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Does Histologic Grade Have a Role in the Management of Head and Neck Cancers?

From the Department of Radiation Oncology and Department of Pathology, L’Hôtel-Dieu de Québec, Québec, Canada.

Address reprint requests to André Fortin, MD, MSc, Department of Radiation-Oncology de l’université Laval, L’Hôtel-Dieu de Québec, 11 Côte du Palais, Québec, Canada G1R 2J6; email: afortin@ videotron.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy.

PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis.

RESULTS: There is a strong correlation of grade with N stage (P < .000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P < .000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P = .001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P = .008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P = .000001) as well as T stage (P = .003), N stage (P = .000001), and neck failure (P = .0003). Higher grade was also an independent predictor of survival (P = .02).

CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THERE ARE NOW many options in the treatment of locally advanced head and neck carcinomas. Treatment options include surgery and postoperative radiotherapy with or without concomitant chemotherapy, radiochemotherapy, and an altered fractionated scheme of radiotherapy. In both options, many variations are possible; there are as many kinds of radiochemotherapy or altered fractionated schemes of radiotherapy as there are oncologic centers in the world. Even the definition of locally advanced carcinomas is not clear. Usually, it stands for inoperable carcinomas, but depending of the surgeon’s experience, his reconstructive procedure ability, almost every thing may become operable.¹ Moreover, even the primary role of surgery in operable cancers is challenged by some authors.² Only one thing seems to be clear, standard radical radiotherapy alone is not a valid option for locally advanced diseased.^3,4

One can try to classify actual available and proven treatments by their mode of action. The advanced stage of head and neck carcinomas has two modes of failure, locoregional and, in an increasing number of cases, distant failure. In fact, with aggressive radiochemotherapy, the pattern of failure has been inverted, and now, distant metastases (DM) are becoming the more frequent mode of failure.^5,6

Currently, most treatments have purely locoregional intent, such as surgery and postoperative radiotherapy, altered fractionated radiotherapy, and some kinds of radiochemotherapy schedules, including radiotherapy and daily or weekly dose of chemotherapy.^7-9 Others radiochemotherapy schedules have some potential to destroy DM if a high dose of chemotherapy is given during or after radiotherapy.^10,11-13

These different modes of action have been clearly identified in lung cancers and cervix carcinomas.^14-17 It is not the best optimal approach to treat a cancer that, at some stage, is at a very high risk of distant failure, with a modality that insists only on the locoregional aspect of the disease.

In head and neck carcinomas, predictors of distant failure have been poorly studied. Only N-stage, neck failure, and site are consistently recognized as being associated with DM.^18-32 Also, predictive factors come often from surgical series and are not available for patients treated with a radical form of radiotherapy. It would be useful to know more precisely which factors may identify patients who are at high risk of DM and, therefore, candidates for a treatment that includes a systemic portion. By the same way, patients at low risk of DM would also be identified and spared the major side effects of a high-dose chemotherapy regimen. The aim of the study is to evaluate if grade, like in other common malignancies, has a role in head and neck carcinomas, particularly to predict the risk of DM and, at the same time, to establish a relation between clinical and immunohistochemical markers.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This is a retrospective analysis of all 1,547 patients consecutively treated by radical radiotherapy (1,020 patients) or postoperative radiotherapy (527 patients) between 1988 and 1997 at the Hotel Dieu of Quebec Hospital, Quebec, Canada. Only the patients for whom grade was known and patients treated with curative intent ( 50 Gy) were included in this study. Therefore, 1,266 patients were available for the analysis.

The following data were compiled when available: age, sex, clinical stage T and N, histology grade, anatomic site, smoking status, and performance status. Photon energy, radiation dose, treatment duration, and boost of brachytherapy were also recorded. For postoperative patients, we recorded surgical margin status, number of positive and excised nodes, presence of extracapsular extension, and tumor size (as the product of the two maximum diameters). Variables obtained from surgical staging were not used in the analysis because we were interested in the presurgical prediction of DM.

Evaluation of Grade
Grade was evaluated by the pathologist of the referring center. The World Health Organization criteria were used as follows: grade 1, well differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated or anaplastic. Grade is dependent on the degree of prickle formation, keratinization, and overall resemblance of carcinoma to normal squamous epithelium. The classification is based on the general picture of the neoplasm rather than the details of individual nuclear.³³

Central review was not performed because it is not the usual clinical practice in our institution. However, more than 90% of the pathologists were trained at our institution (Laval University, Quebec, Canada). Because patients were referred from many hospitals, we divided them into four groups: two groups from institutions that referred more than 150 patients, a third group from centers that referred between 50 and 150 patients, and a fourth group from centers that referred less than 50 patients. Therefore, the effect of grade will be evaluated for the whole cohort of patients and then for each group. Group I includes one institution and 29% of the patients; group II includes one institution and 17% of the patients; group III includes five institutions and 35% of the patients; and group IV includes 19 institutions and 19% of the patients.

Study of Agreement Between Pathologists
It was possible to obtain the initial slides and blocks for 272 patients from 20 referring institutions. Sections were recut and stained with hematoxylin and eosin. One of our pathologists looked at the slides without knowing the grade given by the referring pathologist. The kappa statistic was used to evaluate the agreement between pathologists.

Treatment
Patients with T1/T2 were treated by surgery or radical radiotherapy. For larger tumors, surgery was the first option, and radiotherapy was used when the morbidity associated with surgery was estimated too high. The neck was managed in accordance with the treatment of the primary tumor; patients treated with primary surgery had neck dissection, and patients treated with radiotherapy had their neck irradiated. Two large fields were used to deliver 60 to 70 Gy to patients treated by radical radiotherapy and 50 to 60 Gy to postoperative patients. One hundred twenty patients received a boost of brachytherapy, usually for large carcinomas of the oropharynx. A total of 799 patients had radical radiotherapy, and 467 had surgery and postoperative radiotherapy; 402 patients had neck dissection. No patient had chemotherapy.

Determination of DM
Patients were followed-up every 3 months for 2 years, then every 6 months for 3 years, and then every year. They have an annual pulmonary x-ray and were referred to a pneumologist for diagnosis if appropriate. Bone scan and liver ultrasound were performed only when the patients presented symptoms.

Immunohistochemistry
The method for evaluation of p53, ki-67, and GST pi have been fully described in Raybaud-Diogene et al.³⁴ A correlation between grade and immunohistochemistry was also performed.

Statistical Analysis
DM failure curves were obtained according to the Kaplan-Meier method. Statistical differences between curves were calculated using log-rank tests. A Cox regression multivariate analysis was performed.^35,36 The assumption of proportional hazard was tested using the time-dependent covariate test.³⁷ Neck failure was included in the Cox model as a time-dependant covariate. Comparisons between groups were made using Pearson or maximum-likelihood ² for categorical data and by the Student’s t test for comparison of means. For the comparison of multiple means, the analysis of variance or Kruskal-Wallis exact tests were used.

For the purpose of the analysis, we first record overall DM rate. Then, we evaluate the rate of DM for patients with neck control and then for node-positive patients with neck control. All data analyses were performed with the aid of the Statistica software (Statsoft, Tulsa, OK).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
There were 1,266 patients available for analysis; their median age was 61 years (lower quartile, 53 years; upper quartile, 69 years). The main characteristics of our population are illustrated in Table 1. The median follow-up is 742 days (lower quartile, 387 days; upper quartile, 1,358 days). For patients with locoregional control, median follow-up was 896 days (lower quartile, 479; upper quartile, 1,532 days).

Univariate Analysis of Factors Associated With DM
Distant failure rate is presented for different factors in Table 1. Stage N and T, grade, anatomic site, and neck failure are significantly associated with DM. The relation between grade and DM is shown in Fig 1. The same relation stands if we consider only patients with positive nodes (Fig 2). Grade is also strongly associated with DM in patients with locoregional control (Fig 3). In fact, the same relation between grade and distant failure is observed whether or not the patient had neck failure.

View larger version (18K): [in this window] [in a new window]   Fig 1. Rate of distant metastases for all patients in function of grade. , complete; +, censored.

View larger version (17K): [in this window] [in a new window]   Fig 2. Rate of DM for node-positive patients in function of grade. , complete; +, censored.

View larger version (17K): [in this window] [in a new window]   Fig 3. Rate of DM for node-positive patients and neck control in function of grade. , complete; +, censored.

View larger version (12K): [in this window] [in a new window]   Fig 4. Number of pathologic positive nodes in function of grade.

View larger version (34K): [in this window] [in a new window]   Fig 5. (A) Mean percentage of ki-67 in function of grade. (B) Number of patients with no (0%), low (< 10%), intermediate (10% to 50%), and high (> 50%) GST pi expression. Grade is inversely proportional to GST pi expression.

Grade and Survival Analysis
Grade is associated with survival (Fig 6). In multivariate analysis, grade (P = .02) ranks third for predicting survival, behind T and N stage.

View larger version (19K): [in this window] [in a new window]   Fig 6. Overall survival in function of grade. , complete; +, censored

Grade and Institutions
Our patients were regrouped according to the referring institutions. Four groups were formed. The rate of DM in function of grade was evaluated into each group. The same relation between grade and DM was found in each group.

In the first group (one institution, 29% of patients), DM-free survival rates were 93%, 85%, and 67% for grade 1, 2, and 3, respectively (P = .0004). In the second group (one institution, 17% of patients), DM-free survival rates were 100%, 96%, and 80% for grade 1, 2, and 3, respectively (P = .03). In the third group (five institutions, 35% of patients), DM-free survival rates were 99%, 93%, and 77% for grade 1, 2, and 3, respectively (P = .0003). In the fourth group (19 institutions, 19% of patients), DM-free survival rates were 97%, 90%, and 72% for grade 1, 2, and 3, respectively (P = .01).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We found that grade is a strong and independent factor associated with DM in head and neck carcinomas. Although DM occur essentially in node-positive patients, grade adds useful information to the neck staging. For example, a patient with a stage N1 G3 is at higher risk of DM than a patient with a stage N2 G2 or with a stage N3 G1. We also demonstrated that DM are a problem that has to be addressed in the high-risk group of DM identified by our combination of grade and N stage (Table 2). For example, DM rate is close to 50% in N3 G3 patients.

Although the grade of the tumor does not enter into the staging of the tumor, it should be recorded.³⁸ Unfortunately, grade is not often reported in head and neck literature, even in large prospective studies.^3,39 It is not always easy to know if grade was not reported because it had no prognostic value or simply because it was not recorded at all. However, there may be a publication bias if grade is reported only when it is found to have prognostic value.

It is a difficult task to compare our rate of DM with other series because populations are likely to be different. In large series of general population of patients with head and neck carcinomas, Merino et al,⁴⁰ Leemans et al,²⁵ and Calhoun et al²¹ report a 10% to 12% probability of 5-year DM-free survival. Among patients with locally advanced tumors, Leibel et al³⁹ found a DM rate of 21% and 38% for patients with locoregional control and locoregional failure, respectively. In a general population of 1,244 patients with locoregional control, Leon et al²⁷ reported a DM rate of only 5% after 5 years. In our series, we have similar results, with few DM in patients with locoregional control, except for the G2 and G3 node-positive patients that had a 15% and 32% risk, respectively, of DM at 5 years.

The predicting factors for DM are usually similar to those reported in our series. It is usually recognized that stage N,²¹ site (pyriform sinus²³ and nasopharynx²⁶), neck failure,^24,26 number of nodes,^25,41 anatomic location of neck nodes,^41,22 and extracapsular extension²⁵ are associated with an increased risk of DM. Grade is often associated with the presence of DM in univariate analyses but not in multivariate analyses.^27,30,42,43 Once again, however, grade is rarely reported, even in large prospective series.^3,39,44 In our series, grade ranked second after neck stage in predicting DM. In fact, for our node-positive patients, it is the most powerful predictor of DM. In our Cox model, we do not include two of the factors generally taken into account when estimating DM, extracapsular extension and anatomic location of neck nodes. We could not incorporate these variables into our model as the majority of our patients were treated by radical radiotherapy and not by surgery. This may be one of the reasons for the discrepancy between our series and others. However, even in our 380 patients for whom this information was available, grade is still an important and significant predictor of DM, whereas extracapsular extension²⁸ is not associated with DM. Moreover, it is clear that variables like extracapsular extension, precise anatomic location of the nodes, number of nodes, and nodes outside the sentinel area are not available unless neck dissection and precise mapping of the neck is performed.²⁸ This information would, therefore, not be available for patients treated by a radical form of radiotherapy. The same is true for neck failure, a variable that is not available for the initial management of the patient.

Our initial work-up included only a chest x-ray. With a computed tomography scan of the thorax,^45-47 some patients included in our study would have been excluded if they had been found to have initial lung metastases. In the high-risk group, de Bree et al⁴⁵ found up to 17% of DM by performing a computed tomography scan of the thorax before surgery. The value of a positron emission tomography scan as a tool for screening DM is still under investigation.^{48 49}

Another difficulty in analyzing factors associated with DM in head and neck carcinomas is to distinguish between the pulmonary metastases themselves and primary lung cancers.⁵⁰ However, our database contains some characteristics that may help validate our data. In contrast to DM, our rate of lung cancer is inversely proportional to N stage and is not associated with neck failure (P = .4). Lung cancer rate is not correlated with histology grade. The 3-year survival rate for patients with DM is 16.5%, and it is 49% for patients with lung cancer. Median time to develop DM was 301 days, and it was 696 days for lung cancer (P < .0000001). There is also a tendency toward more lung cancers in patients who are active smokers (6% for current smokers, 4.7% for former smokers, and 1% for someone who has never smoked; P = .08, maximum likelihood ²). These results are comparable with the results of Kim et al.⁵¹ We found no relation between tobacco use and DM (P = .9). All these results indicated that, in our database, patients with DM and patients with lung cancers are distinct.

Like other authors, we found that grade is associated with clinical aspects of the illness. High grade is associated with high N stage^52,53 and with anatomic location like the nasopharynx and the hypopharynx.⁵² As opposed to other authors, in our series, anatomic sublocations were not associated with DM when grade was taken in account in the analyses. The small number of patients in this sublocation area may explain these discrepancies, but it is also conceivable that cancers from these locations had a high distant metastatic potential simply because they are high-grade tumors.

Histologic grade is considered to be subjective and subject to a wide interobserver variability.⁵⁴ We were able to review 273 of our cases. They were regraded by a member of our team (C.C.) who did not know the score given by the initial pathologist. The overall agreement was 72%. The value of the kappa statistic was 0.55, which indicated a moderate agreement. Grade 1 patients were reclassified as grade 1 in 50 (75%) of 66 cases, as grade 2 in 104 (72%) of 149 cases, and as grade 3 in 36 (64%) of 56 cases. The correlation between the pathologists may seem week but is in the same order of magnitude as other subjective classification, like N stage for example.⁵⁵ No numbers are available, but the correlation for T stage or even anatomic location is probably not much better.⁵⁶ Moreover, after classifying patients in the old and the new grade classifications, rates of DM were recalculated and were found to be the same in both groups where grade was still significantly associated with DM (P = .001 in both groups). Despite this problem, grade should be reported, and with training, interobserver variability may improve.^57,58

We also found that grade was associated with local control by radiotherapy.^43,59-62,63 Grade 3, grade 1, and grade 2 were respectively associated with better control. The fact that grade 2 is associated with the worst local control corroborates other larger series.^43,63 In major studies from the Radiation Therapy Oncology Group, grade was not associated with local control.^64,65 However, as opposed to other studies, locoregional control was analyzed instead of local control, which makes the conclusion difficult to interpret because high grade is also associated with high neck stage. Also, in contrast to our own and to most European series, the population entered in the Radiation Therapy Oncology Group database comprises mainly advanced head and neck carcinomas in which ancillary prognostic factors such as grade may be overshadowed by the magnitude of the locoregional disease. In our series, grade is a significant prognostic value for local control only in the early stages of the disease. Again, unfortunately, few authors report on grade and local control, even in large recent randomized studies.^3,44

We found that neck control was marginally associated with grade in univariate analyses.⁵² However, in our multivariate analyses, grade is no longer associated with neck failure when the variable N stage is incorporated in the Cox model.^{66 67}

Grade was not associated with p53 but was correlated well with ki-67 and GST pi. It has also been shown in breast carcinomas that high grade correlates with high ki-67. Other cells kinetic indicators such as potential doubling time or labeling index were not associated with grade.⁴³ To our knowledge, this the first time that a relationship is established between low grade and low GST pi expression. An interesting aspect that will need to be further investigated is the putative resistance to cytotoxic agents from both low-grade tumors²⁶ and from tumor-expressing GST pi.^68,69

Identification of high-risk patients may help in selecting the treatment orientation. If a locoregional approach is adequate for patients with a low probability of DM, it is not optimal for patients with a high risk of DM. Even if we are able to identify a high-risk group for DM, many problems still remain unsolved. The value of systemic treatment is not clearly established. It is generally admitted that chemotherapy has a small but significant effect on DM. But the magnitude of that effect is not easy to evaluate because on the one hand, the addition of chemotherapy reduces the rate of locoregional failure⁷⁰ and consequently, the rate of secondary metastases.^24,39 On the other hand, as the patient is alive for a longer time, this better locoregional control places the patient at a higher risk to develop DM.⁷¹ Therefore, a systemic treatment with no effect at all per se on DM may be associated with a decreased rate of DM through increasing locoregional control. The only way to evaluate the effect on DM would be to compare two treatments that have the same locoregional control rate.

The best locoregional treatment is also an unknown factor. Considering the high response rate,^11,12 and some reported cure with only chemotherapy⁷² and considering that the best locoregional results seem to come from studies using high doses of concomitant cisplatin, it is possible that the systemic treatment may also be the best locoregional treatment.^2,13 Under these circumstance, identification of a high-risk group for DM will be less useful.

In the postoperative setting, Cooper et al⁶⁶ identified patients at high risk for locoregional recurrence as those with two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection. They suggest that these patients are candidates for postoperative radiochemotherapy. However, this group of patients does not bear the same pattern of failure. Patients with positive margins needs local treatment such as high dose of radiotherapy⁷³ and are not at risk of distant failure (P = .7, in our series). In our series, grade 3 patients with two and more lymph nodes have a 45% risk of DM after 5 years and also need efficient systemic treatment as a part of their treatment. The only way to solve these problems is through a study comparing a locoregional with a systemic treatment among patients stratified for their risk of DM failure.

In conclusion, grade may be useful in head and neck oncology, but its usefulness is not straightforward. It is probably associated with local control but only in patients treated by radiotherapy. Grade is also related to N stage but not to neck control. Grade 1 is significantly associated with a higher GST pi overexpression than grade 3, a finding that deserves further investigations.

Grade is also a powerful predictor of DM and that fact added important information to clinical and pathologic neck staging. It helps to identify patients at high risk of DM for whom an efficient systemic treatment is mandatory.

	ACKNOWLEDGMENTS

 
We thank Guylaine Daigle for her technical assistance.

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Submitted November 15, 2000; accepted June 15, 2001.

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