- Email: [email protected]
Ten-year retrospective study of head and neck carcinoma in situ: incidence, treatment, and clinical outcome
Vol. 116 No. 2 August 2013
Ten-year retrospective study of head and neck carcinoma in situ: incidence, treatment, and clinical outcome A. Christensen, MD,a E. Kristensen, MD,b M.H. Therkildsen, MD, DMSc,b L. Specht, MD, DMSc,c J. Reibel, DrOdont,d and P. Homøe, MD, DMSca Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark and School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Objectives. To examine the management and clinical outcome for patients with primary head and neck carcinoma in situ (CIS) and to estimate the incidence in the referral population. Study design. A retrospective study from 2000-2009 of patients with head and neck CIS referred for treatment at Rigshospitalet. The referral area was East Denmark and Greenland with a population of 2.4 million. Results. Fifty-five patients with primary CIS were identified: 21 oral cavity, 7 pharynx, 25 larynx, 2 nasal cavity/paranasal sinuses. The median annual incidence was 0.24/100,000. Eleven patients (20%) had T-site recurrence. The 5-year diseasespecific survival rate and 5-year recurrence-free survival rate were 98% and 74% respectively. Conclusions. The annual incidence of primary head and neck CIS was low and in accordance with previous findings reported in the literature. We recommend that CIS lesions should be treated on T-site and surveilled as T1/T2 head and neck carcinomas. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:174-178)
Head and neck carcinoma in situ (CIS) is a rare diagnosis and our knowledge about this entity is limited. Former studies from the US and Germany have shown annual incidence rates of primary head and neck CIS between 0.14-1.8/100,000.1-4 These studies also included CIS lesions on lip where sun exposure, as opposed to the mucosa-associated CIS lesions, is a key risk factor in the pathogenesis. The diagnosis is based on cytological and architectural changes in the epithelium of the upper aerodigestive tract. A CIS lesion is defined as a full-thickness dysplasia in the viable cell layers of the epithelium. Invasion is not present.5 Therefore regional metastases from true CIS lesions do not occur. CIS represents an in dependent entity in the spectrum of histopathological changes in the epithelium from mild dysplasia to invasive carcinoma. Different classification systems for head and neck precancerous lesions have been evaluated and recommended in the past.6 The World Health Organization classification system has been widely accepted and is a 4-step system with the categories mild, moderate and severe dysplasia and CIS.5 The consistency of grading systems has been a
Department of Otolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital. b Department of Pathology, Rigshospitalet, Copenhagen University Hospital. c Department of Oncology, Rigshospitalet, Copenhagen University Hospital. d Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, School of Dentistry, Faculty of Health Sciences, University of Copenhagen. Received for publication Dec 4, 2012; returned for revision Feb 14, 2013; accepted for publication Mar 3, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.03.002
174
extensively debated and inter-observer and intraobserver variation may affect the accuracy of the histopathological diagnosis.7 From a clinical point of view a classification system should be able to stratify lesions according to malignant potential and facilitate the decision making in the management of the disease. Tumor models suggest a biological process of sequential intermediate stages from healthy epithelium over mild and moderate dysplasia to CIS and finally carcinoma.8 It is widely accepted that some precursor lesions progress to carcinoma and that the degree of dysplasia is a prognosticator for progression to cancer.9,10 This study aimed to examine the management, patterns of recurrence, and clinical outcome in our center for patients with head and neck CIS and to estimate the incidence in the referral population.
MATERIALS AND METHODS The study population included patients with microscopically confirmed primary head and neck CIS referred for treatment in a 10-year period from 2000-2009. The referral area was East Demark and Greenland where the treatment of head and neck cancer is centralized at Rigshospitalet. Exclusion criteria were prior head and neck cancer, lymphoma, skin cancer, cancer of unknown
Statement of Clinical Relevance The annual incidence of primary head and neck CIS was low (0.24/100,000). The recurrence rate was 20% and the recurrences were mainly T1 or T2 carcinomas. CIS lesions should be treated on T-site and surveilled as T1/T2 carcinomas.
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ORIGINAL ARTICLE Christensen et al. 175
Table I. Distribution of recurrences in subgroups and recurrence rate. Recurrence defined as recurrence at the same anatomical location as the primary CIS lesion after primary therapy Anatomical location Total Larynx Oral cavity Pharynx Nasal/paranasal
Recurrence rate (%) (n/N) 20 16 29 14 0
(11/55) (4/25) (6/21) (1/7) (0/2)
primary or metastatic disease in head and neck. Lesions at the labial vermilion were also excluded. If the diagnosis of the lesion was changed to cancer within 2 months after the CIS diagnosis, the patient was also excluded to minimize the risk of sampling error. Patients with a histopathological CIS diagnosis were searched in the Danish National Pathology Register where all pathology reports have been registered since 1985. A search was also made in the pathology registers of the Danish Head and Neck Cancer Group and of the School of Dentistry in Copenhagen. The histopathological diagnosis was based on microscopy of H&E stained sections from formalin-fixed, paraffin embedded tissue. Data were collected from chart reviews, and patient characteristics, diagnosis, treatment, recurrence and death from head and neck cancer or other diseases were recorded. The primary treatment modality was chosen by the ENT specialist based on resectability and clinical presentation of the CIS lesion, findings during surgery and histopathological findings in biopsies or resection specimens. Patients were seen after treatment for periodic annual or midannual clinical control in an ENT or Oncology department. The identified lesions were divided into anatomical subgroups: Oral cavity, pharynx, larynx, and nasal/paranasal sinuses. If the original specimen was available, a confirmatory microscopy was performed by a pathologist (E.K. and M.H.T.). A clear margin was defined as >5 mm distance from the CIS lesion to the surrounding tissue with histological normal epithelium with no dysplasia. A recurrence was defined as CIS or carcinoma at the same anatomical site as the primary CIS lesion. At recurrence tumors were classified according to the Tumor-nodesmetastasis (TNM) classification from International Union Against Cancer (UICC) (2005). Statistical analyses were performed using STATA 11.0 (STATA Corp. Lp, College Station, TX, USA). Survival analysis was calculated by the KaplaneMeier method. Comparisons of groups were performed by Log rank test, Chi-square test or one-way analysis of variance. For all tests significance was 2-sided and set to P < .05 and 95% confidence intervals (CI) were applied. Incidence rates were calculated pr. 100,000 persons based on the average of the population size in 2000 and 2009 in the referral area (www.dst.dk, www.statgreen.gl). The study
Malignant transformation rate (%) (n/N) 18 16 24 14 0
(10/55) (4/25) (5/21) (1/7) (0/2)
Median progression time (months) 28 range (4-56) 22 range (4-50) 29 range (11-55) 28 e
was approved by the local ethical committee and the Danish Data Registry.
RESULTS A total of 55 patients with primary CIS were identified: 21 oral cavity, 7 pharynx, 25 larynx, 2 nasal cavity/ paranasal sinuses. Twenty-four patients (44%) were women and the median age was 62 years (range: 28-81 years). The median annual incidence was 0.24/100,000 persons (range: 0.08/100,000-0.47/100,000) and the median follow-up time was 59 months (range: 10-132 months). In 34 patients (62%) CIS was found in the first biopsy taken during clinical work-up. The patients who had more than 1 biopsy taken prior to the CIS diagnosis had primarily lesions in the oral cavity or the larynx. At the time of diagnosis 49 patients (89%) were past or present smokers with a median consumption of 40 pack years. Six patients (11%) had no history of tobacco consumption and had CIS lesions distributed as 4 glottis, 1 oral cavity and 1 paranasal sinuses. The patient with an oral cavity CIS lesion had a long history of oral lichen planus. Fifty-seven patients with head and neck CIS in the pathology report were identified and in 49 cases (86%) a confirmatory microscopy of the specimen could be performed. In the remaining cases the specimen had either been collected by the patient or could not be provided. In 2 patients the diagnosis was changed from CIS to severe dysplasia and carcinoma respectively after re-examination and they were excluded from the study. In 5 patients the original slides had not been preserved and new slides were prepared from the original paraffin blocks for examination. Eleven patients (20%) had T-site recurrence after primary therapy and the median progression time to recurrence was 28 months (range 4-56 months) (see Table I). There was 1 CIS lesion, 8 T1, and 2 T2 tumors, and the carcinomas were moderately (46%) or well differentiated (46%). At the time of recurrence no patients were diagnosed with regional neck metastases. Six patients (11%) in the cohort developed a second primary head and neck squamous cell carcinomas in other anatomical locations than the primary CIS lesion in the upper aerodigestive tract and 7 patients died from lung cancer. All but 2 patients have had regular
ORAL AND MAXILLOFACIAL SURGERY 176 Christensen et al.
follow-up and have completed or are still in the surveillance program. Two patients with CIS in the larynx were lost for follow-up after 1½ and 3 years respectively, and both patients presented afterward with T1 tumors. Laryngeal subgroup Twenty-five patients had primary CIS in the larynx; 23 glottic, and 2 supraglottic lesions. In 17 patients (64%) the primary therapy consisted only of microsurgery, and in 2 patients laser-surgery was applied. Eight patients had additional radiotherapy (66-70 Gy) as part of primary therapy. The recurrence rate after primary therapy was 16% (4/25). Patients treated with only surgery had a higher, although not significant, recurrence rate (18%) compared with patients also treated with radiotherapy (13%), (P ¼ .74). Two patients were treated with laryngectomy after radiotherapy had failed. Oral cavity subgroup Twenty-one patients had CIS in the oral cavity and the anatomical distribution is shown in Table II. All patients had surgical resection as primary therapy and no patients were reconstructed with local or free flaps. Six patients (29%) had a recurrence and in 4 of these patients the surgical margins in the resection specimen were close (<5 mm) while in the recurrence-free group only 2 out of 15 patients had close margins in the resection specimen (P ¼ .03). After failure of primary treatment loco-regional control was obtained in 5 patients following secondary surgical resections and 1 patient also received additional radiotherapy. One patient with CIS in the oral cavity died of advanced squamous cell carcinoma after primary therapy had failed despite secondary surgery and radiotherapy. Pharyngeal subgroup Seven patients had CIS in the pharynx (see Table II) 1 patient had recurrence. This patient had a CIS lesion in the soft palate and was primarily surgically resected with clear margins (>5 mm) but developed a recurrence 28 months later and was treated successfully with radiotherapy. Three patients had radiotherapy as primary treatment and 2 patients refused treatment. In 1 of the patients who refused treatment, spontaneous regression of a CIS lesion to macroscopically normal epithelium on the epiglottis was observed. Nasal/paranasal sinus subgroup Two patients with CIS in the nasal cavity or paranasal sinuses were identified. One patient had a CIS lesion in the lateral wall of the nasal cavity close to the nasal vestibule and was treated successfully with surgical
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Table II. Anatomical distribution of primary CIS lesions in the oral cavity and pharynx Anatomical location of CIS lesions Oral cavity Floor of mouth Anterior 2/3 of tongue Retromolar trigone Gingiva Hard palate Pharynx Soft palate Tonsillar pillars Epiglottis Piriform recess
No. of CIS lesions 13 4 2 1 1 3 2 1 1
resection and reconstruction. The other patient had extensive inverted papilloma and CIS in the nasal cavity, maxillary, and ethmoid sinuses and was primarily treated with endoscopic resection and subsequent radiotherapy. Survival In total 17 patients in the cohort died, 16 from other causes than recurrence of the primary CIS lesion. For survival data see Table III and Figure 1.
DISCUSSION This study provides population based data for head and neck CIS, adding to our limited knowledge about the epidemiology and management of this entity. Existing epidemiologic data about incidences are mainly derived from the US National Cancer Institute’s Surveillance, Epidemiology and End Results Program from where 2 large retrospective studies from different time periods report an annual incidence between 0.5-0.75/100,000. Recently Guntinas-Lichius published data from Thüringen in Germany in the period 1996-2005 presenting 34 head and neck CIS cases including 3 patients with CIS on the lip and the annual incidence was 0.14/ 100,000.3 Guntinas-Lichius concluded that the low incidence could be due to insufficient surveillance. In our data, where lesions on the lip were excluded, the annual incidence was 0.24/100,000 and thus in between the above mentioned studies. The risk of underestimation of CIS cases in our data exist as some patients may have been treated in local ENT or dentist clinics without being registered in the pathology database. The small sample size and the retrospective design also add some potential uncertainty to our data. In the recurrence group no patients presented with an advanced tumor stage and this seems to indicate an efficient level of surveillance. Only 2 patients had unintended irregular follow-up and both patients had a recurrence. This highlights the importance of close surveillance of head and neck CIS lesions. Regarding
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ORIGINAL ARTICLE Christensen et al. 177
Table III. KaplaneMeier survival analysis. Calculated for the entire cohort and separately for the larynx subgroup and the remaining subgroups joined together (oral cavity, pharynx, nasal/paranasal sinuses) Anatomical location Total Larynx Other than larynx
5-year overall survival (%) (95% CI)
5-year disease-specific survival (%) (95% CI)
5-year recurrence-free survival (%) (95% CI)
74 (58-85) 80 (52-92) 69 (48-84)
98 (87-100) e e
74 (58-85) 80 (54-92) 69 (30-79)
Fig. 1. KaplaneMeier curves. Probability of survival on y-axis. Comparing the larynx subgroup to the remaining subgroups joined together (oral cavity, pharynx, nasal/paranasal sinuses), (A) overall survival and (B) recurrence-free survival.
risk factors of recurrence we did not investigate the human papilloma virus status of the patients in this study. Also it was not possible to collect data about continued tobacco consumption or smoking cessation after primary therapy. Theoretically 2 pathological processes could explain the recurrences: (1) recurrence from residual pathology in the epithelium not eliminated by primary therapy, (2) a second primary invasive cancer at same anatomical site. The concept of “field cancerization” and theories of tumor biology based on clonal origin and expansion may explain the development of a new precancerous intraepithelial lesion progressing to carcinoma in same anatomical location.11,12 As we also observed in this study it is well known that patients with primary head and neck cancer have a notable risk of synchronous or metachronous tumors elsewhere in the head and neck region and this is also suggested to be related to the concept of multiple cancer foci.13 To elucidate if the recurrences in our patients were due to the same primary lesion or a new second primary cancer would have required genetic clonal analysis, which was not attempted in this study. In the oral cavity group where all patients were treated with primary excision the recurrences were significantly related to close surgical margins and therefore a radical excision of the entire primary CIS lesion and adjacent epithelium seems to be a predictor for recurrence, as it is for carcinomas.10 In oral T1/T2 carcinomas dysplasia in the surgical margins has been noted as a significant
predictor of clinical outcome.14 Because CIS is defined as a strictly intraepithelial neoplasia, recurrence caused by metastatic deposits below the basement membrane can be ruled out. However, sampling error may be a problem if the biopsy demonstrating CIS did not represent the entire lesion but in fact was a carcinoma not present in the biopsy.15 In our data we tried to minimize the risk of sample error by excluding patients who were upstaged to carcinoma within 2 months after the CIS diagnosis. In our data the median time to recurrence was 28 months (range: 4-56 months), which is almost similar compared with Guntinas-Lichius who reported a median time to recurrence of 27 months (range: 14-56 months). In a retrospective study of 45 patients with laryngeal or oral dysplasia, Spielmann observed that patients with severe dysplasia or CIS progressed to cancer within 3 years after primary therapy if a relapse occurred.16 Compared with head and neck carcinomas, where T-site recurrences after primary therapy usually occur within 12-24 months, CIS seems to have a somewhat longer time to relapse.17 In a recent retrospective study of precancerous laryngeal lesions by Rohde the malignant transformation rate was 19% after primary therapy in 32 CIS lesions. The same study reviewed selected publications concerning laryngeal lesions with severe dysplasia or CIS showing malignant transformation rates ranging from 6%-22% after therapy.18 Reichart reviewed malignant transformation rates of oral severe dysplasia or CIS after therapy and reported a range of 14%-50%.19 In a
ORAL AND MAXILLOFACIAL SURGERY 178 Christensen et al.
smaller series of 6 oral CIS lesions 33% progressed into carcinoma after therapy.15 Limited information about the natural course of untreated CIS exists.20 In a study of severe dysplasia or CIS in the larynx, Stenersen reported a spontaneous malignant transformation rate of 46% within a median time of 51 months.21 Like others we also observed a case of CIS with complete spontaneous regression after biopsy.20 In this case another explanation could be that the CIS lesion was ablated with the first biopsy taken. The treatment of CIS in the larynx has been controversial and both radiotherapy and surgery have proved to be effective in terms of loco-regional control, larynx preservation, and functional outcome.22 Our data support the notion that both treatment modalities are eligible as primary therapy to obtain local control. When surgery failed radiotherapy served as salvage treatment. The survival analysis of our data shows that the treatment outcome for head and neck CIS was excellent with a 5-year disease-specific survival rate of 98%. The 5-year recurrence-free survival rate and 5-year overall survival rate were highest for CIS in the larynx, probably because of early presentation of symptoms in the larynx and effective treatment. Our data also demonstrate the malignant potential of CIS with a 20% recurrence rate and the majority of the recurrences being carcinomas. The malignant potential of head and neck CIS emphasizes the importance of surveillance, as for carcinomas. In conclusion the annual incidence of primary head and neck squamous cell CIS was low (0.24/100,000) and in accordance with previously reported numbers in the literature. Primary therapy consisted of surgery or radiotherapy, or a combination of both and the overall 5-year disease-specific survival rate was 98%. The recurrence rate after primary therapy was 20% and the median progression time to recurrence was 28 months. In the recurrence group all but 1 patient presented with T1 or T2 carcinoma. We recommend that CIS lesions should be treated on T-site and surveilled as T1/T2 head and neck squamous cell carcinomas. REFERENCES 1. Bouquot JE, Gnepp DR. Epidemiology of carcinoma in situ of the upper aerodigestive tract. Cancer. 1988;61:1685-1690. 2. Bouquot JE, Kurland LT, Weiland LH. Carcinoma in situ of the upper aerodigestive tract. Incidence, time trends, and follow-up in Rochester, Minnesota, 1935-1984. Cancer. 1988;61:1691-1698. 3. Guntinas-Lichius O, Wendt T, Buentzel J, et al. Head and neck in situ carcinoma: survival analysis of the Thuringian cancer registration database. Oral Oncol. 2010;46:e5-e9. 4. Reid BC, Winn DM, Morse DE, Pendrys DG. Head and neck in situ carcinoma: incidence, trends, and survival. Oral Oncol. 2000;36:414-420. 5. Gale N, Pilch BZ, Sidransky D, Westra W, Califano J. Tumours of the hypopharynx, larynx and trachea (epithelial precursor lesions). In: Barnes L, Eveson LW, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology
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and Genetics. Head and Neck Tumours. Lyon, France: IARC Press; 2005:140-143. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;37:127-133. Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E. Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med. 1995;24:198-200. Califano J, van der RP, Westra W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 1996;56:2488-2492. Lumerman H, Freedman P, Kerpel S. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;79:321-329. Woolgar JA. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2006;42:229-239. Braakhuis BJ, Leemans CR, Brakenhoff RH. A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med. 2004;33:317-322. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, Kummer JA, Leemans CR, Braakhuis BJ. Genetically altered fields as origin of locally recurrent head and neck cancer: a retrospective study. Clin Cancer Res. 2004;10:3607-3613. Lippman SM, Hong WK. Second malignant tumors in head and neck squamous cell carcinoma: the overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys. 1989;17:691-694. Weijers M, Snow GB, Bezemer PD, van der Wal JE, van der Waal I. The clinical relevance of epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma: an analysis of 37 patients. J Oral Pathol Med. 2002;31:11-15. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant lesions: is a biopsy reliable? J Oral Pathol Med. 2007;36:262-266. Spielmann PM, Palmer T, McClymont L. 15-Year review of laryngeal and oral dysplasias and progression to invasive carcinoma. Eur Arch Otorhinolaryngol. 2010;267:423-427. Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol. 1999;35:257-265. Rohde M, Grontved AM, Krogdahl A, Godballe C. Aggressive elimination of precancerous lesions of the vocal cords to avoid risk of cancer. Dan Med J. 2012;59:A4399. Reichart PA, Philipsen HP. Oral erythroplakia e a review. Oral Oncol. 2005;41:551-561. van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol. 2009;45:317-323. Stenersen TC, Hoel PS, Boysen M. Carcinoma in situ of the larynx: an evaluation of its natural clinical course. Clin Otolaryngol Allied Sci. 1991;16:358-363. Sadri M, McMahon J, Parker A. Management of laryngeal dysplasia: a review. Eur Arch Otorhinolaryngol. 2006;263: 843-852.
Reprint requests: A. Christensen, MD Department of Otolaryngology-Head and Neck Surgery and Audiology, 2071, Rigshospitalet Copenhagen University Hospital, Blegdamsvej 9 DK-2100 Copenhagen East, Denmark [email protected]
Ten-year retrospective study of head and neck carcinoma in situ: incidence, treatment, and clinical outcome A. Christensen, MD,a E. Kristensen, MD,b M.H. Therkildsen, MD, DMSc,b L. Specht, MD, DMSc,c J. Reibel, DrOdont,d and P. Homøe, MD, DMSca Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark and School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Objectives. To examine the management and clinical outcome for patients with primary head and neck carcinoma in situ (CIS) and to estimate the incidence in the referral population. Study design. A retrospective study from 2000-2009 of patients with head and neck CIS referred for treatment at Rigshospitalet. The referral area was East Denmark and Greenland with a population of 2.4 million. Results. Fifty-five patients with primary CIS were identified: 21 oral cavity, 7 pharynx, 25 larynx, 2 nasal cavity/paranasal sinuses. The median annual incidence was 0.24/100,000. Eleven patients (20%) had T-site recurrence. The 5-year diseasespecific survival rate and 5-year recurrence-free survival rate were 98% and 74% respectively. Conclusions. The annual incidence of primary head and neck CIS was low and in accordance with previous findings reported in the literature. We recommend that CIS lesions should be treated on T-site and surveilled as T1/T2 head and neck carcinomas. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:174-178)
Head and neck carcinoma in situ (CIS) is a rare diagnosis and our knowledge about this entity is limited. Former studies from the US and Germany have shown annual incidence rates of primary head and neck CIS between 0.14-1.8/100,000.1-4 These studies also included CIS lesions on lip where sun exposure, as opposed to the mucosa-associated CIS lesions, is a key risk factor in the pathogenesis. The diagnosis is based on cytological and architectural changes in the epithelium of the upper aerodigestive tract. A CIS lesion is defined as a full-thickness dysplasia in the viable cell layers of the epithelium. Invasion is not present.5 Therefore regional metastases from true CIS lesions do not occur. CIS represents an in dependent entity in the spectrum of histopathological changes in the epithelium from mild dysplasia to invasive carcinoma. Different classification systems for head and neck precancerous lesions have been evaluated and recommended in the past.6 The World Health Organization classification system has been widely accepted and is a 4-step system with the categories mild, moderate and severe dysplasia and CIS.5 The consistency of grading systems has been a
Department of Otolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital. b Department of Pathology, Rigshospitalet, Copenhagen University Hospital. c Department of Oncology, Rigshospitalet, Copenhagen University Hospital. d Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, School of Dentistry, Faculty of Health Sciences, University of Copenhagen. Received for publication Dec 4, 2012; returned for revision Feb 14, 2013; accepted for publication Mar 3, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.03.002
174
extensively debated and inter-observer and intraobserver variation may affect the accuracy of the histopathological diagnosis.7 From a clinical point of view a classification system should be able to stratify lesions according to malignant potential and facilitate the decision making in the management of the disease. Tumor models suggest a biological process of sequential intermediate stages from healthy epithelium over mild and moderate dysplasia to CIS and finally carcinoma.8 It is widely accepted that some precursor lesions progress to carcinoma and that the degree of dysplasia is a prognosticator for progression to cancer.9,10 This study aimed to examine the management, patterns of recurrence, and clinical outcome in our center for patients with head and neck CIS and to estimate the incidence in the referral population.
MATERIALS AND METHODS The study population included patients with microscopically confirmed primary head and neck CIS referred for treatment in a 10-year period from 2000-2009. The referral area was East Demark and Greenland where the treatment of head and neck cancer is centralized at Rigshospitalet. Exclusion criteria were prior head and neck cancer, lymphoma, skin cancer, cancer of unknown
Statement of Clinical Relevance The annual incidence of primary head and neck CIS was low (0.24/100,000). The recurrence rate was 20% and the recurrences were mainly T1 or T2 carcinomas. CIS lesions should be treated on T-site and surveilled as T1/T2 carcinomas.
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ORIGINAL ARTICLE Christensen et al. 175
Table I. Distribution of recurrences in subgroups and recurrence rate. Recurrence defined as recurrence at the same anatomical location as the primary CIS lesion after primary therapy Anatomical location Total Larynx Oral cavity Pharynx Nasal/paranasal
Recurrence rate (%) (n/N) 20 16 29 14 0
(11/55) (4/25) (6/21) (1/7) (0/2)
primary or metastatic disease in head and neck. Lesions at the labial vermilion were also excluded. If the diagnosis of the lesion was changed to cancer within 2 months after the CIS diagnosis, the patient was also excluded to minimize the risk of sampling error. Patients with a histopathological CIS diagnosis were searched in the Danish National Pathology Register where all pathology reports have been registered since 1985. A search was also made in the pathology registers of the Danish Head and Neck Cancer Group and of the School of Dentistry in Copenhagen. The histopathological diagnosis was based on microscopy of H&E stained sections from formalin-fixed, paraffin embedded tissue. Data were collected from chart reviews, and patient characteristics, diagnosis, treatment, recurrence and death from head and neck cancer or other diseases were recorded. The primary treatment modality was chosen by the ENT specialist based on resectability and clinical presentation of the CIS lesion, findings during surgery and histopathological findings in biopsies or resection specimens. Patients were seen after treatment for periodic annual or midannual clinical control in an ENT or Oncology department. The identified lesions were divided into anatomical subgroups: Oral cavity, pharynx, larynx, and nasal/paranasal sinuses. If the original specimen was available, a confirmatory microscopy was performed by a pathologist (E.K. and M.H.T.). A clear margin was defined as >5 mm distance from the CIS lesion to the surrounding tissue with histological normal epithelium with no dysplasia. A recurrence was defined as CIS or carcinoma at the same anatomical site as the primary CIS lesion. At recurrence tumors were classified according to the Tumor-nodesmetastasis (TNM) classification from International Union Against Cancer (UICC) (2005). Statistical analyses were performed using STATA 11.0 (STATA Corp. Lp, College Station, TX, USA). Survival analysis was calculated by the KaplaneMeier method. Comparisons of groups were performed by Log rank test, Chi-square test or one-way analysis of variance. For all tests significance was 2-sided and set to P < .05 and 95% confidence intervals (CI) were applied. Incidence rates were calculated pr. 100,000 persons based on the average of the population size in 2000 and 2009 in the referral area (www.dst.dk, www.statgreen.gl). The study
Malignant transformation rate (%) (n/N) 18 16 24 14 0
(10/55) (4/25) (5/21) (1/7) (0/2)
Median progression time (months) 28 range (4-56) 22 range (4-50) 29 range (11-55) 28 e
was approved by the local ethical committee and the Danish Data Registry.
RESULTS A total of 55 patients with primary CIS were identified: 21 oral cavity, 7 pharynx, 25 larynx, 2 nasal cavity/ paranasal sinuses. Twenty-four patients (44%) were women and the median age was 62 years (range: 28-81 years). The median annual incidence was 0.24/100,000 persons (range: 0.08/100,000-0.47/100,000) and the median follow-up time was 59 months (range: 10-132 months). In 34 patients (62%) CIS was found in the first biopsy taken during clinical work-up. The patients who had more than 1 biopsy taken prior to the CIS diagnosis had primarily lesions in the oral cavity or the larynx. At the time of diagnosis 49 patients (89%) were past or present smokers with a median consumption of 40 pack years. Six patients (11%) had no history of tobacco consumption and had CIS lesions distributed as 4 glottis, 1 oral cavity and 1 paranasal sinuses. The patient with an oral cavity CIS lesion had a long history of oral lichen planus. Fifty-seven patients with head and neck CIS in the pathology report were identified and in 49 cases (86%) a confirmatory microscopy of the specimen could be performed. In the remaining cases the specimen had either been collected by the patient or could not be provided. In 2 patients the diagnosis was changed from CIS to severe dysplasia and carcinoma respectively after re-examination and they were excluded from the study. In 5 patients the original slides had not been preserved and new slides were prepared from the original paraffin blocks for examination. Eleven patients (20%) had T-site recurrence after primary therapy and the median progression time to recurrence was 28 months (range 4-56 months) (see Table I). There was 1 CIS lesion, 8 T1, and 2 T2 tumors, and the carcinomas were moderately (46%) or well differentiated (46%). At the time of recurrence no patients were diagnosed with regional neck metastases. Six patients (11%) in the cohort developed a second primary head and neck squamous cell carcinomas in other anatomical locations than the primary CIS lesion in the upper aerodigestive tract and 7 patients died from lung cancer. All but 2 patients have had regular
ORAL AND MAXILLOFACIAL SURGERY 176 Christensen et al.
follow-up and have completed or are still in the surveillance program. Two patients with CIS in the larynx were lost for follow-up after 1½ and 3 years respectively, and both patients presented afterward with T1 tumors. Laryngeal subgroup Twenty-five patients had primary CIS in the larynx; 23 glottic, and 2 supraglottic lesions. In 17 patients (64%) the primary therapy consisted only of microsurgery, and in 2 patients laser-surgery was applied. Eight patients had additional radiotherapy (66-70 Gy) as part of primary therapy. The recurrence rate after primary therapy was 16% (4/25). Patients treated with only surgery had a higher, although not significant, recurrence rate (18%) compared with patients also treated with radiotherapy (13%), (P ¼ .74). Two patients were treated with laryngectomy after radiotherapy had failed. Oral cavity subgroup Twenty-one patients had CIS in the oral cavity and the anatomical distribution is shown in Table II. All patients had surgical resection as primary therapy and no patients were reconstructed with local or free flaps. Six patients (29%) had a recurrence and in 4 of these patients the surgical margins in the resection specimen were close (<5 mm) while in the recurrence-free group only 2 out of 15 patients had close margins in the resection specimen (P ¼ .03). After failure of primary treatment loco-regional control was obtained in 5 patients following secondary surgical resections and 1 patient also received additional radiotherapy. One patient with CIS in the oral cavity died of advanced squamous cell carcinoma after primary therapy had failed despite secondary surgery and radiotherapy. Pharyngeal subgroup Seven patients had CIS in the pharynx (see Table II) 1 patient had recurrence. This patient had a CIS lesion in the soft palate and was primarily surgically resected with clear margins (>5 mm) but developed a recurrence 28 months later and was treated successfully with radiotherapy. Three patients had radiotherapy as primary treatment and 2 patients refused treatment. In 1 of the patients who refused treatment, spontaneous regression of a CIS lesion to macroscopically normal epithelium on the epiglottis was observed. Nasal/paranasal sinus subgroup Two patients with CIS in the nasal cavity or paranasal sinuses were identified. One patient had a CIS lesion in the lateral wall of the nasal cavity close to the nasal vestibule and was treated successfully with surgical
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Table II. Anatomical distribution of primary CIS lesions in the oral cavity and pharynx Anatomical location of CIS lesions Oral cavity Floor of mouth Anterior 2/3 of tongue Retromolar trigone Gingiva Hard palate Pharynx Soft palate Tonsillar pillars Epiglottis Piriform recess
No. of CIS lesions 13 4 2 1 1 3 2 1 1
resection and reconstruction. The other patient had extensive inverted papilloma and CIS in the nasal cavity, maxillary, and ethmoid sinuses and was primarily treated with endoscopic resection and subsequent radiotherapy. Survival In total 17 patients in the cohort died, 16 from other causes than recurrence of the primary CIS lesion. For survival data see Table III and Figure 1.
DISCUSSION This study provides population based data for head and neck CIS, adding to our limited knowledge about the epidemiology and management of this entity. Existing epidemiologic data about incidences are mainly derived from the US National Cancer Institute’s Surveillance, Epidemiology and End Results Program from where 2 large retrospective studies from different time periods report an annual incidence between 0.5-0.75/100,000. Recently Guntinas-Lichius published data from Thüringen in Germany in the period 1996-2005 presenting 34 head and neck CIS cases including 3 patients with CIS on the lip and the annual incidence was 0.14/ 100,000.3 Guntinas-Lichius concluded that the low incidence could be due to insufficient surveillance. In our data, where lesions on the lip were excluded, the annual incidence was 0.24/100,000 and thus in between the above mentioned studies. The risk of underestimation of CIS cases in our data exist as some patients may have been treated in local ENT or dentist clinics without being registered in the pathology database. The small sample size and the retrospective design also add some potential uncertainty to our data. In the recurrence group no patients presented with an advanced tumor stage and this seems to indicate an efficient level of surveillance. Only 2 patients had unintended irregular follow-up and both patients had a recurrence. This highlights the importance of close surveillance of head and neck CIS lesions. Regarding
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ORIGINAL ARTICLE Christensen et al. 177
Table III. KaplaneMeier survival analysis. Calculated for the entire cohort and separately for the larynx subgroup and the remaining subgroups joined together (oral cavity, pharynx, nasal/paranasal sinuses) Anatomical location Total Larynx Other than larynx
5-year overall survival (%) (95% CI)
5-year disease-specific survival (%) (95% CI)
5-year recurrence-free survival (%) (95% CI)
74 (58-85) 80 (52-92) 69 (48-84)
98 (87-100) e e
74 (58-85) 80 (54-92) 69 (30-79)
Fig. 1. KaplaneMeier curves. Probability of survival on y-axis. Comparing the larynx subgroup to the remaining subgroups joined together (oral cavity, pharynx, nasal/paranasal sinuses), (A) overall survival and (B) recurrence-free survival.
risk factors of recurrence we did not investigate the human papilloma virus status of the patients in this study. Also it was not possible to collect data about continued tobacco consumption or smoking cessation after primary therapy. Theoretically 2 pathological processes could explain the recurrences: (1) recurrence from residual pathology in the epithelium not eliminated by primary therapy, (2) a second primary invasive cancer at same anatomical site. The concept of “field cancerization” and theories of tumor biology based on clonal origin and expansion may explain the development of a new precancerous intraepithelial lesion progressing to carcinoma in same anatomical location.11,12 As we also observed in this study it is well known that patients with primary head and neck cancer have a notable risk of synchronous or metachronous tumors elsewhere in the head and neck region and this is also suggested to be related to the concept of multiple cancer foci.13 To elucidate if the recurrences in our patients were due to the same primary lesion or a new second primary cancer would have required genetic clonal analysis, which was not attempted in this study. In the oral cavity group where all patients were treated with primary excision the recurrences were significantly related to close surgical margins and therefore a radical excision of the entire primary CIS lesion and adjacent epithelium seems to be a predictor for recurrence, as it is for carcinomas.10 In oral T1/T2 carcinomas dysplasia in the surgical margins has been noted as a significant
predictor of clinical outcome.14 Because CIS is defined as a strictly intraepithelial neoplasia, recurrence caused by metastatic deposits below the basement membrane can be ruled out. However, sampling error may be a problem if the biopsy demonstrating CIS did not represent the entire lesion but in fact was a carcinoma not present in the biopsy.15 In our data we tried to minimize the risk of sample error by excluding patients who were upstaged to carcinoma within 2 months after the CIS diagnosis. In our data the median time to recurrence was 28 months (range: 4-56 months), which is almost similar compared with Guntinas-Lichius who reported a median time to recurrence of 27 months (range: 14-56 months). In a retrospective study of 45 patients with laryngeal or oral dysplasia, Spielmann observed that patients with severe dysplasia or CIS progressed to cancer within 3 years after primary therapy if a relapse occurred.16 Compared with head and neck carcinomas, where T-site recurrences after primary therapy usually occur within 12-24 months, CIS seems to have a somewhat longer time to relapse.17 In a recent retrospective study of precancerous laryngeal lesions by Rohde the malignant transformation rate was 19% after primary therapy in 32 CIS lesions. The same study reviewed selected publications concerning laryngeal lesions with severe dysplasia or CIS showing malignant transformation rates ranging from 6%-22% after therapy.18 Reichart reviewed malignant transformation rates of oral severe dysplasia or CIS after therapy and reported a range of 14%-50%.19 In a
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smaller series of 6 oral CIS lesions 33% progressed into carcinoma after therapy.15 Limited information about the natural course of untreated CIS exists.20 In a study of severe dysplasia or CIS in the larynx, Stenersen reported a spontaneous malignant transformation rate of 46% within a median time of 51 months.21 Like others we also observed a case of CIS with complete spontaneous regression after biopsy.20 In this case another explanation could be that the CIS lesion was ablated with the first biopsy taken. The treatment of CIS in the larynx has been controversial and both radiotherapy and surgery have proved to be effective in terms of loco-regional control, larynx preservation, and functional outcome.22 Our data support the notion that both treatment modalities are eligible as primary therapy to obtain local control. When surgery failed radiotherapy served as salvage treatment. The survival analysis of our data shows that the treatment outcome for head and neck CIS was excellent with a 5-year disease-specific survival rate of 98%. The 5-year recurrence-free survival rate and 5-year overall survival rate were highest for CIS in the larynx, probably because of early presentation of symptoms in the larynx and effective treatment. Our data also demonstrate the malignant potential of CIS with a 20% recurrence rate and the majority of the recurrences being carcinomas. The malignant potential of head and neck CIS emphasizes the importance of surveillance, as for carcinomas. In conclusion the annual incidence of primary head and neck squamous cell CIS was low (0.24/100,000) and in accordance with previously reported numbers in the literature. Primary therapy consisted of surgery or radiotherapy, or a combination of both and the overall 5-year disease-specific survival rate was 98%. The recurrence rate after primary therapy was 20% and the median progression time to recurrence was 28 months. In the recurrence group all but 1 patient presented with T1 or T2 carcinoma. We recommend that CIS lesions should be treated on T-site and surveilled as T1/T2 head and neck squamous cell carcinomas. REFERENCES 1. Bouquot JE, Gnepp DR. Epidemiology of carcinoma in situ of the upper aerodigestive tract. Cancer. 1988;61:1685-1690. 2. Bouquot JE, Kurland LT, Weiland LH. Carcinoma in situ of the upper aerodigestive tract. Incidence, time trends, and follow-up in Rochester, Minnesota, 1935-1984. Cancer. 1988;61:1691-1698. 3. Guntinas-Lichius O, Wendt T, Buentzel J, et al. Head and neck in situ carcinoma: survival analysis of the Thuringian cancer registration database. Oral Oncol. 2010;46:e5-e9. 4. Reid BC, Winn DM, Morse DE, Pendrys DG. Head and neck in situ carcinoma: incidence, trends, and survival. Oral Oncol. 2000;36:414-420. 5. Gale N, Pilch BZ, Sidransky D, Westra W, Califano J. Tumours of the hypopharynx, larynx and trachea (epithelial precursor lesions). In: Barnes L, Eveson LW, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology
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Reprint requests: A. Christensen, MD Department of Otolaryngology-Head and Neck Surgery and Audiology, 2071, Rigshospitalet Copenhagen University Hospital, Blegdamsvej 9 DK-2100 Copenhagen East, Denmark [email protected]