Carcinoid Tumors of the Lung: Do Atypical Features Require Aggressive Management?

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1 Carcinoid Tumors of the Lung: Do Atypical Features Require Aggressive Management? Charles-Henri Marty-An6, MD, Val6rie Costes, MD, Jean-Louis Pujol, MD, Michel Alauzen, MD, Pierre Baldet, MD, and Henri Mary, MD Service de Chirurgie Thoracique et Vasculaire, and Service de Pneumologie, H6pital Arnaud de Villeneuve, and Service d'anatomie Pathologique, H6pital Lapeyronnie, Montpellier, France Atypical carcinoids are an intermediate form of tumor between low-grade malignant typical carcinoid and highgrade malignant small cell carcinoma, which represent the two ends of the spectrum of neuroendocrine bronchopulmonary tumors. Between 1983 and 1993, 27 patients with atypical carcinoids underwent surgical treatment. The histologic diagnosis of an atypical carcinoid was established if the criteria proposed by Arrigoni and associates were fulfilled. Seven pneumonectomies, 16 lobectomies, 2 segmentectomies, and 2 wedge resections were performed. Thirteen patients (48.1%) had regional nodal metastases and 6 patients (22%) had N2 disease at the time of surgical therapy. Distant metastases devel- oped in 5 patients (18.5%) after initial treatment. The 10-year survival in patients with an atypical carcinoid was 49%, versus the 84% 10-year survival rate observed in patients with a typical carcinoid. We conclude that the aggressive behavior of atypical carcinoids precludes the use of limited surgical resection and requires a more aggressive approach, with lobectomy and mediastinal lymph node dissection constituting a minimal procedure. The same criteria used for well-differentiated lung carcinoma should apply to this form of neuroendocrine lung tumor. Adjuvant chemotherapy is recommended for patients with stage III or distant metastases. (Ann Thorac Surg 1995;59:78-83) B ronchial carcinoids account for approximately 0.5% to 1% of all bronchial tumors. Initially considered a bronchial adenorna, which is a misnomer, they were distinguished from the less common cylindroid tumors by Hamperl in It is now widely held that typical carcinoids (TCs) and small cell lung carcinomas (SCLCs) represent the two ends of the spectrum of neuroendocrine bronchopulmonary tumors that arise from Kulchitsky cells. An atypical carcinoid (AC) is an intermediate form of tumor between a low-grade malignant TC (less than 5% lymph node metastasis at presentation) and a high-grade malignant SCLC. Arrigoni, Mills, and Paladugu recognized this entity and accurately described its atypical histologic characteristics. Considering the aggressive behavior of these tumors (50% lymph node metastasis at presentation), there is still much controversy with regard to the ideal forms of treatment in terms of the extent of resection and the value of systemic adjuvant therapy. We present here a retrospective review of our experience, with an emphasis on the clinicopathologic features, prognosis, and surgical management of ACs. Our data are compared with the data for bronchial carcinoids reported in the literature. Material and Methods Between 1983 and 1993, 79 patients with bronchial carcinoids were operated on, and 27 of these had atypical Accepted for publication June 28, Address reprint requests to Dr Marty-An6, Service de Chirurgie Thoracique et Vascu aire, H6pital Arnaud de Villeneuve, Centre Hospitalier Universitaire, 34295, Montpellier Cedex 5, France. carcinoids. Histologic diagnosis was established on the basis of the finding, yielded by hematoxylin-eosinstained slides of paraffin-embedded tissue sections. Diagnosis of an AC was established according to the criteria proposed by Arrigoni and associates [1]: (1) increasing mitotic activity in presence of recognizable carcinoid pattern; (2) pleomorphism, nuclear irregularity, hyperchromatism, and abnormal nuclear-cytoplasmic ratio; (3) Hypercellularity with disorganization of the architecture; and (4) areas of tumor necrosis. Immunochemical staining with monoclonal antibodies to neuron-specific enolase, chromogranin A, and synaptophysin was performed in 49 of the 79 patients. Data on the age, sex, presenting symptoms, radiologic features, surgical procedures, and evolution of the disease in each patient were reviewed in detail. All patients were followed up, and 16 patients with ACs were followed up for more than 5 years. Definitive staging was determined according to the revised International Clinical Staging System [2]. Survival curves were calculated by the Kaplan-Meier method. Results Atypical Carcinoids There were 21 men and 6 women with ACs. The average age at diagnosis was 55 years (range, 26 to 75 years). No patient had an occupational history of exposure to a known carcinogen. Eight patients were smokers (four to sixty packs per year) and I patient was an exsmoker. The presenting symptoms were recurrent bronchopulmonary infections in 4 patients, hemoptysis in 6 patients, cough in 2 patients, and Cushing's syndrome in 2 patients 1995 by The Society of Thoracic Surgeons /95/$ (94)00630-P

2 Ann Thorac Surg MARTY-ANI~ ET AL ;59:78-83 MANAGEMENT OF ATYPICAL BRONCHIAL CARCINOIDS Table 1. Presenting Findings in Patients With Bronchial Carcinoids Table 3. Postsurgical Staging Results Typical Atypical Typical Atypical Stage Carcinoids Carcinoids Finding Carcinoids Carcinoids Stage I Bronchopulmonary recurrent 17 4 T1 NO 18 6 infections T2 NO 24 8 Hemoptysis 13 6 Stage li Cough 1 2 T1 N1 1 2 Dyspnea 3 0 T2 N1 1 5 Cushing's syndrome 0 2 Stage lii Carcinoid syndrome 2 0 T1 N2 0 1 Screening chest x-ray study finding T2 N2 0 2 Total T3 NO T3 N2 Total (Table 1). Thirteen patients (48%) had no initial symptoms and the diagnosis was based on screening chest roentgenograrn findings. All patients except I underwent fiberoptic bronchoscopy, which revealed an endobronchial lesion in 13 patients, was normal in 12 patients, and showed an extrinsic compression in I patient. Endoscopic biopsy was performed in 10 patients and the tissue findings permitted an accurate histologic diagnosis in 5. In these 10 patients, there were no instances of troublesome hemorrhage. In 3 patients, biopsy was not performed because of the risk of hemorrhage. Radiologic studies and computed tomographic scans showed a central mass or atelectasis in 10 patients (37%) and a small peripheral mass in 17 patients (63%). Enlarged lymph nodes were detected on the computed tomographic scans in 5 of the 6 patients with mediastinal lymph node involvement (N2 disease) identified at thoracotomy. Data on the surgical procedures are detailed in Table 2. In all patients, the procedure included a standard lymph node dissection. There were no operative deaths and no major postoperative complications. The definitive staging results are given in Table 3 and findings from immunocytochemical staining of the tumor tissue are given in Table 4. Seven patients (26%) exhibited metastasis in the lobar or hilar lymph nodes (N1 disease) and 6 patients (22%) exhibited mediastinal lymph node metastasis (N2 disease). Five patients with N2 disease received adjuvant therapy (Table 5). The mean follow-up was 60 months (range, 5 to 134 months). Eighteen patients (67%) are still alive and free of disease. In the 2 patients with Cushing's syndrome, complete removal of the bronchial carcinoid led to clin- Table 2. Surgical Procedures Typical Atypical Operation Carcinoids Carcinoids Pneumonectomy 6 7 Lobectomy Segrnentectomy 3 2 Wedge resection 3 2 Bronchoplastic procedures 10 0 Total ical and biologic reversal of the endocrine manifestations. There were three deaths unrelated to the disease: one occurred 9 years postoperatively and was due to heart failure, one occurred 6 years postoperatively and was due to cerebral stroke, and the third patient died 4 years postoperatively of pulmonary embolus. Five patients (18.5%) suffered recurrence and 4 of them died: one at 10 months of local recurrence, one at 13 months of local recurrence and adrenal metastasis, one at 30 months of bone metastasis, and one at 84 months of liver metastasis. The 2 patients who suffered local relapse postoperatively had undergone a lobectomy. One patient is still alive 12 months postoperatively despite bone metastasis. The 2 patients (T1 NO, T2 NO) who underwent limited resections did not suffer recurrence. The follow-up findings in patients with N2 disease requiring adjuvant therapy are given in Table 4. One patient with an AC, initially staged as T2 NO M0, presented with local relapse and adrenal metastasis 6 months postoperatively and died 13 months postoperatively despite radiotherapy and chemotherapy. The 10-year survival rate was 49% in our patients with AC. Typical Carcinoids There were 25 men and 27 women with TCs. The average age at diagnosis was 45 years (range, 14 to 75 years). The presenting symptoms are summarized in Table 1. Bronchoscopy revealed an endobronchial lesion in 42 patients but an accurate histologic diagnosis was possible in only 10 patients. Biopsy was not performed in 15 patients because of the risk of hemorrhage. Radiologic studies Table 4. Results from Immunocytochemical Staining" Typical Atypical Stains Carcinoids Carcinoids Neuron-specific enolase 26]28 19/21 Chromogranin A 23/28 19/21 Synaptophysin 13/28 5/21 a Number of positive findings/number of patients studied.

3 80 MARTY-ANI~ ET AL Ann Thorac Surg MANAGEMENT OF ATYPICAL BRONCHIAL CARCINOIDS 1995;59:78-83 Table 5. Clinical Data in Patients With N2 Disease Patient Stage at Adjuvant No. Presentation Treatment Follow-up 1 T2 N2 M0 Chemotherapy a Died 30 months postop, bone metastasis 2 T1 N2 M0 Radiotherapy and Alive and free of chemotherapy a disease 8 months postop 3 T3 N2 M0 Immunotherapy Alive and free of (interferon) disease 42 months postop 4 T1 N2 M0 Radiotherapy and Alive and free of chemotherapy a disease 41 months postop 5 T3 N2 M0 Radiotherapy Alive with bone metastasis 12 months postop a Cisplatin, etoposide, 4-OH-epirubicine, and cyclophosphamide. demonstrated central lesions in 34 patients and peripheral nodules in 18 patients. The surgical procedures performed and definitive staging results are given in Tables 2 and 3. Two patients presented with metastasis in the intrapulmonary nodes (N1 disease), but no patients presented with mediastinal node metastasis (N2 disease). There were no deaths related to the disease in this group of patients. The 10-year survival rate in these patients was 84%, which is significantly higher than the 49% 10-year survival rate in the 27 patients with ACs treated during the same period (Wilcoxon test, p < 0.02) (Fig 1). Comment The three controversial aspects of ACs are the tumor nomenclature, the recommended surgical treatment, and the value of adjuvant chemotherapy. The variety of names used to refer this form of neuroendocrine lung tumor reflect the lack of understanding of the nature of ACs. The terminology proposed by Paladugu and Warren and their associates (Table 6) stresses the histogenetic continuum of progressively increasing malignancy starting with TC and extending to SCLC. Atypical carcinoid shows no clinical specificity. About 50% of our patients had no symptoms, and diagnosis was ~ ~ Typical Months -- Atypical Fig 1. Survival curves for patients with bronchial carcinoids. The lo-year survival was 49% for those with the atypical form and 84% for those with the typical form (p < 0.02). Table 6. Classifications of Neuroendocrine Tumors of the Lung Paladugu and Associates Warren and Associates Our Classification [10] [12] Typical carcinoid KCC-I Bronchial carcinoid Atypical carcinoid KCC-II Well-differentiated neuroendocrine carcinoma Small cell carcinoma KCC-III Small cell neuroendocrine carcinoma KCC Kulchitsky cell carcinoma. based on the findings revealed by screening chest roentgenograms. In Mills and associates' [3] series, the tumors were detected incidentally during routine examination in 65% of the patients. Rea and colleagues [4] reported that, in their patients with bronchial carcinoids, the carcinoid syndrome was always associated with the atypical form when liver metastases had occurred. Two of our patients with carcinoid syndrome had TCs and 2 with Cushing's syndrome had ACs, with complete reversal of the symptoms after tumor removal. Radiologic studies in our patients revealed a predominance of peripheral nodules (63%) and a central mass or atelectasis in 37% of the patients. Choplin and associates [5] noted that a round or ovoid, lobulated peripheral mass is the most common radiologic presenting feature of ACs (80%). Wilkins and co-workers [6] reported that 60% of their patients with peripheral bronchial carcinoids had ACs. Forster and colleagues [7] suggested that tumor size may be a prognostic factor in the differentiation of neuroendocrine lung tumors. They concluded that any tumor measuring more than 2.5 cm on a computed tomographic scan is more likely to be an AC than a TC. On contrast-enhanced computed tomographic scans, bronchial carcinoids enhance uniformly, and this can be differentiated from the lesser enhancement typical of bronchial carcinomas [8]. The positive yield for bronchoscopy was low in patients with ACs, in that tumors were revealed in 50% of our patients and the histologic diagnosis was accurate in 20%. Endoscopy revealed an endobronchial tumor in 81% of the patients with TCs, but biopsies were not performed in 15 of 52 patients (29%) because of the risk of hemorrhage. Attempts at partial or complete endoscopic removal of the tumor can precipitate serious hemorrhage, and this must be avoided. Todd and associates [9] noted that 26% of the biopsies performed in their patients were associated with considerable hemorrhage, but no patients went on to require blood transfusions or thoracotomy. Atypical carcinoids have no specific identifying gross characteristics except massive necrosis. There have been difficulties in distinguishing between an AC and SCLC in microscopic studies of tissue obtained by bronchoscopic biopsy because of the limited amount of tissue available. Cytologic studies of bronchial brushing specimens and percutaneous transthoracic needle biopsy specimens ob-

4 Ann Thorac Surg MARTY-ANI~ ET AL ;59:78-83 MANAGEMENT OF ATYPICAL BRONCHIAL CARCINOIDS Table 7. Metastatic Extension of Bronchial Carcinoids ~ Authors Lymph Nodes Distant Metastasis Typical Atypical Typical Atypical Paladugu et al [10] Okike et al [16] Wilkins et al [6] McCaughan et al [15] Rea et al [4] Mills et al [5] Warren et al [12] Present series a All numbers are percentages. Fig 2. Typical bronchial carcinoid tumor composed of small uniform cells arranged in cords and nests with an acinar pattern. (Hematoxylin and eosin; 250 before 54% reduction.) rained under computed tomographic control are not useful for establishing diagnosis. However, accurate diagnosis can be achieved through careful examination of the entire tumor by an experienced pathologist because an AC and SCLC can be easily distinguished on large sections. Pathologic confirmation of typical or atypical carcinoid is usually based on the appearance of routine light microscopic sections prepared with standard stains (Figs 2, 3). Arrigoni [1] and Paladugu [10] and their colleagues have described the histologic features that are currently recommended in the diagnosis of ACs. Any of these pathologic findings are considered sufficient to identify a carcinoid as histologically atypical. The most common features of an AC that differentiate it from a TC are necrosis and increased mitotic activity [10]. Argyrophilic staining techniques and the use of electron microscopy to demonstrate neurosecretory granules are useful for confirming the neuroendocrine nature of tumors, and Fig 3. Atypical carcinoid tumor. High-power view showing small spindle cells with irregular nuclear features, hyperchromatism, mitosis, and disordered architecture. (Hematoxylin and eosin; 250 before 54% reduction.) thus excluding other pulmonary tumors such as non- SCLCs and lymphomas. Studies of immunocytochemical staining have shown that chromogranin and neuronspecific enolase are good markers for tumors with neuroendocrine features, but are not useful for accurately identifying the neuroendocrine tumor subtypes. Ultrastructural studies performed with electron microscopy have shown that neurosecretory granules tend to become smaller and less numerous along the spectrum from TC to SCLC. Image analysis of the nuclear DNA content has revealed a significantly progressive increase in the DNA content from TC to SCLC, suggesting a correlation between the increased DNA content and tumor aggressiveness [10, 11]. Warren and co-workers [12] noted that preoperative serum neuron-specific enolase levels may be useful in distinguishing bronchial carcinoids (TCs) or well-differentiated neuroendocrine carcinomas (ACs), which have normal or slightly elevated neuron-specific enolase levels, from intermediate-sized cell neuroendocrine carcinomas (large cell undifferentiated carcinoma) and SCLC, which show significantly elevated levels of neuron-specific enolase. There are currently many controversies concerning the ideal forms of treatment and the extent of resection required to accomplish local control of ACs. In our series, 48% of the patients presented with lymph node metastasis and 22% with mediastinal lymph node metastasis (N2 disease). Distant metastasis was detected during follow-up in 18.5% of the patients. In other series, lymphatic involvement was found in 30% to 66% of the patients and distant metastasis in 9% to 19.5% (Table 7). De Caro and co-workers [13] noted that half of their patients with ACs were in stage Ill at the time of diagnosis. Because of its metastatic potential, an AC behaves like an authentic malignant tumor, with a postoperative survival rate of 50% to 64% (Table 8). In contrast, TCs are characterized by slow growth, a low incidence of lymph node metastasis, very uncommon distant metastasis, and very high survival rates (see Tables 7, 8). In our series of patients with TCs, major resections were performed in patients with central lesions (in or near a segmental bronchus), in those with obstructing tumors with distal suppuration, and in the event of an incorrect preoperative diagnosis of bronchial carcinoma. We consider that

5 82 MARTY-ANE ET AL Ann Thorac Surg MANAGEMENT OF ATYPICAL BRONCHIAL CARCINOIDS 1995;59:78-83 Table 8. Postoperative Survival Rates in Patients With Bronchial Carcinoids ~ Typical Atypical Authors Carcinoid Careinoid b Paladugu et al [10] (41) Okike et al [16] (29) McCaughan et al (10 years) [15] (23) Lawson et al (10 years) [19] (8) Rea et al (10 years) [4] (18) Attar et al (10 years) [17] (12) Present series (10 years) (27) a Numbers are percentages, of patients. b Numbers in parentheses are numbers the aggressive behavior of ACs calls for a large resection, and this led us to perform major procedures (lobectomy or pneumonectomy) in 85% of our patients and lesser procedures (segmentectorny or wedge resection) in 15%. Conservative surgical procedures (bronchoplastic procedures, segmentectomy, or wedge resection) are justified in patients with TCs without lymph node metastasis and distal pulmonary suppuration. In those with ACs, we recommend lung-sparing procedures if the preoperative pulmonary assessment indicates that conventional resections are not possible. Okike and associates [14] reported 18 successful bronchoplastic procedures, but all their patients had small peripheral TCs without lymph node metastasis (NO) or distal suppuration. When endoscopic resection (laser) was performed, diagnosis, staging, and excision proved to be incomplete, and this method should therefore be reserved for patients with centrally localized tumors whose respiratory state rules out performance of a thoracotomy [15]. Some authors [1, 9, 10, 12, 16] advocate a more conservative approach, as recurrence in patients with ACs more commonly involves distant metastasis than local redux. Paladugu and co-workers [10] recommend a conservative approach consisting of minimal pulmonary resection that includes the entire tumor with free section margins. However, these authors reported performing large resections in 85% of their patients and lesser procedures in 15%, thus probably explaining the low incidence of local recurrence in their series. The malignant behavior of ACs requires an aggressive approach to surgical treatment, with lobectomy and lymph node dissection the minimal procedure [4, 6, 15, 17-19]. Regardless of the extent of resection, systematic mediastinal lymph node dissection must be routinely performed to ensure accurate staging and adequate tumor management. In 40% of the patients, peroperative decision-making is sometimes thwarted by the inability of pathologists to determine an accurate histologic diagnosis based on the frozen section findings [15]. In such situations, conventional pulmonary resection is required, as is the case for primary lung cancer [4, 15]. It is widely held that it is very difficult to distinguish between an AC and SCLC when the biopsy specimens are small. The good results reported for the surgical treatment of SCLC should be evaluated with regard to the common confusion between AC and SCLC in microscopic examinations [20]. The role of adjuvant chemotherapy is not clear and only limited data are available on its effects on ACs. The long-term survival potential, even in patients with distant metastasis, emphasizes the slow growth of this type of tumor. Systemic treatment is recommended for the management of metastatic disease at the time of presentation or at the time of systemic recurrence. Because of the life-threatening side effects and unproven benefits with regard to prolonged survival, the use of chemotherapy as an adjuvant treatment for an apparently controlled stage I or II AC is still controversial. However, chemotherapy for the control of a stage III AC seems justified. Paladugu and associates [10l reported that their 7 patients with grade II Kulchitsky's cell carcinoma (AC) and distant metastasis, treated with surgical removal and adjuvant chemotherapy, were still alive from 23 to 127 months postoperatively. Grote and co-workers [21] noted a 40% response rate in a series of 8 patients with metastatic disease treated with chemotherapy. The chemotherapy regimen they used was similar to that used in the treatment of small cell carcinoma, but the response rate was not as high as that seen for small cell carcinoma. The use of systemic adjuvant therapy in patients with ACs is still controversial, and should be the subject of cooperative clinical trials. Atypical carcinoid is a distinct clinicopathologic entity, with surgical resection the only curative therapy. Because of the aggressive behavior and high rate of lymphatic spread typical of this tumor, the same treatment criteria that apply to lung cancer should be applied to this neuroendocrine tumor subtype, which is comparable to well-differentiated carcinoma of the lung. References 1. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64: Mountain CF. A new international system for lung cancer. Chest 1986;89(Suppl):225S-33S. 3. Mills SE, Walker AN, Cooper PH, Kron IL. Atypical carcinoid tumors of the lung. Am J Surg Pathol 1982;6: Rea F, Binda R, Spreafico G, et al. Bronchial carcinoids: review of 60 patients. Ann Thorac Surg 1989;47: Choplin RH, Kawamoto EH, Dyer RB, Geisinger KR, Mills SE, Pope TL. Atypical carcinoid of the lung: radiologic features. AJR 1986;146: Wilkins EW Jr, Grillo HC, Moncure AC, Scannell JG. Changing times in surgical management of bronchopulmonary carcinoid tumor. 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