Department of ORL, Head and Neck Surgery andDepartment of ORL, Head and Neck Surgery andDiagnostic Interventional and Pediatric RadiologyDiagnostic Interventional and Pediatric RadiologyDiagnostic, Interventional and Pediatric Radiology, Diagnostic, Interventional and Pediatric Radiology, University Hospital Bern, SwitzerlandUniversity Hospital Bern, Switzerland

R t T i th LR t T i th LRecurrent Tumor in the LarynxRecurrent Tumor in the Larynxand Hypopharynx after (Chemo)radiation:and Hypopharynx after (Chemo)radiation:

Clinical and Histopathological AspectsClinical and Histopathological Aspects

P Zbaeren H ThoenyP Zbaeren H ThoenyP. Zbaeren, H. ThoenyP. Zbaeren, H. Thoeny

Background

With the onset of new chemotherapy regimens, py gnew treatment strategies for advanced carcinomas were developed: combined chemoradiotherapy, concomitant

ti lor sequential

Currently, many T3 and even T4 carcinomas are initiallyCurrently, many T3 and even T4 carcinomas are initially treated by chemoradiotherapy while primary total laryngectomies are becoming rare

As recurrent laryngeal carcinomas are increasingly being treated by voice preservation salvage surgery a precisetreated by voice-preservation salvage surgery, a precise diagnostic work-up is currently mandatory.

Spirano et al Head Neck 2002

Yiotakis et al Ortolaryngol Head Neck Surg 2003

Questions

Do tissue changes - observed on imaging studies or during endoscopies - correspond to sequelaeor during endoscopies - correspond to sequelae

of (chemo)radiation or are they due to tumor recurrence?tumor recurrence?

How is the reliability of imaging studies and endoscopies in the assessment of recurrent

disease extent?

Grading system for radiation reactions

Chandler JR Ann Otol Rhinol Laryngol 1979

Endoscopic findings

Endoscopic findings

Definition Chondroradionecrosis

Histologic characteristicsHistologic characteristics

► Lack of perichondrium► Lack of perichondrium

►Cartilage erosion►Cartilage erosion

►Severe inflammation►Severe inflammationAbscesses

►Destroyed cartilage with sequestrationwith sequestration

Imaging findings of radionecrosis

Cricoarytenoid sclerosis

Anterior dislocation and sloughing of the arytenoidsAnterior dislocation and sloughing of the arytenoids

P f b bblPresence of gas bubbles

Fragmentation and collapse of cartilages

Hermans et al Am J. Neurolradiol 1998

Imaging findings of radionecrosis

Radionecrosis versus recurrent disease

Patients

Radiation or radiochemotherapy 341

Symptoms suggestive of tumor recurrence

92recurrence

Tumor recurrence found by imagingTumor recurrence found by imaging studies and endoscopy with biopsy

72

No tumor recurrence 20

Zbaeren et al Otolaryngol Head Neck Surg 2006

Patients

Study group

20 patients with symptoms suggestive20 patients with symptoms suggestive of recurrence but without evidence of recurrence on initial imaging studiesrecurrence on initial imaging studies

and endoscopy

Methods

Retrospective studyRetrospective study

Analysis of clinico-pathologic findings, a ys s o c co pat o og c d gs,diagnostic work-up and treatment modalities

Tumor staging according the UICC 1997 classificationthe UICC 1997 classification

Laryngectomy specimes were analyzed on whole organ slices

Symptoms

Increase of dysphonia with progessive dyspnoea 20

Respitarory distress needing tracheotmy 12

Severe dysphagia 4

Acute laryngeal hemorrhage 2

Pharyngocutaneous fistula 1

L t fi t l 1Laryngocutaneous fistula 1

Imaging findings

CT scan 40CT scan 40

MR imaging 11

Fi di T iti f 3Findings True positive for recurrence 3

False positive 1False positive 1

True negative 13True negative 13

False negative 3False negative 3

True negative for recurrenceTrue negative for recurrence

Results Imaging studies

14.10.01 13.01.02

True positive for recurrence

True negative for recurrence

Endoscopic findings and biopsies

Endoscopies with biopsies 40

Marked edema with severe occlusionof airways needing a tracheotomy 12

Denuded bone or cartilage or sequesters 5

Ulceration without denuded bone or cartilage 2

Pathologic tissue suggesting tumor recurrence 2

Results Biopsies

Biopsies performed during 40 endoscopies 40

Positive biopsies (during 2nd or 3rd endoscopy) 4Positive biopsies (during 2nd or 3rd endoscopy) 4

Negative biopsies 36

Reccurences in laryngectomy specimens 6y g y p

Incidence of chondroradionecrosis

Chondroradionecrosis in laryngectomy specimens

10

Cartilage sequester 2

(Patients with tracheotomies)2

Frank fragmentation of cartilage

(Patients with tracheotomies)3

Total 17Total 17

Summary

In case of recurrent or progressive symptomsIn case of recurrent or progressive symptoms such as hoarseness, dysphagia and dyspnea, repeated imaging studies and endoscopiesrepeated imaging studies and endoscopies must be performed, as

in about 22% of cases it may be difficult to differentiate between persistent or recurrentdifferentiate between persistent or recurrent tumor and severe radiation effects

In a few cases a total laryngectomy must be performed despite repeated negative biopsiesperformed despite repeated negative biopsies

Questions

Do tissue changes - observed on imaging studies or during endoscopies - correspond to sequelaeor during endoscopies - correspond to sequelae

of (chemo)radiation or are they due to tumor recurrence?tumor recurrence?

How is the reliability of imaging studies and endoscopies in the assessment of recurrent

disease extent?

To understand the difficulty in assessingTo understand the difficulty in assessing the extent of recurrent carcinoma, one

must know the histologicmust know the histologic characteristics and tumor spread of

recurrent carcinomasrecurrent carcinomas

Histologic characteristics and tumor spread of recurrent glottic carcinomasecu e t g ott c ca c o as

Aim of the studyy

T l th tt f t dTo analyze the pattern of tumor spread

To compare the growth patternTo compare the growth pattern of pr T3 / pr T4 (n=21) carcinoma with that of de novo“ p T3 / p T4 carcinoma (n=52)of „de novo p T3 / p T4 carcinoma (n=52)

Zbaeren et al Head Neck 2007

Patients

Initial (chemo)radiation ofcT1 /cT2 N0 glottic carcinoma 168cT1 /cT2 N0 glottic carcinoma 168

Recurrence 32(19%)Recurrence 32(19%)

Total or classical partialTotal or classical partial salvage laryngectomy 29

pr T1 / pr T2 8pr T1 / pr T2 8pr T3 / pr T4 21

Results

Multicentric foci

Salvage Laryngectomy17/21 (81%)

„De novo“ Laryngectomy15/52 (23%)( ) ( )

Results

Dissociated tumor cellsDissociated tumor cells

Salvage Laryngectomy16/21 (76%)

„De novo“ Laryngectomy15/52 (33%)15/52 (33%)

Results

Subglottic and supraglottic tumor extensions

Results

Perineural infiltration

Salvage Laryngectomy17/21 (81%)17/21 (81%)

„De novo“ Laryngectomy„ y g y28/52 (54%)

Results

Pattern of cartilage infiltrationSalvage Laryngectomy „De novo“

Laryngectomy

Summary

Recurrent glottic carcinomas present withRecurrent glottic carcinomas present with multiple tumor foci dispersed in different

regions of the larynxregions of the larynx

Assessment of recurrent tumor extent

H i th li bilit f tiHow is the reliability of preoperative imaging studies and clinical and

d i i ti i th tendoscopic examination in the assessment of the extent and staging of

t l l i ?recurrent laryngeal carcinomas?

Assessment of recurrent tumor extent

Aim of the study

T l th f th

Aim of the study

To analyze the accuracy of the preoperative imaging studies and endoscop in the assessment ofendoscopy in the assessment of recurrent laryngeal carcinomas

Patients

R di ti di h th 241Radiation or radiochemotherapy 241

Tumor recurrence 60

Excluded from the study 18Excluded from the study 18

no appropriate histology 9

no appropriate imaging studies 9no appropriate imaging studies 9

Included in the study 42

Patients N = 42

Initial TInitial TT1a 9

T1b 5

T2 18

T3 10

Initial tumor locationInitial tumor locationGlottic level 15

Supraglottic level 8Supraglottic level 8

Glottosupraglottic levels 8

Glottosubglottic levels 5Glottosubglottic levels 5

Transglottic 6

Patients N = 42

Treatment of rec rrent t morTreatment of recurrent tumor

Total laryngectomy 37

Supraglottic laryngectomy 3p g y g y

Supracricoid laryngectomy 2Supracricoid laryngectomy 2

Methods

Retrospective studyRetrospective study

The laryngectomy specimens were analyzed onThe laryngectomy specimens were analyzed on axial whole-organ slices

The CT scans (n=25) or MR imaging (n=17) i d b t i d di l i twere reviewed by two experienced radiologists

Th d i d i i fi diThe endoscopic and imaging findings were compared with histologic findings

Methods

The follo ing items ere anal edThe following items were analyzed

► T t i di t th l l► Tumor extension according to the levels

► Contralateral tumor spread► Contralateral tumor spread

► Cartilage infiltration

► Preepiglottic space

► Paraglottic space

► T l ifi ti► crT classification

Results

Histopathologic analysis

Glottic carcinoma 2

Supraglottic carcinoma 7

Glottosupraglottic carcinoma 4Glottosupraglottic carcinoma 4

Glottosubglottic carcinoma 7

Transglottic carcinoma 22

Contralateral tumor spread 36Contralateral tumor spread 36

Results

Histopathologic analysis

Preepiglottic space 16

Tumor involvement of the

Preepiglottic space 16

Paraglottic space 29

Thyroid cartilage 25

Cricoid cartilage 17Cricoid cartilage 17

Arytenoid cartilage 16

Results

Imaging findings

Accuracy Sensitivity Specificity

Preepiglottic space 83 59 100Preepiglottic space 83 59 100

Paraglottic space 60 73 25

Thyroid cartilage 64 48 88

Cricoid cartilage 65 47 80g 65 47 80

Arytenoid cartilage 86 62 95

C t l t l t dContralateral tumor spread 52 50 67

Tumor at this level?

Results

Endoscopic findings

correctover- under-

correctestimated estimated

Involved levels 22 (52%) 4 1522 (52%) 4 15

Contralateral tumor spread

22 (52%)tumor spread

Results

crT pT

T1 1 3T1 1 3

T2 6 4

T3 27 13

T4 7 22

Accuracy 50%y

Overclassification 3

Underclassification 18Underclassification 18

Discussion

Recurrent tumor assessment is difficult forRecurrent tumor assessment is difficult for the following reasons:

► T ft di ti th i► Tumor may recur after radiation therapy in multicentric foci, undetectable by imaging studies

► Residual inflammation changes associated with radiation therapy

► Tumor recurrence may be localized submucosally – invisible during endoscopyy g py

► Differentiation between radionecrosis and tumor recurrence often not obvious

Zbären Head and Neck 2007Zbären Otolaryngol Head Neck 2007

recurrence often not obvious

Discussion

Comparison with assessment of de novo

C i idTh id

Comparison with assessment of de novo laryngeal carcinoma

De novoRe-

current

Cricoid

De novoRe-

current

Thyroid

MRICT

current

MRICT

current

83

88

100

92

47

65

62

83

95

72

48

64

Sensitivity

Accuracy

90

83

87

100

80

47

97

62

56

95

88

48

Specificity

Sensitivity

Becker Radiology 1995; 194: 661 -669 Zbären Cancer 1996; 77: 1263-73

Summary

In many cases, the assessment of tumor t i i i t ith b dextension is inaccurate either by endoscopy or

by imaging studies

The assessment of recurrent laryngealThe assessment of recurrent laryngeal carcinoma is much more difficult than the assessment of «de novo» carcinoma either byassessment of «de novo» carcinoma either by endoscopy or by imaging studies

New imaging modalities

PET - CT

For all negative PET scans (n=27), the Teerhard 2001

PET CT

g ( ),biopsies taken were negative and no recurrence was seen for at least 1 year thereafterthereafter

In 7 patients PET did not confirm the recurrence, which was suspected clinically and by CT scan

Périé 2007

clinically and by CT scan

Terhaard CH. Head Neck 2001Périé S. Otolaryngol Head Neck Surg 2007

New imaging modalities

Male 60 yearsPET - CTMale 60 years

2000 cT2 glottic - supraglottic carcinoma treated by chemoraditherapychemoraditherapy

2007 Pain and progressive dysphagia

New imaging modalities

Diffusion - weighted MRI

Male 54 years

1991 cT2 glottic carcinoma treated by radiation

1999 recurrent disease rT3 treated by

supracricoid larygectomy

2007 progressive dysphonia and dyspnoe

b=1000 ADC map

New imaging modalities

Female 52 yearsDiffusion - weighted MRIFemale 52 years

2004 cT2 hypopharyngeal carcinoma treated by CO2 - laser - resection and adjuvant radiationj

2007 Pain and dysphagie

New imaging modalities

Institutional experienceInstitutional experience

Diffusion - weighted MRI 12

true positive findings 5

f l iti fi di 1false positive findings 1

true negative findings 6

Conclusions

CT scan and conventional MR imaging cannot differentiate between recurrence and tissue changes

due to (chemo) radiotherapy in many casesdue to (chemo) radiotherapy in many cases

M d di ti d liti h PET CTModern diagnostic modalities such as PET - CT and diffusion - weighted MR imaging are

promising diagnostic toolspromising diagnostic tools

To impro e the q alit of ork pTo improve the quality of work - upprospective studies are needed

Endoscopic findings

Patients

Radiation or radiochemotherapy 341ad at o o ad oc e ot e apy 3

L l i 237Laryngeal carcinomas 237Hypopharyngeal carcinomas 104

T1/T2 272T3/T4 69

Conclusions

To improve the assessment of recurrent plaryngeal carcinomas,

prospective studies comparing the p p p gendoscopic and imaging findings with whole-organ sections of laryngectomy g y g y

specimens should be performed

Patients

Radiation or radiochemotherapy 341ad at o o ad oc e ot e apy 3

L l i 237Laryngeal carcinomas 237Hypopharyngeal carcinomas 104

T1/T2 272T3/T4 69

Background

T1 d T2 l l d h h l iT1 and T2 laryngeal and hypopharyngeal carcinomas can be managed either by organ-sparing surgery or by radical radiotherapyradical radiotherapy

With the onset of new chemotherapy regimens, y gnew treatment strategies for advanced carcinomas were developed: combined chemoradiotherapy, concomitant

ti lor sequential

Currently many T3 and even T4 carcinomas are initiallyCurrently, many T3 and even T4 carcinomas are initially treated by chemoradiotherapy while primary total laryngectomies are becoming rarey g g

Background

Salvage surgery after irradiation was historically id d t b ibl l ith t t l l tconsidered to be possible only with total laryngectomy,

wherefore the knowledge of an exact tumor extension was not requiredwas not required.

As recurrent laryngeal carcinomas are increasingly beingAs recurrent laryngeal carcinomas are increasingly being treated by voice-preservation salvage surgery, a precise diagnostic work-up is currently mandatory.diagnostic work up is currently mandatory.

Spirano et al Head Neck 2002

Yiotakis et al Ortolaryngol Head Neck Surg 2003

Conclusions

All patients with symptoms suggestive of tumor recurrence but negative on initial work-up presentedrecurrence but negative on initial work-up presented

finally with documented radionecrosis or Chandler IV radiation reaction

Recurrent carcinoma is not always visible on endoscopy. Therefore biopsies

b f l timay be false negative

Patients

Surgical treatment Total laryngectomy 10Surgical treatment Total laryngectomy 10

Tracheotomy 10Tracheotomy 10

Results Biopsies

Biopsies performed during 40 endoscopies 40

Positive biopsies (during 2nd or 3rd endoscopy) 4p ( g py)

Negative biopsies 36

Total laryngectomy with positive biopsies 4

Total laryngectomy despite repeated negative biopsies

6

Radionecrosis versus recurrent disease

Aim of the study

To analyze the incidence and diagnostic difficultiesand diagnostic difficulties of chondroradionecrosisafter (chemo)radiotherapy

Zbaeren et al Otolaryngol Head Neck Surg 2006

Incidence of chondroradionecrosis

Chondroradionecrosis in laryngectomy specimens

10+2

Cartilage sequester 2

(Patients with tracheotomies)2

Frank fragmentation of cartilage

(Patients with tracheotomies)3

Total 17/341 (5%)Total 17/341 (5%)

Results Endoscopic findings

fMarked edema with severe occlusion of airways

Patients

Surgical treatment Total laryngectomy 10Surgical treatment Total laryngectomy 10

Total laryngectomy with positive biopsies 4y g y p p

Total laryngectomy despite repeated negative biopsies

6biopsies