB might not be of value in those patients who did not manifest with hyponatraemia before the definitive treatment, as in patient 7 in Table I.

This retrospective study was limited by the small sample size and loss of follow up of the two patients who had hyponatraemia associated with ONB. However, to ensure non-bias and representativeness, we have included all those consecutive patients of ONB who were encountered during the study period, and have included the parameters from all these patients for evaluating the clinicopathological associations of SIADH. However, for the prognostic ability of serum sodium levels, only those with SIADH who had received treatment were considered. Nevertheless, the trends presented here, backed by the relevant literature review, should aid decision making for clinicians and researchers handling the ONB cases, and could pave the way for further larger and prospective studies, as well as high-quality reviews.

To conclude, the association of hyponatraemia with ONB tends to prevail mostly in young patients, and could have diagnostic and prognostic significance. In addition, serum sodium levels could be a simple and reliable predictor of surgical clearance of the disease, and recurrence of the disease during post-therapeutic surveillance. Although further studies are necessary to generate high quality evidence that could substantiate our results, the available evidence does show a positive trend and support its utility in clinically appropriate contexts.