Adenoid cystic carcinoma of the head and neck.

Oral Oncology (2005) 41, 328–335

http://intl.elsevierhealth.com/journals/oron/

Adenoid cystic carcinoma of the head and neck. Clinicopathological analysis of 23 patients and review of the literature Alexander D. Rapidis a,*, Nikolaos Givalos a, Hariklia Gakiopoulou b, Gregory Faratzis a, Spyros D. Stavrianos a, George A. Vilos a, Emmanuel E. Douzinas c, Efstratios Patsouris b a

Department of Maxillofacial Surgery, Greek Anticancer Institute, St. Savvas Hospital, 171 Alexandras Avenue, Athens 115 22, Greece b Department of Pathology, University of Athens Medical School, Goudi, Athens, Greece c Department of Critical Care Medicine, University of Athens Medical School, Evangelismos General Hospital, Athens, Greece Received 1 November 2004; accepted 4 December 2004

KEYWORDS

Summary Adenoid cystic carcinoma (ACC) is a rare epithelial tumor with a distinct natural history characterized by an indolent but persistent growth, late onset of distant metastases and eventual death of patients. Between 1991 and 2003, 23 patients with ACC were treated in our Department. Surgery with a curative intent followed by radiotherapy (RT) was applied in 22 patients. Complete resection was achieved in 72.73% of patients. Local recurrence occurred in 26% of patients. Positive margins emerged as the only statistically significant parameter (p < 0.0001) influencing the development of local recurrence. Distant metastasis (DM) occurred in 47.8% of patients. In 54.5% of the patients developing DM, this occurred between 5 and 10 years after the initial treatment. DM was influenced by perineural invasion (p = 0.04) and was disassociated from local control of the tumor. The mean overall survival of our patients was 70.58 months and the mean disease free survival 61.85 months. Perineural invasion (p = 0.048) and DM (p = 0.001) had a statistically significant impact on final patients’ outcome. The most important factor influencing survival was DM. Its late onset, irrespectively of local control, supports the hypothesis that ACC has a potential to develop DM in the very early phases of tumor growth. c 2005 Elsevier Ltd. All rights reserved.

Adenoid cystic carcinoma; Local recurrence; Distant metastasis; Overall and disease free survival



*

Corresponding author. Tel.: +30 210 6409477; fax: +30 210 6420146. E-mail address: [email protected] (A.D. Rapidis).



1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2004.12.004

Adenoid cystic carcinoma of the head and neck

Introduction Adenoid cystic carcinoma (ACC) of the salivary glands is a malignant epithelial tumor with bidirectional differentiation towards luminal (ductal) and abluminal (myoepithelial and basal) cells.1,2 The myoepithelial cells predominate.1 The reported rates of incidence of ACC have changed since the polymorphous low-grade adenocarcinoma (terminal duct carcinoma), a tumor that was frequently misinterpreted as ACC, emerged as a distinct pathological entity.1 In the past, ACC was frequently reported as the most common malignant tumor affecting the minor salivary glands.3,4 Recent studies however have shown that polymorphous low-grade adenocarcinoma and mucoepidermoid carcinoma are more common malignancies than the ACC.1,5 ACC constitutes about 7.5% of all epithelial salivary gland malignancies and 4% of all salivary gland tumors.1 ACC was first described by Billroth in 1856.6 Growth patterns are characterized as cribriform, tubular and solid. As the cribriform pattern of the tumor forms cylindrical accumulations of basal lumina, glycosaminoglycans and stroma, the term cylindroma had been applied in the past.6 Cylindroma, though, is a confusing term as a benign eccrine dermal tumor bears the same name.1 Little information exists on cytogenetic abnormalities in salivary gland neoplasms, but in the ACC, anomalies in the terminal part of 6q and 9p chromosomes have been reported.7,8 Recent studies have demonstrated a high incidence of loss of heterozygosity (LOH) at chromosome 6q23-35.9 ACC has classically been described as having an indolent but persistent and recurrent growth, late onset of metastases and eventual death of patients.10–12 In contrast to other epithelial malignancies with poor prognosis, ACC has a good 5-year survival rate.1,10–12 However, overall survival continues to drop after the 5-year follow up period, producing considerably lower 10- and 20-year survival rates.1,10–12 The aim of the present study was to report on a cohort of 23 patients with ACC and to investigate the impact of various clinicopathological parameters on disease-free and overall survival, and the development of local recurrence and distant metastases.

Material and methods During the years 1991 to 2003, 23 patients with ACC in the head and neck region were treated in our Department. The mean age of patients at the

329 time of diagnosis was 60.39 years (range 38– 84 years). The demographic data of the patient population, clinical and pathological tumor characteristics, treatment modalities offered and their results were obtained from a retrospective chart review. Patients were staged according to the 1988 revision of the criteria of the American Joint Committee on Cancer (AJCC) staging system.13 Information regarding patient survival, local recurrence and distant metastasis were available for all patients. There were 10 male and 13 female patients, producing a male to female ratio of 1:1.3. None of the patients presented with distant metastases, and all but one were treated surgically with intent to cure. One patient refused surgical treatment. ACCs were classified according to their morphological growth pattern into three types: cribriform, tubular and solid. Cribriform and tubular ACCs were considered as low grade tumors, while solid ACCs as high grade tumors. In 22 cases, treatment consisted of surgery followed by radiotherapy. In 5 of these cases adjuvant chemotherapy was also applied. One patient refused surgery and was treated with chemoradiation. The surgical resection was considered complete when negative margins were described on the surgical specimens. However, when the tumor margins extended within 5 mm from the resected specimen, or when there was tumor directly involving the margins, the resection was considered incomplete. Statistical analysis was performed with the SPSS program version 11. Correlations between the different clinicopathological parameters were investigated through PearsonÕs Chi-Square. Overall and disease-free survivals were calculated with the Kaplan–Meier method. Log Rank test was used to compare survival between different groups of patients. A p-value of equal or less than 0.05 was considered statistically significant.

Results Seven (30.93%) ACCs originated from the major salivary glands, 13 (56.52%) from the minor salivary glands and 2 (8.69%) from the lacrimal gland. The distribution of ACCs according to site of origin is shown in Table 1. Histologically, 13 (56.5%) ACCs were classified as solid type and therefore as high grade lesions, while 10 (43.5%) ACCs were of the ethmoid/tubular type and were classified as low grade lesions. Perineural invasion was histologically documented in

330

A.D. Rapidis et al.

Table 1 Distribution of 23 ACCs of head and neck according to site of origin Primary site Major salivary glands Parotid gland Submandibular gland Sublingual gland Minor salivary glands Maxilla: palate Maxillary antrum Maxillary antrum + orbital extension Lacrimal gland Lacrimal gland + orbit + maxilla

n

(%) 7 2 4 1

30.93 8.69 17.39 4.34

13 6 2 5

56.52 26.08 8.69 21.73

2 1

8.69 4.34

18 (81.81%) out of 22 patients treated with surgery. Resection margins were positive in 6 (27.27%) out of these 22 patients. Eighty percent of patients with positive margins had a high grade ACC. In 83.3% of patients with positive margins, perineural invasion was also documented. However, correlations among histological grade, perineural invasion and margins of resection did not reach statistical significance. Mean follow up was 5.64 years (range: 0.18–12.5 years). All alive patients were followed up for at least 22 months with a mean follow up time of 5.9 years (Table 2). Local recurrence was observed in 6 (26%) patients. In 2 of them, local recurrence was the only type of treatment failure. The association between local recurrence and perineural invasion was not statistically significant (p = 0.9). On the other hand, a statistically significant correlation was calculated between local recurrence and surgical margin status (x2 = 13.072, p < 0.0001). Indeed, 83.3% of patients with positive margins developed local recurrence while 93.8% (15/16) of patients with free margins did not develop local recurrence. No statistically significant correlation could be demonstrated between local recurrence and histological grade (p = 0.3), although 80% of the tumors that recurred locally were classified as ‘‘high-grade’’. This may be explained by the fact that there was an even distribution of tumors, that did not recur locally, between ‘‘low-’’ and ‘‘high-grade’’ histology. Distant metastasis was documented in 11 (47.8%) patients. Pulmonary metastases developed in 10 of these patients, either as the sole site of distant metastatic spread (5 cases) or in association with metastases to other sites, like the skeleton (2 cases), the liver (1 case) or both (2 cases). One patient developed brain and liver metastases. Metastases developed in the time frame between

18 and 120 months (mean: 62.5 months, median: 60 months) after the initial surgical treatment of the primary tumors. Additionally, 5 (45.4%) of the 11 patients with distant metastases were diagnosed within 5 years after the initial treatment of the primary site, and the remaining 6 (54.5%) between 5 and 10 years. In 4 cases, local recurrence had preceded the development of distant metastasis. Local recurrence did not lead to the subsequent development of distant metastasis, as no statistically significant correlation (p = 0.221) was demonstrated between these two parameters. Similarly, no statistically significant correlation was established between margin status and the development of distant metastasis (p = 0.22). The occurrence of distant metastasis was associated with the histological grade of ACCs: 80% of cases occurred in patients with high-grade ACCs. In contrast 77.8% of low grade ACCs did not manifest distant metastatic spread. However, the association between histological grade and distant metastasis was not statistically significant (p = 0.069). A statistically significant correlation was established between perineural invasion and distant metastasis (p = 0.044), as in all patients (100%) with distant metastasis, perineural invasion was a prominent histological finding. Mean overall survival of our patients was 70.58 months (standard error: 8.80, 95% confidence interval: 53.34–87.82) with a median value of 60 months. Disease-free intervals ranged from 8 to 150 months. Mean disease-free survival was 61.85 months (standard error: 8.51, 95% confidence interval: 45.17–78.52) with a median value of 52 months. Kaplan–Meier curves of overall and disease-free survival are shown in Figs. 1 and 2, respectively. Eleven patients died of disease, and two of other causes. Seven patients are alive without disease, and three are alive with disease. A statistically significant association was demonstrated between final outcome and the previous development of distant metastasis (x2 = 16.685, p = 0.001). It was interesting to note that the status of surgical margins did not alter significantly the overall survival of the patients (Fig. 3). The impact of various histological (grade/histological type, perineural invasion, status of margins) and clinical (age, sex, primary site, local recurrence, distant metastasis) parameters on diseasefree survival, overall survival and final outcome (patient status) was statistically analyzed, in order to establish prognostically useful factors. However, no statistically significant associations emerged between disease-free or overall survival and the above parameters, probably suggesting either the

Adenoid cystic carcinoma of the head and neck need for longer follow-up periods or the need for larger number of patients. When patients were stratified according to primary tumor site (major, minor salivary glands and lacrimal gland), no significant differences in survival was also observed (Log Rank test: p = 0.64). Apart from the previously described significant association between final outcome and the development of distant metastasis, a statistically significant association was also established between perineural invasion and adverse final outcome (x2 = 7.915, p = 0.048).

Discussion ACC is a rare tumor accounting for less than 2% among all head and neck malignancies.14 In our material ACC’s constituted 1.4% of head and neck malignancies. A 1:1.3 male to female ratio was observed and agrees with the commonly reported female predominance for ACC, and other salivary gland tumors.1 However, there are studies reporting a male predominance for ACC,9 and others reporting an equal gender distribution.15,16 ACC is predominantly a tumor of adulthood with a definite peak incidence in the fourth through sixth decade of life.1 The mean age of our patients was 60.39 years. In our series, ACC was a tumor originating predominantly in minor salivary glands and this is in agreement with previous reports.4,17,19 The most common group of minor salivary glands reported to be affected with ACC are those of the palate.4 Indeed, 56.5% of the tumors in our patients originated in minor salivary glands, with nearly half of them occurring in the palate.20,21 Several prognostic factors have been suggested for ACC of the head and neck. Histological subtype and histological grade are among them. Several studies report a favorable prognosis for the tubular and cribriform form of ACC, than for the solid variety.11,14,21–23 In the present study, solid ACC was associated with a higher incidence of distant metastases, which agrees with the results of Sung et al.12 However, this association was not statistically significant. Additionally, no statistically significant correlation emerged between histological grade and final outcome, a finding previously reported by Spiro et al.24 Grading of ACCs is not always feasible, since many ACCs display multiple patterns.16 Studying cribriform ACC, Santucci and Bondi25 reported a positive correlation between the number of gland-like spaces per square millimeter of tumor and the survival of patients. Yamamoto et al.26 found that as the disease progresses, tumors may actually transform from

331 tubular in early stages, to cribriform, and finally to solid. Although the solid growth pattern is generally thought to carry the worse prognosis, many authors question the prognostic value of tumor grade and express the need for standardization using quantitative classification systems.16 Unlike histological grade, perineural invasion was associated with both distant metastasis and adverse final outcome in a statistically significant way. Perineural invasion has been identified as an unfavorable prognostic factor.11,18,23 Controversies still remain on the relationship between perineural invasion and distant metastasis.14,21,27 Van der Waal et al.28 found no significant correlation between the two parameters. Vrielinck et al.29 reported that 40% of tumors with perineural invasion subsequently metastasized in contrast to those without perineural invasion that did not cause distant metastases. In their multivariate analysis, Mendenhall et al.17 state that perineural invasion was a significant prognostic factor for the development of distant metastasis. The observed association of perineural invasion with the development of distant metastasis in our study, suggests that perineural invasion facilitates distant metastatic spread, thus affecting final outcome. The adequacy of surgical resection did not seem to influence metastatic spread or final outcome, which is in accordance with the results of Garden et al.18 (Fig. 3). An association was established between margin status and local recurrence. Positive margins emerged as the only parameter leading in a statistically significant manner to the subsequent development of local recurrence. Given that all patients were treated with a combination of surgery and radiotherapy, it is doubtful whether adjuvant radiotherapy is of value in preventing local recurrence. Despite the fact that 83.3% of patients with positive margins developed local recurrence, radiotherapy probably contributed to achieving local control in the remaining 16.7% of tumors with positive margins. In general, radiation therapy as the sole treatment modality seems to be inadequate for ACC. Radiation treatment as an adjuvant modality to surgery has been shown to improve local tumor control, especially when there is microscopic residual tumor.1,17,30,31 Multicentric prospective randomized clinical trials are needed to establish the value of adjuvant radiotherapy in the treatment of ACC.32 Unlike most other types of salivary gland carcinoma, in the ACC distant metastasis is far more frequent than regional lymph node involvement.1 Our findings demonstrated a statistically significant association between the development of distant metastasis and adverse final outcome. Forty-eight

332

Table 2

Demographic, clinical, histological, treatment and outcome characteristics of our patients

No.

Age

Sex

Location

Neck

Histologic subtype

Grade

Surgery

Margins

Perineural inv.

CT

Local rec.

Dist. Met. (site)

Status

OS

DFS

SSLR

SSDM

1 2

61 56

M F

(R) Parotid (L) Submandibular

No No

Solid Solid

High High

Total parotidectomy RND

+ +

Yes Yes

Yes Yes

Yes Yes

DOD DOD

96 136

84 120

12

6 16

3 4 5 6

70 69 84 63

F F M F

No No No No

Ethmoid Ethmoid Solid Ethmoid

Low Low High Low

RND SHOND Local excision Hemimaxillectomy

Yes Yes Yes Yes

No No No No

No No No No

AND AND DOC AND

48 150 36 38

48 150 36 38

7

50

M

(R) Submandibular (R) Sublingual (R) Submandibular (R) Maxilla (palate) (R) Parotid

Yes (lungs) Yes (lungs, liver, spine) No No No No

Yes

Solid

High

Yes

Yes

No

Yes (lungs)

AWD

36

18

8

67

F

(L) Submandibular

No

Ethmoid

Low

Yes

No

No

No

AND

22

22

9 10 11

46 41 68

M F F

No No No

Solid Ethmoid Solid

High Low High

No Yes No

No Yes No

Yes No No

No Yes (lungs) No

AWD DOD AND

48 80 24

32 72 24

12

57

M

(R) Lacrimal (L) Lacrimal (L) Maxilla (palate) Maxilla

Total parotidectomy Hemimandibulectomy + Neck dissection I–II Orbital resection Orbital resection Hemimaxillectomy

No

Solid

High

No

No

No

No

AWD

40

40

13

77

F

No

Solid

High

Maxillectomy–Neck (I–III) RFA Intraoral palatectomy

No

No

No

No

AND

52

52

14

38

M

No

Ethmoid

Low

Intraoral palatectomy

Yes

No

Yes

No

DOD

118

96

22

15

60

F

Yes

No

Yes

Yes (lungs)

DOD

62

48

14

16

75

M

Yes

No

No

Yes (brain, liver)

DOD

84

60

24

17

62

M

Yes

No

No

No

AND

136

136

18

55

M

Yes

No

No

DOD

138

120

–

18

19

60

F

Yes

No

Yes

DOD

76

60

16

4

20

70

F

–

Yes

–

Yes (lungs, liver) Yes (lungs, spine) Yes (lungs, spine, liver)

DOD

30

21

Maxilla (palate) Maxilla (palate) (R) Maxillary antrum (L) maxillary antrum + orbit

Intraoral maxillectomy

No

Solid

High

No

Ethmoid

Low

No

Solid

High

No

Solid

High

Yes

Ethmoid

Low

Extended maxillectomy + orbital exenteration Extended maxillectomy + orbital exenteration Extended maxillectomy + orbital exenteration Maxillectomy No (refused surgical treatment)

+

+

16

6

9

A.D. Rapidis et al.

(R) Maxillary antrum + orbit (R) Maxillary antrum + orbit (R) Maxillary antrum + orbit (R) Maxillary sinus + orbit

No

+

18

F 73 23

F 40 22

333 Survival Function 1.0

Cum Survival

.8

.6

.4

.2 Survival Function 0.0

Censored

20

60 40

100 80

140 120

160

OVERALL SURVIVAL IN MONTHS

Fig. 1 Kaplan–Meier overall survival curve of patients with ACC.

Survival Function 1.2 1.0 .8

Cum Survival

No No Yes + Low No

Ethmoid

Orbital exenteration Maxillectomy High Solid No

Maxillectomy High Solid No

(R) Maxilla (palate) (L) lacrimal + orbit + maxilla (R) Maxilla ethmoids M 47 21

OS: overall survival; DFS: disease free survival; SSLR: survival since local recurrence; SSDM: survival since distant metastasis; M: male; F: female; RND: radical neck dissection; SHOND: supra homohyioid neck dissection; RFA: radical forearm free flap; DOD: dead of disease; AND: alive no disease; DOC: died of other causes; AWD: alive with disease.

60 60 DOC

32 36 DOD

Yes (lungs, spine) No No Yes

No

Yes Yes

No

Yes (lungs)

DOD

30

8

–

4

24

Adenoid cystic carcinoma of the head and neck

.6 .4 .2 0.0

Survival Function

-.2

Censored 0

40 20

80 60

120 100

160 140

DISEASE FREE SURVIVAL

Fig. 2 Kaplan–Meier disease-free survival curve of patients with ACC.

percent of our patients developed distant metastases, a percentage that falls right in the middle of the reported range (22–60%).10,12,15,16,18,33–38 Lung metastases predominate whereas other sites of distant metastatic spread include the skeleton, the liver, and the brain.39,40 Distant metastasis of the ACC seem to occur irrespectively of and despite complete control of the primary tumor and this was confirmed from our material.12,14 Spiro34 reported that about one third of the patients with ACC developed distant

334

A.D. Rapidis et al. Survival Functions

1.0

Cum Survival

.8

.6

.4

MARGINS

.2

POSITIVE 0. 0

NEGATIVE 20

40

60

80

100

120

140

160

OVERALL SURVIVAL IN MONTHS

Fig. 3 Kaplan–Meier survival curve between diseasefree and positive surgical margins.

metastasis during the follow-up period without any evidence of locoregional failure. In the study of Sung et al.,12 half of the patients with distant metastasis did not show evidence of locoregional failure. As distant failure in ACCs seem to occur independently of local control, Kokemueller et al.16 and other authors41,42 consider distant metastasis as an independent disease process and argue that its presence should not reduce the effort for local disease control. Another peculiarity of ACC is its late onset of distant disease spread.11,12,14 This was confirmed in our study: the median time between the diagnosis of the primary lesion and the detection of distant metastasis was 60 months (range: 18– 120 months). Metastasis from an ACC primary can remain asymptomatic for a long period of time.12,15 This seems to apply particularly in pulmonary metastases that seem to progress slowly.15,34,37,39 As the development of distant metastases has not been associated with previous local recurrence or T stage at presentation, it is safe to speculate that microscopic deposits to distant sites occurs early in the growth of the primary tumor.12 The detection of distant metastases to the lungs or to other organs in asymptomatic patients is not an indication for further treatment, as radiotherapy and chemotherapy are ineffective for the management of secondary ACC deposits.15,34,37,43–45 Chemoradiation or even surgical excision of secondary deposits have some palliative benefit in cases of symptomatic metastatic disease. The results from our study indicated that distant metastasis is the only important prognostic factor

affecting final outcome of ACC patients in a statistically significant way. In more than half of our patients, distant metastases was detected later than a 5-year follow-up period, confirming the delayed appearance reported in the literature. Development of distant metastasis occurred irrespectively of and despite complete control of the tumor in the primary site. Margin status (positive vs. clear) was significantly associated with local recurrence but not with distant metastasis. No other histological or clinical parameter proved to be a reliable prognostic factor for the development of distant metastases, other than perineural invasion. Our observations showed that although ACC has a slow growing pattern, it has a distinct biologic potential to develop micrometastases in the very early phases of tumor growth. Investigations at the molecular level may further elucidate the peculiar natural history of this intriguing malignant tumor.

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