Basaloid squamous cell carcinoma of the larynx—A systematic review

Basaloid squamous cell carcinoma of the larynx—A systematic review

Auris Nasus Larynx 39 (2012) 397–401 Contents lists available at SciVerse ScienceDirect Auris Nasus Larynx journal homepage: www.elsevier.com/locate...

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Auris Nasus Larynx 39 (2012) 397–401

Contents lists available at SciVerse ScienceDirect

Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl

Basaloid squamous cell carcinoma of the larynx—A systematic review Krishnakumar Thankappan * Head and Neck Institute, Amrita Institute of Medical Sciences, Kochi, 682041, India

A R T I C L E I N F O

A B S T R A C T

Article history: Received 2 May 2011 Accepted 29 July 2011 Available online 24 August 2011

Objectives: This study pools all the cases of Basaloid squamous cell carcinoma of the larynx in the English literature to investigate the clinical course of this rare clinico-pathological disease entity. Methods: We found and analyzed 100 cases with individual patient data from 36 publications spanning 20 years. Results: It is a rare disease of the elderly with strong male predominance and more common in the supraglottis. Patients typically present with locoregionally advanced stage. Surgery alone or combined with radiotherapy is commonly reported. It has a worse survival outcome when compared to laryngeal cancers in general. Twenty-two percent eventually develop distant metastases with the lung being the predominant site. Conclusions: Given the rarity of this clinical condition and the lack of data from studies with adequate number of cases, this systematic literature analysis provides the best possible relevant evidence. ß 2011 Elsevier Ireland Ltd. All rights reserved.

Keywords: Basaloid squamous cell carcinoma Laryngeal cancer Head and neck cancer Survival analysis

1. Introduction Basaloid squamous cell carcinoma (BSCC) was first described in 1986 by Wain et al. [1] World Health Organization has included this entity in its revised edition in 1991 [2]. It has been reported in various sites of upper aero-digestive tract including larynx, hypopharynx, oral cavity, oropharynx and nasopharynx [3–5]. In larynx, most of the evidence comes from case reports and case series with very few numbers of cases. The largest reported series in this sub-site had only 16 cases [6]. This study attempts to pool all the cases of laryngeal BSCC from the literature with individual patient data to investigate the clinical course of this rare clinicopathological disease entity. 2. Materials and methods The Pubmed-Medline database was searched with the terms ‘‘basaloid squamous cell carcinoma larynx’’ and ‘‘basaloid squamous cell carcinoma head and neck’’. The search was limited to English language publications and human subjects. The titles, abstracts and full text publications were screened for original data. ‘‘Related articles’’ option in the pubmed and the references of the articles identified were further reviewed. This search strategy resulted in 36 publications reporting on this clinico-pathological entity in larynx sub-site. Of these, only 23 articles had individual patient data with age, gender, sub-site, criteria for diagnosis, TNM

* Corresponding author. Tel.: +91 484 2801234; fax: +91 484 2802082. E-mail address: [email protected] 0385-8146/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2011.07.018

staging, treatment modality, outcome data including disease status at last follow up, and duration of follow up. 100 cases were identified with at least five of these variables. The criterion for inclusion in the analysis was only the availability of the individual patient data. A summary of the publications from which these cases were obtained is given in Table 1. A database was created to include all these cases with the above variables. 58 other cases were also identified in the larynx sub-site [3–5,7–16] but were excluded from the analysis due to the lack of individual patient data. Reports on BSCC from other sites, including hypopharynx were excluded. When the studies reported cases from multiple sites from head and neck, only cases from larynx were entered into this review. Pathological and molecular studies without clinical and outcome data were excluded from this analysis. When there was more than one publication from the same group, only the most recent publication was used for data entry. Two of the case series [17,18] from the same institution were included but from two time periods with minimal overlap. The individual cases were screened before entry to avoid overlap. Statistical evaluations were performed using SPSS Statistics 17.01 package. Descriptive analysis on age, gender, sub-site, staging, treatment modality and disease status was obtained. Kaplan Meier curves were used to study the survival. Data regarding disease status at the end of follow up were entered as ‘‘no evidence of disease’’, ‘‘alive with disease’’, ‘‘died of disease’’ or ‘‘died of other cause’’. The duration of follow up for each case was obtained from the reports. The ‘‘event’’ in Kaplan Meier survival analysis was ‘‘death’’ for the calculation of overall survival and ‘‘death due to disease’’ for the estimation of disease specific survival. 5-year overall survival and disease specific survival rates

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Table 1 Summary of publications with individual patient details from which the data was derived. Period of study was not specified in few of the case reports. Serial no.

Author

Publication year

Period of study

Number of cases

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Wain et al. [1] Shvili et al. [33] Klijanienko et al. [34] Larner et al. [35] Raslan et al. [25] Ereno et al. [36] Muller et al. [37] Akyol et al. [22] Sato et al. [38] Ferlito et al. [17] Kruslin et al. [39] Kim et al. [10] Sheen et al. [40] Paulino et al. [23] Prasad et al. [24] Eryilmaz et al. [41] Bahar et al. [21] Rodri´guez Tojo et al. [42] Salerno et al. [6] Alkan et al. [43] Marioni et al. [18] Deniz et al. [44] Koutis et al. [32]

1986 1990 1993 1993 1994 1994 1995 1995 1997 1997 1998 1998 1999 2000 2002 2002 2003 2005 2006 2006 2006 2008 2008

1953–1984 – 1985–1989 1980–1990 1987–1991 1974–1989 – – – 1989–1995 – 1988–1995 – 1975–97 – – 1986–2000 1980–1996 1987–2000 – 1992–2006 1997–2006 –

3 1 2 3 1 5 1 2 1 9 2 4 1 5 1 1 4 11 16 2 9 15 1

Total

100

were obtained. Differences in survival between the stage groups (Stage I/II vs. Stage III/IV) and nodal groups (N0 vs. N+) were compared using log rank test. 3. Results 100 cases of BSCC of the larynx were identified from the publications with adequate individual patient data. The median age was 62 years with a range of 35–85 years.67.1% of the patients were in the age group from 50 to 69 years. 96% of the subjects were males. Smoking was reported only in 36 patients of this series. The smoking status of the remaining patients was unknown. Similarly 11 patients had positive alcohol history and 12 had no alcohol history. The status of the remaining patients regarding alcohol consumption was not specified. Supraglottis was the commonest

Table 2 Patient and tumor characteristics. No of patients (%) Age group (n = 97)

30–49 years 50–69 years 70 and above

13(13.4) 65(67.1) 19(19.5)

Sex (n = 100)

Male Female

96(96) 4(4)

Subsite (n = 83)

glottic supraglottic transglottic

12(14.5) 57(68.6) 14(16.9)

T stage (n = 92)

T1 T2 T3 T4

7(7.6) 24(26.1) 38(41.3) 23(25.0)

N Stage (n = 96)

N0 N1 N2 N3

52(54.1) 23(24.0) 19(19.8) 2(2.1)

I II III IV

7(7) 16(16) 36(36) 41(41)

Stage group (n = 100)

sub-site involved with 57(68.6%) patients. The pathological criteria elaborated by Wain et al. [1] were used for diagnosis. Some authors have divided BSCC further into subgroups depending on the percentage of the basaloid component [5]. Majority of the cases presented at an advanced stage, either stage III (36%) or stage IV (41%). 45.9% had nodal metastasis at presentation. None of them had distant metastasis at presentation. The patient and tumor characteristics are summarized in Table 2. Treatment modality was specified in 88 patients. 84 of these cases were treated surgically. Surgery alone was done in 25(28.5%) patients. Combined modality treatment was administered in 59(67%). Patients underwent either laser excision, partial, near total or total laryngectomy. Total laryngectomy was the commonest surgery performed. Partial pharyngectomy included 16 cases of supraglottic laryngectomy and six cases of supra-cricoid laryngectomy. Near total laryngectomy was performed in three of the subjects. The type of surgery was not specified in 7 patients. In patients undergoing surgery, 63 had a neck dissection. The levels and laterality of the neck dissection also varied across the series. Supraglottic patients were offered bilateral neck dissection. The treatment characteristics are summarized in Table 3. The follow up ranged from zero to 156 months (median: 27.5 months). Two of the patients had zero Table 3 Treatment characteristics. No. of patients (%) Treatment modality (n = 88)

Surgery alone Radiotherapy alone Chemotherapy alone Surgery + RT Surgery + RT + Chemotherapy PreopRT + Surgery

25(28.5) 3(3.4) 1(1.1) 53(60.2) 4(4.6) 2(2.2)

Type of surgery (n = 84)

Laser excision Partial laryngectomy Total/near total laryngectomy Not specified

3(3.5) 24(28.6) 50(59.5) 7(8.4)

Neck dissection (n = 84)

Done Not done Not specified

63(75.0) 14(16.6) 7(8.4)

[(Fig._1)TD$IG]

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Table 4 Outcome. No. of patients (%) Recurrence (n = 100)

Present Absent

50(50) 50(50)

Disease status at last follow up (n = 100)

No evidence of disease Alive with disease Died of other cause Died of disease

45(45) 9(9) 5(5) 41(41)

Site of distant metastasis (n = 22)

Lung Brain Liver Bone Skin (nose)

20 4 3 2 2

follow up. One of these patients was reported as lost immediately after the treatment and the other had no follow up period specified. 45 patients had no evidence of disease at the last follow up. Recurrence developed in 50 of the subjects. Only few papers specified the mode of loco-regional recurrence. The time of development of the recurrence was also not specified by most of the papers and hence the disease free survival could not be derived. 22 patients developed distant metastasis while on follow up. Lung was the commonest site of distant failure. At the end of the follow up 41 patients (41%) died due to causes related to the cancer while five (5%) died of other causes not specified. The outcome data is summarized in Table 4. Overall 5-year survival rate as 47.5%. Stage wise, 5-year overall survival rate was 80.2%, 74.0%, 46.6% and 28.9% for Stage I, II, III and IV respectively. Early stage (Stage I and II) and advanced stage disease (Stage III and IV) had an overall 5-year survival rate of 72.9% and 39.0% respectively. This difference was statistically significant (p = 0.035). T stage information was available for 92 patients only. 5-year overall survival rate for T1, T2, T3 and T4 stage patients was 81.2%, 56.9%, 52.3% and 32.4% respectively. 96 patients had their nodal stage reported. 44(45.9%) had node positive disease (N+) and 52(54.1%) were node negative (N0). The 5-year overall survival in N0 group was 61.3% and that in N+ group was 36.4%. This difference was also statistically significant (p = 0.014). The Kaplan Meier survival curves depicting the overall survival are shown in Fig. 1(a–c). The 5-year disease specific survival rate was 50.6%. The 5-year disease specific survival for early and late stage disease were 76.4 and 42.0% respectively (p = 0.004). Similarly this rate for the N0 and N+ groups were 62.7 and 37.4% respectively (p = 0.004). The Kaplan Meier survival curve depicting the disease specific survival is shown in Fig. 2. 4. Discussion The commonest laryngeal malignancy is squamous cell carcinoma, which comprises more than 90% of the cases. Verrucous, spindle cell and basaloid subtypes are rarer variants. BSCC first described in 1986 [1] has been reported in larynx, hypopharynx, oral cavity, oropharynx [3–5] and other sites in the upper aero-digestive tract as well as other anatomical sites [19,20]. In larynx the largest reported case series included only 16 cases [6]. It is a rare disease. Though approximately one fourth of the cases reported in the upper aero-digestive tract is in larynx [21], it comprises only less than 1% of the laryngeal cancers [22]. BSCC displays distinct morphological and biological features and is reported to have a different clinical course [1,17]. In head and neck sites it generally affects elderly men who are smokers and/alcoholics [17,23,24]. Ferlito et al. [17] reported an average age of 63 years at initial evaluation in a study of 15 patients of larynx and hypopharynx. The present analysis confirms that, in larynx it is

Fig. 1. (a) Kaplan Meier survival curve showing overall survival for 100 patients. (b) Overall survival difference between Stage groups (Stage I/II vs. Stage III/IV) n = 100. (c) Overall Survival difference between Nodal groups (N0 vs. N+) n = 96.

a disease of the older age group with 84% of the patients of the age of 50 years or above. Raslan et al. [25] in a collective review of 10 cases in head and neck reports a mean age of 63 years with 82% males. It is interesting to note that 96 (96%) of the patients in this analysis were males. This shows a strong male predominance in the larynx. Though alcohol and smoking are considered the etiological factors similar to the conventional squamous cell carcinoma (SCC), the smoking and alcohol history was not specified in the majority of the patients in this analysis and hence no conclusions could be made. No other specific etiological factor

[(Fig._2)TD$IG]

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K. Thankappan / Auris Nasus Larynx 39 (2012) 397–401

Fig. 2. Kaplan Meier survival curve showing disease specific survival for 100 patients.

could be identified from the reported evidence. There are studies that reported predilection for the supraglottic subsite [11]. The present study also confirms this observation with 68.6% patients with tumor predominantly arising from the supraglottis. The patients usually presented at an advanced stage. In a study of laryngeal cancer by Shah et al. [26] less than 40% presented with advanced disease (stage III or IV) as compared to the 76% in BSCC of the larynx in this report. To date there are no clinical studies that allow the proposal of a therapeutic strategy specific to BSCC. This analysis finds that literature favors surgical modality for the BSCC of the larynx. Majority of the patients were treated with surgery alone or along with radiotherapy. The type of surgery and the level of neck dissection varied according to the sub-site and extend of the disease. Total laryngectomy was the commonest surgery performed. Soriano et al. [5], taking into consideration the high risk of distant metastasis and the morbidity of surgery had suggested an organ preservation approach with induction chemotherapy. This strategy was not seen to be applied in this pool of reported patients. One of the reasons for this could be that, clinicopathological reports on this clinical entity may have decreased in this era of organ preservation approach since the novelty as a condition has faded. But these patients might be good candidates for regimens incorporating chemotherapy and radiotherapy since majority of them present with advanced stages and many develop distant metastasis. It is generally believed that BSCC has a worse prognosis than the more commonly encountered SCC [1,17,21]. There are also reports that contradict this [3,27]. Three studies compare BSCC with matched SCC controls. Wizenburg et al. [28] found that the 2-year survival was 23.5% for BSCC and 53%for SCC. In the study by Erdamar et al. [11] the 3-year survival was 50% in BSCC and 72% in SCC group. The above two studies included multiple head and neck sites. In contrast Luna et al. [27] did not find any differences comparing six BSCC with 47 SCC of the pyriform sinus. They concluded that survival would be similar to that of conventional SCC when the anatomical site, clinical stage and treatment were matched. The present pooled analysis deals with larynx sub-site exclusively and finds the overall 5-year survival rate as 47.5. The Surveillance Epidemiology and End Results (SEER) 5-year overall relative survival rate for the larynx cancers together for the years 1996–2004 is 62.5 [29]. Similarly this study finds the 5-year overall survival rate for localized (N0) and regional disease (N+) as 61.3% and 36.4% respectively. An analysis of SEER data by Carvalho

et al. [30] reported the 5-year survival rate for larynx cancers as 79.2% and 54.8% for localized and regional disease respectively. In a study of 16,213 patients with laryngeal cancer by Shah et al. [26], overall 5-year disease-specific survival was 75% compared to that of 50.6% in the present study. Patients with stage I or II disease had 5-year disease-specific survival rates ranging from 78% to 91%, whereas those with stage III or IV had rates ranging from 42% to 67% in the same study [26] compared to 76.4% and 42% in this study. The above comparisons with the historical data confirm that BSCC of the larynx has a worse survival outcome. Soriano et al. [5] found no statistically significant difference in specific survival rates among the patients with BSCC in oropharynx, hypopharynx or larynx. This is in contrast to the higher specific survival rates of conventional SCC of the larynx compared to that of oropharynx and hypopharynx. One of the reasons for the observed poorer survival rates in BSCC could be their predominant origin from the supraglottic subsite or transglottic involvement. These subsites in general, have poorer outcome compared to the glottic carcinoma. Begum and Westra [31] in a recent study noted that human papilloma virus 16 (HPV16) status had an impact on the survival of BSCC patients. Their study, but had a majority of oropharyngeal patients which would have caused an improvement in survival. Only 8 patients had disease in the larynx and all of them were HPV negative. BSCC is reported to be characterized by high incidence of early regional and distant metastasis to lungs, liver, bones, brain and skin [1,17,23,25]. Though none of the patients had no distant metastasis at presentation, 22 patients were found to develop distant metastasis during follow up, in this review. Lung was the commonest site of distant failure. Two of the patients had a peculiar nasal tip skin metastasis [32,33]. Soriano et al. [5] found 50% of the BSCC metastasis involved multiple organs and suggested early screening for these lesions. Seidman et al. [45] in a report found second primary tumors associated with two cases of BSCC in pyriform sinus and vallecula. The incidence of second primary tumors was not specifically reported in majority of the studies included in this analysis on larynx. Ferlito et al. [17] had three cases with synchronous or metachronous second primary lesions. Vesoulis [46] reported a case of metastatic pulmonary laryngeal basaloid carcinoma simulating primary small cell carcinoma of the lung on fine needle aspiration cytology. 5. Conclusions Basaloid squamous cell carcinoma of the larynx is a rare clinical entity. It is a disease of the elderly with strong male predominance. It is more common in supraglottis. Patients usually present with a loco-regionally advanced stage. Surgery alone or a combined modality treatment with radiotherapy is commonly reported. Data on the organ preservation approach is lacking. It has a worse survival outcome when compared to laryngeal cancers in general. Twenty-two percent eventually develop distant metastases with the lung being the predominant site. Given the rarity of this clinical condition and the lack of data from studies with adequate number of cases, this systematic literature analysis provides the best possible evidence. While case reports do not provide strong evidence, compilation of these reports when analyzed can provide relevant information. Conflict of interest None. Acknowledgements The author is indebted to Dr Moni Abraham Kuriakose and Dr Subramania Iyer for their help and guidance.

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