Delayed radionecrosis of the larynx

Delayed

Radionecrosis

Patrick J. Fitzgerald,

of the Larynx

MD, and R. James Koch, MD

Radiation has been used to treat carcinoma of the larynx for more than 70 years. Radionecrosis is a well-known complication of this modality when treating head and neck neoplasms. It has been described in the temporal bone, midface, mandible, and larynx. Laryngeal radionecrosis is manifested clinically by dysphagia, odynophagia, respiratory obstruction, hoarseness, and recurrent aspiration. The vast majority of patients who develop laryngeal radionecrosis present with these symptoms within 1 year of treatment; however, delayed presentations have been reported up to 25 years after radiotherapy. We present, in a retrospective case analysis, an unusual case of laryngeal radionecrosis in a patient who presented more than 50 years after treatment with radiotherapy for carcinoma of the larynx. The cases of delayed laryngeal necrosis in the literature are presented. This represents the longest interval between treatment and presentation in the literature. The details of the presentation, clinical course, and diagnostic imaging are discussed. The pathogenesis, clinical features, and treatment options for this rare complication are reviewed. Early stage (Chandler I and II) laryngeal radionecrosis may be treated conservatively and often observed. Late stage (Chandler III and IV) cases are medical emergencies, occasionally resulting in significant morbidity or mortality. Aggressive diagnostic and treatment measures must be implemented in these cases to improve outcome. This case represents the longest interval between initial treatment and presentation of osteoradionecrosis in the literature. A structured diagnostic and therapeutic approach is essential in managing this difficult problem. (Am J Otolaryngol1999;20:245-249. Copyright 0 1999 by W.B. Saunders Company)

comment: The authors report a rare but important and crippling complication of which every head and neck surgeon should be aware.)

(Editorial

With advances in radiation technology over the last 50 years, external-beam radiation has become a safe and effective treatment modality for certain stages of squamous cell carcinoma of the larynx. It is well known, however, that it causes temporary and occasionally permanent morbidity. Therapeutic radiation for squamous cell carcinoma of the larynx invariably produces some element of permanent laryngeal edema, cutaneous erythema, and injury to underlying vascular and lymphatic channels. Fortunately, in the majority of cases, the pathological changes leave no long-standing clinical sequellae. Occasionally, however, radiation-induced From the Division of Otolaryngology-Head and Neck Surgery, Stanford University Medical Center, Stanford, CA. Presented at the Meeting of the Western Section of the American Laryngological, Rhinological and Otological Society, Inc, San Diego, CA, January 11, 1998. Address reprint requests to Patrick J. Fitzgerald, MD, 15644 Pomerado Rd, Suite 105, Poway, CA 92064. Copyright o 1999 by W.B. Saunders Company 0196-0709/99/2004-0009$10.00/0 American

Journal

of Otolatyngology,

Vol20,

soft tissue injury may lead to permanent consequences. Severe radiation reactions after 5,000 to 6,000 rads to the larynx has reportedly decreased from 5% to l~%l,~ in 1970 to approximately 1% in the 1990s.3s4 It has been suggested, however, that there is an increasing frequency of postirradiation complications, most likely secondary to the current trends of treating advanced-stage laryngeal tumors with organ-sparing protocols.3 These protocols typically use high-dose radiotherapy and, when combined with preexisting cartilagenous invasion, act as a setup for postirradiation necrosis. The four main complications of radiation therapy for cancer of the larynx are (1) laryngeal edema, (2) skin damage, (3) perichondritis, and (4) cartilage necrosis.5 Patients manifest clinically with cutaneous erythema, weight loss, dysphagia, odynophagia, hoarseness, aspiration, airway obstruction, fetor, and fistula. In 1979, Chandler” described a grading system for radiation reactions occurring in the larynx (Table l).’ Grades I and II are expected side effects of radiation and do not require treatment. Grades III and IV are complications and may progress or become fatal despite aggresNo 4 (July-August),

1999:

pp 245249

245

246

FITZGERALD

TABLE 1.

Chandler

Classification

for Radiation

Reactions

in the Larynx Grade

0 I

II

Ill

IV

Symptoms

Sian

None Slight hoarseness, slight dryness Moderate hoarseness, moderate dryness Severe hoarseness, dyspnea, moderate odynophagia, and dysphagia Respiratory distress, severe pain, weight loss, dehydration, fever

Treatment

None Slight edema, telengiectasis

None None

Impairment of vocal cord mobility, moderate edema, and erythema Fixation of vocal cord, marked edema and skin changes

None

Steam, otics

Fistula, fetor oris, fixation of skin to larynx, airway obstruction

Cases

Author Robson and Dawes’ Kapur16 Berger et ali7 Fitzgerald5

of Delayed

Radiation

Injury

literature. The clinical presentation, graphic analysis, and histopathologic teristics are emphasized.

KOCH

radiocharac-

CASE REPORT In 1943, a 22-year-old external-beam radiotherapy

man was treated for an early-stage

with squa-

mous cell carcinoma of the larynx (dose unknown).

antibi-

Tracheotomy and/or laryngectomy

sive treatment measures. Although the vast majority of patients who develop these clinical symptoms present within the first year after treatment, delayed presentations have been reported up to 25 years (Table 2).7 Delayed radionecrosis applies to changes in the larynx that occur years after radiation. In this rare scenario, it is typical for the initial inflammatory reaction and cellular damage to subside and remain quiescent for a long period. During this phase, the patient is asymptomatic. The tissues sustain a stable state of relative ischemia, and the development to chondritis and necrosis may occur anytime thereafter. We present a case that shows the longest time interval between treatment and clinical presentation of laryngeal radionecrosis in the TABLE 2.

AND

He remained without evidence of disease and free of symptoms until 1996, when he presented to the Palo Veterans Hospital in acute respiratory distress. He had developed significant laryngeal edema, cutaneous erythema, hoarseness, and odynophagia over a s-day period after an upper respiratory infection. He was dyspneic at rest and had audible stridor. His temperature was 103.1'F. Flexible fiberoptic examination showed marked supraglottic edema, especially of the false vocal cords and arytenoids. He had significant anterior neck erythema and appreciable subcutaneous emphysema (Fig 1). He was admitted to the surgical intensive care unit for airway observation. Decadron and ceftriaxone were administered intravenously. Mist mask oxygen was delivered, and oxygen saturation levels were monitored closely. Sputum samples were obtained for aerobic, anaerobic, and timgal culture. The white blood cell count was 14.6 (103) (normal, 4.5 to 11) and the sedimentation rate was 86 mm/hr (normal, 0 to 20 mm/hr). Over the next 24 hours, his clinical condition markedly improved. A computed tomographic (CT) scan of the neck showed subcutaneous emphysema, periglottic edema, and dystrophic calcification of the thyroid cartilage on the right side (Fig 2). He was discharged on hospital day 12 receiving a tapering dose of oral steroids and ciprofloxacin. At the time of discharge, the sedimentation rate was 25. The patient did well for the next 3 months, until he experienced a recurrent episode. He again presented with voice alteration, cutaneous

to the Larynx

Year

No. of Patients

Age(s)* (Y)

Lengtht

Grade*

1961 1968 1983 1997

1 3 3 1

75 38,55,69 63,38,82 75

25 7,18,21 13,19,22 53

I I,IV,II lV,lV,lV Ill

*Age at the time of radionecrosis presentation. TLength in years from radiation treatment to presentation. *Chandler classification at time of presentation. gCurrent report.

Fig 1. Patient showing thema and subcutaneous neck (Chandler class III).

moderate emphysema

cutaneous etyof the anterior

DELAYED

RADIONECROSIS

OF THE

LARYNX

Fig 2. Axial CT showing right-sided glottic edema, irregular calcification patterns of the thyroid lamina, and extravasated air into the cervical soft tissues.

erythema, and subcutaneous emphysema. His airway was stable, and he was admitted to the surgical ward for monitoring. The sedimentation rate was 98. He again received intravenous steroids and antibiotics with improvement. A positron emission tomographic (PET) scan showed no focal uptake of tracer in the larynx. He was discharged on hospital day 15 receiving oral prednisone and clindamycin. He has remained without recurrence now with an 18-month follow-up.

DISCUSSION When a patient develops new-onset pain, laryngeal edema, and hoarseness months to a few years after radiation treatment to the larynx, the clinician must be suspicious of recurrent cancer. Radionecrosis in these situations becomes a diagnostic dilemma, and it is feared that repeat laryngeal biopsies may expedite present clinical demise. Patients will typically after a long asymptomatic period with voice alteration, sore throat, odynophagia, and weight loss. On examination, there is cutaneous erythema, laryngeal edema, ulceration, and often intraluminal cartilagenous exposure. In severe cases, there is vocal cord fixation, laryngeal stenosis, and airway obstruction. After an acute inflammatory reaction subsiding within weeks to a few months after treatment, the soft tissues of the larynx remain in a stable state of ischemia for a variable length of time. The mucus membranes of the larynx return to a normal appearance within 2 months; however, there is a tendency toward dryness, inflammatory exacerbations, and spasmodic

247

cough. Obstruction of lymphatic channels and increased vascular permeability lead to transient laryngeal edema.8 Hyperkeratosis and heaping up of the epithelium causing pseudotumor formation have also been described.g These effects are expected, and the patient can be reassured they will improve with time. Permanent histological effects can occur within the soft tissues of the neck with radiation doses as little as 1,200 rads.lO These can be progressive and initiate clinical symptoms many years after treatment. The ciliated epithelium of the larynx is highly susceptible to radiation, whereas the squamous epithelium is quite resistant. The most pronounced loss of ciliary function and goblet cell population seems to occur in the ventricles and false vocal cords.l” Histological analyses of human irradiated larynges have shown preservation of the architecture of the true vocal cords with marked fibrosis of the underlying submucosa, implying that damage to the submucosal venous plexus is primarily responsible for radiation-induced laryngeal edema. Skeletal muscle is highly resistant to radiation. In tumoricidal doses, however, the muscle can undergo atrophy, fatty degeneration, and fibrosis, leading to paralysis of the vocal cord. Perichondrium undergoes progressive degeneration of the nuclei and superficial degeneration. Infiltration of polymorphonuclear cells and lymphocytes eventually predisposes to aseptic necrosis. Factors that predispose to cartilage necrosis include infection, pretreatment tumor invasion, and trauma. It has been suggested that previous surgical intervention markedly increases the incidence of persistent postradiation edema and precipitates the development of cartilagenous necrosis.ll The arytenoid cartilages are most commonly involved. Bone becomes brittle, and the microarchitecture becomes irregular. Infection easily induces osteomyelitis and necrotic bone, which can act as a foreign body. Perhaps the most devastating effects of radiation injury occur within the vascular and lymphatic channels. Endothelium undergoes irreversible damage when exposed to just 1,200 rads.lO After early proliferation, the endothelium undergoes vacuolization and subsequent necrosis. This leads to obliteration of the capillaries, atrophy, and eventual fibrosis. At this stage, there is no possibility for regenera-

248

tion. These changes continue for months to many years after treatment and are most likely responsible for the late clinical presentations of laryngeal radionecrosis. The development of systemic illnesses that affect the vasculature, such as hypertension, atherosclerotic disease, and diabetes mellitus, probably contribute to progressive injury.ll Larger vessels, as well, undergo progressive fibrosis and weakening of the walls, predisposing to rupture from adjacent cartilagenous or osseous fragmentation. The diagnosis of radiation necrosis is made on clinical presentation and examination. Although radioimaging is often part of the workup, both CT and magnetic resonance imaging are not helpful in distinguishing between radionecrosis and recurrent tumor.12 It has been suggested that PET scanning may be beneficial in identifying occult malignancy in this situation. Greven et all3 showed in 11 patients that there were no false-negatives (none of five patients) and only one falsepositive (one of six patients). In early-stage reactions (grades I and II], a conservative trial of humidification and an anti-reflux regimen is usually effective. Regular examination, including fiberoptic visualization, is necessary to ensure progress and to detect early cancer recurrence. One should be cautious regarding overzealous biopsies in this group because this can predispose to a more advanced process.1,3 Uncomplicated grade III patients require the addition of oral steroids, sputum for culture and sensitivity, and appropriate antibiotics. Most of these patients will respond favorably. In 1979, Chandie? reported 13 cases of grade III radionecrosis treated with humidification and antibiotics, with clinical resolution in all of them. In persistent or recurrent cases, a longer course of medical management (6 weeks) is warranted. Some have advocated the use of PET scanning in this situation to detect occult malignancy.3 The role of hyperbaric oxygen therapy in this setting has not been determined, although several investigators have suggested beneficial effects.14 The nonresponsive grade III and grade IV patients present a challenging diagnostic and therapeutic problem for the otolaryngologist. The primary roles lie in airway preservation and support against overwhelming systemic

FITZGERALD

AND

KOCH

infection. Most patients presenting with grade IV laryngeal radionecrosis progress to either total laryngectomy or death from airway obstruction, major vessel rupture, or overwhelming necrosis and sepsis.1J~6~*1 Based on the severity of the situation, the patient is admitted for intravenous antibiotics, steroids, and oxygen saturation monitoring. If airway obstruction is present, a local tracheostomy is performed. Laryngeal endoscopy and biopsy is indicated to rule out malignancy. If biopsy results are positive, a laryngectomy should be performed. We recommend caution in the use of myocutaneous reconstruction at the same setting because recipient tissues are ischemic and colonized with pathogenic bacteria. PET scanning may be helpful in the setting of negative biopsy results. Some have advocated laryngectomy in the setting of positive PET scan and negative biopsy results, given early reports on its success in detecting occult carcinoma. Total laryngectomy is warranted in the setting of a nonfunctional, necrotic larynx despite the lack of histological evidence for carcinoma. Although the role of hyperbaric oxygen in late-stage radionecrosis is still being investigated, most clinical studies are very encouraging. In 1987, Ferguson et all treated four patients with grade IV laryngeal radionecrosis with hyperbaric oxygen. Two patients required temporary tracheostomy, and only one of the four patients required eventual laryngectomy. In the presence of occult carcinoma, however, there have been reports of rapid tumor progression while receiving hyperbaric oxygenation.15 It seems clear at the present time that hyperbaric oxygen therapy is beneficial in grade IV patients and may prevent total laryngectomy. Its role in grade III patients is less certain, but it may reduce hospital stays and costs and improve pain management. CONCLUSION Although the vast majority of patients with delayed laryngeal radionecrosis present with this problem within 1 year of radiation treatment, delayed presentations are possible because of progressive tissue ischemia over many years. The patient described in this report presented 53 years after treatment. There is a limited role for CT or magnetic

DELAYED

RADIONECROSIS

OF THE

LARYNX

resonance imaging in diagnosis; however, the use of PET scanning in detecting occult malignancy is promising. Grades I and II radionecrosis usually require only observational management. Grades III and IV require intensive medical management and close follow-up. Recalcitrant grade III and all grade IV cases should proceed to hyperbaric oxygenation and often require laryngectomy. REFERENCES 1. Ferguson BJ, Hudson WR, Farmer JC: Hyperbaric oxygen therapy for laryngeal radionecrosis. Ann Otol Rhino1 Laryngol96:1-6,1987 2. Stell PM, Morrison MD: Radiation necrosis of the larynx. Arch Otolaryngol98:111-113,1973 3. McGuirt WF: Laryngeal radionecrosis versus recurrent cancer. Otolaryngol Clin North Am 30:243-250, 1997 4. Oppenheimer RW, Krespi YP, Einhorn RK: Management of laryngeal radionecrosis: Animal and clinical experience. Head Neck 11:252-256,1989 5. Rowley H, Walsh M, McShane D, et al: Chondroradionecrosis of the larynx: Still a diagnostic dilemma. J Laryngol Otol109:218-220, 1995 6. Chandler JR: Radiation fibrosis and necrosis of the larynx. Ann Otol Rhino1 Laryngol88:509-514,1979 7. Robson FC, Dawes JDK: A case of perichondritis and necrosis of laryngeal cartilage 25 years after treatment with radium. J Laryngol 75:997-998, 1961

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8. Calceterra TC, Stern FS, Ward PH: Dilemma of delayed radiation injury of the larynx. Ann Otol Rhino1 Laryngol81:501-507,1972 9. Morrison R: Radiation therapy in diseases of the larynx. Br J Radio1 44:489-504,197l 10. Alexander FW: Micropathology of radiation reaction in the larynx. Ann Otol Rhino1 Laryngol 72:831-841, 1963 11. Keene M, Harwood AR, Bryce DP, et al: Histopathological study of radionecrosis in laryngeal carcinoma. Laryngoscope 92:173-180,198Z 12. Briggs RJS, Gallimore AP, Howard DJ: Laryngeal imaging by computerized tomography and magnetic resonance following radiation therapy: A need for caution. J Laryngol Otol107:565-568,1993 13. Greven KM, Williams DW III, Keyes JW, et al: Distinguishing tumor recurrence from irradiation sequelae with positron emission tomography in patients treated for larynx cancer. Int J Radiat Oncol 29:841-845, 1994 14. Feldmeier JJ, Heimbach RD, Davolt DA, et al: Hyperbaric oxygen as an adjunctive treatment for severe laryngeal necrosis: A report of nine consecutive cases. _ Undersea Hyperb Med 26329-335, 1993 15. Bradfield IT. Kinsella TB. Mader IT. et al: Rauid progression of head and neck squamous’carcinoma aher hyperbaric oxygenation. Otolaryngol Head Neck Surg 114:793-797,1996 16. Kapur TR: Late post-radiation changes in the larynx, pharynx, oesophagus and the trachea. J Laryngol Otol 82:447-457,1968 17. Berger G, Freeman JL, Briant DR, et al: Late postradiation necrosis and fibrosis of the larynx. J Otolaryngol 13:160-164,1984 I I .