Laryngeal Dysplasia: To Biopsy or Not?

Abstract

A renal transplant recipient with chronic hepatitis B underwent multiple laser excisions over 4 years for laryngeal keratosis. From the initial histopathology reports of mild to moderate dysplasia, a progression to squamous carcinoma was noted over 4 years. This case report highlights the possible role of immunosuppressants and hepatitis virus in the aetiopathogenesis of laryngeal carcinoma.

Introduction

Laryngeal dysplasia is a premalignant lesion from which laryngeal carcinoma develops [1]. The progression of laryngeal dysplasia to invasive carcinoma varies between 1.7 and 46.3% [2–4]. Therefore early clinical detection, excision biopsy of suspicious lesions and stringent follow up is mandatory. Immunosuppressive states such as post organ transplantation, or chronic infections like hepatitis, Human Immunodeficiency virus (HIV) have a higher chance of developing denovo malignancies [5].

Case Report

A 53 year old renal transplant recipient on immunosuppressants presented with hoarsness for a year. He was also on entecavir for chronic hepatitis B infection and isoniazid prophylaxis for latent pulmonary tuberculosis and had no history of tobacco or alcohol usage. A clinical diagnosis of laryngeal keratosis was made with the flexible laryngoscopic findings of keratotic lesions over the anterior third of both true vocal cords (TVC). Microlaryngeal surgery and excision biopsy was done and histopathology reported as mild to moderate dysplasia.

Patient was on regular follow up for the next 4 years with multiple laser excision biopsies done for all clinically suspicious lesions that kept cropping up. The biopsies over the first three years showed mild to moderate dysplasia. However in the fourth year, biopsy of the lesions over the anterior third of both cords involving anterior commissure revealed epithelial hyperplasia with low grade dysplasia (Fig. 1). Five months later excision biopsy of the lesion over the anterior third of both TVC, anterior commissure and subglottis was done (Fig. 2a). The lesion from the TVC revealed a progression to well differentiated squamous cell carcinoma {SCC)} (Fig. 2b), for which he was advised radiotherapy. However after 14 fractions radiotherapy, it had to be discontinued as he developed lobar pneumonia and type 1 respiratory failure. Subsequently he was also diagnosed with interstitial lung disease and the immunosuppressants (prednisolone and azathioprine) were hiked up and advised close monitoring  as the dose was to be tapered weekly, with a follow up imaging at the end of two months.

Fig. 1.

Mild grade dysplasia -Epithelial hyperplasia and keratosis with disordered maturation

Fig. 2.

a Pre-operative image-Keratotic lesion involving the supero-medial surface of the anterior two third of bilateral true vocal cords. b Invasive squamous cell carcinoma—Moderate nuclear pleomorphism, dyskeratosis, mitosis, keratin pearl formation, atypia

The patient however declined further treatment.

Discussion

The presence of dysplasia is the most important prognostic factor in considering risk of conversion to malignancy [4]. The transition from a normal epithelium to SCC of the larynx may be a lengthy, dynamic, and a rather unpredictable process ranging from no atypia, through varying degrees of atypia, to carcinoma in situ until finally breaching the basement membrane resulting in invasive carcinoma. It is not always that one can differentiate a premalignant lesion from a malignant lesion on physical examination. Solid organ recipients on chronic immunosuppression are at a higher risk for malignancy. Malignancy is the third most common cause of death among these patients, the first two being cardiovascular disease and infection. The average post-transplant time to develop cancer is 3 years and non-melanoma (squamous cell carcinoma) skin cancers are the most common ones. Factors contributing to denovo neoplasia include the chronic immunosuppressive drugs given after transplant, genetic predisposition to cancer, viral infection and pre- transplant dialysis [6].

It is hypothesized that immunosuppression weakens the immunological surveillance mechanism and thus promotes cancer development. However, experimental evidence has shown that even immunocompetent host are incapable of sequestering immunologically escaped tumours. Thus considering these two contradictory statements,one must assume that in non-virus-induced tumors, non-immunologic surveillance mechanisms such as DNA repair and the induction of p53-dependent apoptosis of cancer cells might be more important [5].

Azathioprine is believed to affect carcinogenesis by intercalation at the DNA level, inhibiting repair, splicing and eliciting codon misreads. It also produces microsatellite DNA instability and the development of myelodysplastic syndrome [6]. Herman et al. studied the effect of cyclosporine and azathioprine on DNA repair and found that inhibition of DNA repair is significantly lower in Cyclosporine treated peripheral blood mononuclear cells and in kidney transplanted patients than azathioprine [5].

A study by Song et al. [7] reported a 59% higher incidence of oral cancer among HBsAg seropositive patients. The study also found 6 other cancer sites (aerodigestive tract, lung, kidney, skin (squamous cell carcinoma), thyroid gland, and leukemia) which were at an increased risk among individuals with Hepatitis B infection. A prevalence of 5.9% HBsAg sero-positivity among head and neck cancer patients compared to 3.3% among controls has been reported. Similar to hepatitis C virus and human papilloma virus having a synergistic role towards the development of oropharyngeal malignancy, hepatitis B virus too could play a role in head and neck cancers [8].

The investigation of choice for a keratotic lesion on the vocal cord is videostroboscopy as the increased mass and stiffness at the site of early cancer can impair the mucosal wave. Irrespective of the grade of dysplasia a long term close follow up is needed. At the earliest sign of growth or progression the lesion should be biopsied. Multiple biopsies from different sites may be necessary to establish the true nature of the lesion. Spielmann et al. [9] have proposed discontinuation of follow up after 3 years if mild to moderate dysplasia show no progression to carcinoma. But, in this patient malignant transformation occurred in the fourth year of follow up. In a review of case series and meta-analysis by Weller and colleagues [2], the overall mean time to malignant transformation was 5.8 years.

Consensus statement by Otorhinolaryngologists and pathologists published in 2010 proposed a follow up in the same manner as T1 laryngeal carcinoma for high risk patients. The high risk patients included those with severe dysplasia or carcinoma in situ, mild or moderate dysplasia with smoking, hoarseness and lesion on endoscopy. A monthly follow up for the first year, two monthly for the second year, three monthly in the third year and six monthly in years 4 and 5. Low risk patients should be followed up for a minimum period of six months [10].

Conclusion

Transformation of dysplastic lesions to malignancy is highly unpredictable with no correlation with the grade of dysplasia. Chronic immunosuppressive agents may have a contribution to the development of malignancies. Hence a stringent follow up with regular biopsies of suspicious lesions ensure early detection of a malignant lesion especially in a patient on immunosuppression.

Compliance with Ethical Standards

Conflict of interest

The author declares that they have no conflict of interest.

Ethics Approval

For case report our institution policy does not require ethics approval.

Research Involving Human Participants and/or Animals

The submitted manuscript is a descriptive narration of the management of a case and does not involve human participants and or/animals research.

Informed Consent

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