Prognosis of Resected Well-differentiated Neuroendocrine Carcinoma of the Lung* Cosima l£quaglie, M.D., F.C.C.R; Carlo Patriarca, M.D.; 19nazio Cataldo, M.D.; Giuseppe Muscolino, M.D.; Ferdinando ITeda, M.D.; and Gianni Raoosi, M.D. Among lung tumors, weU-difTerentiated neuroendocrine carcinomas are often misdiagnosed or may go unrecognized. Nineteen cases of weU-difTerentiated neuroendocrine carcinoma (WDNC) were assessed at the National Caocer Institute of Milan over a ten-year period. There was only one woman and the age range was 50 to 77 years. Most of the patients were smokers (83 percent). All tumors were radically resected. There were 11 lobectomies, two sleevelobectomies, three bilobectomies, one pneumonectomy, and two segmentectomies (one patient had two synchrooous WDNCs). There was neither operative mortality nor major complications. Sixteen tumors were stage I, three were stage D, and one was stage DIa. Five patients had adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine [CAV] regimen). One patient was given local or regional radiotherapy. In ten patients the tumors recurred, even though four had had adjuvant treatment. The brain was the 6rst site of metastasis in seven cases. The pathologic
stage seemed not to be closely related to the appearance of metastases (six patients with stage I disease had recurrences). Only two patients with recurrence were still alive 11 aDd 103 months after the procedure. The percentage of survival for patients with stage I disease after more than 100 months was 68 percent. WDNC is similar to small-ceD lung carcinoma (SCLC) with regard to the neurotropism of metastases. Surgery is curative for more than one half of the patients with localized disease. Therefore, multimodal therapy, probably based on tumor behavior and investigations of tumor markers, is advisable. (Chat 1991; 100:1053-56)
lung tumors represent a wide N euroendocrine spectrum of disease. At one end are typical
In this article, we present the ten-year experience of the National Cancer Institute of Milan with welldifferentiated neuroendocrine lung carcinomas according to the criteria of Gould et al. 10.I 3-15
carcinoids, with a low incidence of metastases and excellent prognosis following surgical resection. At the other end are small-cell lung carcinomas (SCLC) that metastasize early. For the latter, surgery with or without chemotherapy is rarely curative and prognosis remains poor, with few long-term survivors. Welldifferentiated neuroendocrine carcinomas (WDNCs) For editorial comment see page 892 are intermediate between bronchial carcinoids and SCLCs. In 1944, Engalbreth-Holm1 first described two cases of bronchial carcinoid with histologic features different from those of typical carcinoid. Since then, many names have been given to this subtype of tumor: malignant carcinoid, 2 metastasizing bronchial adenoma, 3 carcinoid carcinoma," pleomorphic carcinoid,5 nonbenign carcinoid tumor,6 peripheral carcinoid,5 deeply invasive carcinoid,7 atypical carcinoid,8 Kulchitsky cell carcinoma grade 11,9 and, finall~ welldifferentiated neuroendocrine carcinoma. 10 However, WDNCs are misdiagnosed in more than 50 percent of patients or are not recognized. H •l2 *From the Department of OncolQgic Thoracic Surgery (Drs. Lequaglie, Cataloo, Muscolino, Preda, and Ravasi) and the Pathology Service (Dr. Patriarca), Istituto Nazionale Tumori, Milan, Ital~ Manuscript received October 1; revision accepted February 1. Reprint requeBts: Dr. uquaglie, Istituto NaziontJle 7Umoril' Via \enezian I, 20133 Milan, Italy
=
CAV cyclophosphamide, doxorubicin, and vincristine; crx
=
_ ; epi-DX=epirubicin; MTX=methotreute; SCLC=sDudI-eeD lung carcinoma; WDNC=weU-difJerentiated neuroendocriDe carcinoma.
MATERIALS AND METHODS
From November 1978 to January 1989, all available material from resected lung tumors was reviewed. Only WDNCs were included in this analysis. WDNCs were classiJied according to the criteria of Gould et al. IO.13-15 Histologically, these tumors showed an organoid pattern with trabeculae, ribbons, nests, and pseudoglandular structures. Pseudorosettes and peripheral palisading were occasionally evident. Necrosis was usually found in the center of solid nests. Mitoses ranged from 3 to 20 per 10 HPF ( X 250) (Fig 1). All patients were operated on in the Department ofOncologic Thoracic Surgery. The patients were studied retrospectively for age, sex, clinical presentation, history of smoking, preoperative diagnosis, location, type oftreatment, TNM stage according to the International Staging System, site of recurrence, treatment of recurrence, and survival. The cause of death was obtained from clinical records or death certificates. All living patients were contacted and interviewed with regard to their present health status. Foll~up was closed on January 19, 1990, after minimum of 12 months ofclinical foU~up. The probability of survival was calculated by the Kaplan-Meier method. Ie RESULTS
Nineteen patients with pulmonary WDNCs had resection. There were 18 men and one woman, aged 50 to 77 years (mean, 60.3 years). Sixteen patients were smokers: 13 had been smoking more than 15 cigarettes a day for 20 to 30 years. Ten patients were CHEST I 100 I 4 I OCTOBER, 1991
1053
Table I-Site of Firat &currmce and Suroivol (Cloeing DaIe,}an 19, 1990): WDNC Pathologic
Site of Recurrence
Free Disease Interval, mo
Survival, mo
T2,NO T2,NO T2,NO Tl,N2 T2,NO T2,Nl T2,NO T2,Nl Tl,Nl T2,NO
Brain Brain
35 11
60 16 34 21 S 21
Stage
FIGURE 1. Well-differentiated neuroendocrine carcinoma (x 250). The 6gure shows the most common features in WDNC: areas of tumor necrosis, peripheral palisading, and pleomorphism of nuclei with prominent nucleoli.
asymptomatic and their conditions were detected from an abnormal chest roentgenogram on check-up or during examination for other diseases or surgical procedures. In the remaining patients, the pulmonary symptoms that occurred most frequently were cough, fever, hemoptysis, and thoracic pain. Eleven tumors were located centrally in the main-stem or lobar bronchi and nine were located peripherally (one patient had two synchronous bilateral tumors). There were 13 (65 percent) right-side and 7 left-side tumors. Neither pleural effusions nor chest wall invasions were observed. Bronchoscopy was performed in all patients and showed neoplastic lesions in nine patients. Bronchoscopic biopsy specimens were positive for malignant tumors in three patients. Preoperative cytologic examinations of sputum and/or of bronchial brushings revealed malignant cells in five patients. Percutaneous aspiration needle biopsies were performed for only two patients with peripheral lesions and were positive for malignant neoplasms. For all patients, results of routine blood chemistry studies were unremarkable. All tumors were radically resected. There were 12 lobectomies, two right upper sleeve-lobectomies, three bilobectomies, one left pneumonectomy, and two segmentectomies of the right upper lobe (one patient had two synchronous WDNCs). There was neither operative mortality nor major complications. Table I-Pathologic Stage ofWDNC: 19 patieratI* Stage
II IlIa
TNM·
No. of Patients
Tl,NO,MO T2,NO,MO Tl,Nl,MO T2,Nl,MO Tl,N2,MO
*One patient with two stage I synchronous tumors. tTwo originally classi6ed as small cell carcinoma. *Two originally small cell carcinoma and six carcinoid. tOne originally small cell carcinoma.
1054
St 11*
1
2t It
3
Bone Lung
18
Brain Brain
3
Brain
21 23 11
103*
Brain
4
12*
Brain
7
Lung
18 22
*Alive.
The size of the tumors ranged from 0.8 to 8 cm in diameter. For nineteen patients, the initial histopathologic diagnoses were carcinoid (six patients), SCLC (six patients), and WDNC for the remaining seven patients. Table 1 reports the pathologic stages of the tumors: 16 tumors were stage I, three were stage II, and one was stage IlIa. Five patients had adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine [CAV] regimen), and one had only local and regional radiotherapy, because all these patients had been previously classified as having SCLC. Metastases were observed in ten patients (Table 2) despite adjuvant treatment of four. The brain was the first site of metastasis in seven patients. Two of the remaining three patients had local recurrences and the third had a recurrence in one rib at the site of thoracotomy three months later. Six patients with stage I disease had recurrences, five in the brain and one in one rib. Fifty percent of the N + patients had recurrences in the brain and all four died 18 to 22 months after surgery. Only two patients with recurrences are living, 12 and 103 months after the procedure, one 8 and the other 80 months after recurrence. The longest survivor among these patients had surgical resection of a solitary metastasis, and the other had
":R. 0
90
'i
80
•
70
~
:J
60
0
60
months
120
FIGURE 2. Stage I percentage curve of survival after resection in WDNC.
PlognoeIs 01 N8UfD811doc:rlIl8 CaICinoma 01 the Lung (1AquagIIe lit aI)
radio-chemotherapy (40 Gy plus methotrexate [MTX], epirubicin (epi-Dx), cyclophosphamide [CTX] at three-week intervals for eight cycles) for two brain lesions. They are now free of disease. Fifty-seven percent of the patients were alive at the end of the stud~ The percentage of survival for stage I after ten years was 68.1 percent (Fig 2). DISCUSSION
Bronchopulmonary neuroendocrine neoplasms cover a large range of tumors, including bronchial carcinoids, WDNCs, and SCLCs. Over the past 15 years, we have witnessed considerable progress in the understanding and knowledge of neuroendocrine lung tumors. The treatment of these tumors depends on the aggressiveness of each histotype. Unfortunately, correct preoperative diagnosis is not always possible. The recent recognition ofWDNCs as an entity and their specific histologic problems is one reason for errors in classifying these tumors (vide infra)!5 as for example, in the first 12 cases in our stud~ Six tumors were initially classified as bronchial carcinoids and the remaining six were diagnosed as SCLCs. The tumors classified as bronchial carcinoids were treated only by surgery; the six tumors classified as SCLCs were treated by surgery plus an adjuvant treatment: radiotherapy and/or chemotherap~ The final diagnosis ofthe reviewed specimens was WDNC. The limits of the diagnosis by biopsy specimen or cytologic study, because of poor material and neoplastic morphologic heterogeneity, should always be taken into account, especially since there is no general agreement on the subject. 17,18 The cytologic criteria for distinguishing WDNC are the arrangement in small epithelial aggregates with acinar or palisading structures, without the loose streaming of small densely hyperchromatic cells typical of SCLC. Indeed, compared with SCLC cells, WDNC cells are larger and without a background of diffuse nuclear debris. On the other hand, carcinoids are easily distinguished cytologically, being composed of extremely monomorphic nuclei, without mitosis and necrosis. Moreover, they tend to present as cohesive nests of cells. Even in surgical specimens, differential diagnosis ofWDNC from other tumors can be difficult. Sometimes the mitotic count is as high as in SCLC and differential diagnosis from the latter in these cases is based on the organoid pattern and the limited extension of the necrosis. Also, there are no crushing artifacts in WDNC. Differential diagnosis from typical carcinoids is based on increased cellularity, with disruption of the orderly pattern. Increased nuclearcytoplasmic ratios, moderate nuclear hyperchromasia with finely granular chromatin distribution and mitoses, which are very rare in typical carcinoids, are important for distinguishing WDNC.
All our cases satisfied the morphologic criteria of Gould et al. lO We also found that most patients are male (94.7 percent), and older than 55 years (14 patients), as did Bruschweiler and Megevand. 19 Smoking history was strongly correlated with WDNC: 84.2 percent of our patients smoked. This would suggest that the abuse of tobacco is probably an essential etiologic factor in this disease, as it is for SCLCs. This is in accord with Mills et aloo and McCaughan et al,21 but not with some others. 22 Forty-seven percent of patients had asymptomatic tumors and 45 percent had peripheral tumors. The management and prognosis ofWDNC are not well established, due in part to the relative rarity of the tumor. 8 Every case was treated as we usually treat non-SCLCs. Obviously, radical resection, including mediastinal lymph node dissection, was performed. We found lymph node involvement in 20 percent of the tumors. Other investigators reported lymph node metastases in 27 percent to 70 percent of WDNCs when systematic dissection was performed routinely.5,9,oo,21 There were only two local failures in ten patients with recurrences. These two are not surprising since they occurred in two patients with N + tumors, and is well known, these patients more frequently have local recurrences. The role of adjuvant therapy is not yet known. Five patients were given adjuvant chemotherapy, with a schedule similar to that applied in SCLC. Three of these patients died after recurrences. Some groups theorize that patients with WDNC who were treated with adjuvant chemotherapy as SCLCs do not respond to CAY regimen. 15 Others9,23
think that chemotherapy is the treatment of choice for patients with widespread disease, and that adjuvant therapy may well be indicated after surgery. In our stud~ pathologic stage seemed not to be related to the appearance of metastases. Six patients with stage I and 4 N + have had recurrences and only two stage I patients are living 12 and 103 months after the surgical procedure and 8 and 80 months after the recurrence. The brain, in our patients, was the first site of metastasis in seven of ten cases. Some investigators think there is a relationship between peripheral primary tumor and brain metastases. 24 We had six patients with central primary tumors. Four patients were not given therapy for the recurrence because of the disseminated disease.. Only two patients with brain metastases are living. The longest survivor among these patients had surgical resection of the solitary metastasis, and the other one had whole brain irradiation plus chemotherapy for two brain lesions. They are now free of disease. Similar observations have been reported by Gould et al. 10 In other studies, the most common sites for distant metastases were liver, bone, and brain. 5 ,22 The prognosis of WDNC seems to be somewhere between bronchial carcinoids CHEST I 100 I 4 I OCTOBER, 1991
1055
and SCLCS.5,8,14,20,25 An average of 65 percent of patients with WDNC were alive Bve years after surgical resection,21,25,26 in our group 57.8 percent. In conclusion, well-differentiated neuroendocrine lung carcinoma is more like SCLC than carcinoid tumor with regard to its clinical course, and especially, in our patients, in the neurotropism of the metastases. We think that surgery is curative, for non-SCLC, for more than halfofthe patients with localized disease. Finally, since ploidy and proliferative activity in lung cancer have been studied in the last decade, many groups have found a correlation between aneuploid lung cancers with high proliferative activity and shorter survival,27-29 particularly carcinoids and SCLCS.9 Therefore, a multimodal therap~ probably based on such tumor indices as DNA content, cell kinetics, or others, and investigations of tumor markers, is advisable. ACKNOWLEDGMENTS: The authors would like to thank Mrs. M. Stefani and Ms. S. McGrawth for the help in the preparation of the text.
13
14
15
16 17 18
REFERENCES 1 Engelbreth-Holm J. Benign bronchial adenomas. Acta Chir Scand 1944; 90:383 2 Mark EJ, Ramirez JF. Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. Arch Pathol Lab Med 1985; 109:263-69 3 McBurney ~ Kirklin ~ Woolner LB. Mestastasizing bronchial adenomas. Surg Gynecol Obstet 1953; 96:482-92 4 Lawson RM, Ramanathan L, Hurley G, Hinson K~ Lennox SC. Bronchial adenoma: review of an 18-year experience at the Brompton Hospital. Thorax 1976; 31:245-53 5 Warren H~ Faber LJ: Gould E\': Neuroendocrine neoplasms of the lung: a clinicopathologic update. J Thorac Cardiovasc Surg 1989; 98:321-32 6 Goodner JT, Berg ~ Watson W The nonbenign nature of bronchial carcinoids and cylindromas. Cancer 19fH; 14:539-46 7 Hajdu SI, Winawer SJ, Myers WPL. Carcinoid tumors: a study of204 cases. Am J Clin Patho11974; 61:521-28 8 Arrigoni MG, Woolner LB, Bernatz PEe Atypical tumors of the lung. J Thorac Cardiovasc Surg 1972; 64:413-21 9 Paladugu RR, Ben6eld JR, Pale HY, Ross RK, Teplitz RL. Bronchopulmonary Kulchitsky cell carcinomas: a new classification scheme for typical and atypical carcinoids. Cancer 1985; 55:1303-11 10 Gould VE, Linnoila HI, Memoli VA, Warren WHo Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 1983; 49:519-37 11 Lequaglie C, Patriarca C, Ongari M, Cataldo I, Muscolino, Alloisio M, et ale Neuroendocrine neoplasms of the bronchopulmonary tract (no-oat ceD). In: Montorsi M, Granelli J: eds. Thoracic surgery. Bologna: Monduzzi Editore SpA; 1988:15963 12 Lequaglie C, Patriarca C, Cataldo I, Preda F, Musoolino G,
1056
19 20 21 22 23 24
25 26 27 28 29
Alloisio M, et ale Bronchial carcinoid and well-differentiated neuroendocrine carcinoma: surgical treatment and long term results. In: Motta G, ed. Lung cancer: advanced concepts and present status. Genova: Cra6ca LP; 1989;389-96 Warren WH, Memoli VA, Gould VEe Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms, II: well-ditIerentiated neuroendocrine carcinomas. Ultrastroct Pathol 1984; 7: 185-99 Warren WH, Gould VE, Faber L~ Kittle CF, Memoli VA. Neuroendocrine neoplasms of the bronchopulmonary tract: a classification ofthe spectrum ofcarcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg 1985; 89: 819-25 Warren WH, Memoli VA, Jordan AG, Gould VEe Reevaluation of pulmonary neoplasms resected as small cell carcinomas: significance of distinguishing between well-ditIerentiated and small cell neuroendocrine carcinomas. Cancer 1990; 65:100310 Kaplan EL, Meier E Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:437-81 Jordan AG, Predmore L, Sullivan MM, Memoli VA. The cytodiagnosis of well-ditIerentiated neuroendocrine carcinoma: a distinct clinicophatologic entity. Acta Cytoll987; 31:464-70 Szyfelbein WM, Ross JS. Carcinoids, atypical carcinoids, and small-cell carcinomas of the lung: ditIerentiai diagnosis of 6neneedle aspiration biopsy specimens. Diagn Cytopatholl988; 4: 1-8 Broschweiler I, Megevand R. Carcinoides broncho-pulmonaires. Med Hyg 1988: 46:1969-72 MiDs SE, Walker AN, Cooper PH, Kron IL. Atypical tumor of the lung: a clinicopathologic study of 17 cases. Am J Surg Pathol 1982; 6:643-54 McCaughan BC, Martini N, Bains MS. Bronchial carcinoids: review of 124 cases. J Thorac Cardiovasc Surg 1985; 89:8-17 Grote TH, Macon WR, Davis B, Greco FA, Johnson DH. Atypical carcinoid of the lung: a distinct clinicopathologic entity. Chest 1988; 93:370-75 Allen MB, Shamash J, Kerr KM, Leitch AG. Hypercalcemia in atypical carcinoid tumors. Chest 1989; 96:1206-08 Tomlison BE, Perry RH, Stewart-Wynne EG. Influence on site of origin of lung carcinomas on clinical presentation and central nervous system metastases. J Neurol Neurosurg Psychiatry 1979; 42:82-8 Choplin RH, Kawamoto EH, Dyer 88, Geisinger KR, Mills SE, Pope TL. Atypical carcinoid of the lung: radiographic features. Am J Roentgenoll986; 146:665-68 Rea F, Binda R, Sprea6co G, Calabro F, Bonavina L, Cipriani A, et ale Bronchial carcinoids: a review of 60 patients. Ann Thorac Surg 1989; 47:412-14 Volm M, Mattern J, Vogt-Schaden M, Wayss K. Flow cytometric analysis of primary lung carcinomas and their lymph node metastases. Anticancer Res 1987; 7:71-6 Zimmerman P~ Hawson GAT, Bint MH, Parson PC. Ploidy as a prognostic determinant in surgically treated lung cancer. Lancet 1987; 2:530-33 Salvati F, Teodori L, Gagliardi L, Signora M, Aquilini M, Storiello G. DNA Bow cytometric studies of 66 human lung tumors analyzed before treatment: prognostic implications. Chest 1989; 96: 1092-98
Prognosis of NeuroeI adocrit Nt Carcinoma of the Lung (Lequaglie et aI)
stage seemed not to be closely related to the appearance of metastases (six patients with stage I disease had recurrences). Only two patients with recurrence were still alive 11 aDd 103 months after the procedure. The percentage of survival for patients with stage I disease after more than 100 months was 68 percent. WDNC is similar to small-ceD lung carcinoma (SCLC) with regard to the neurotropism of metastases. Surgery is curative for more than one half of the patients with localized disease. Therefore, multimodal therapy, probably based on tumor behavior and investigations of tumor markers, is advisable. (Chat 1991; 100:1053-56)
lung tumors represent a wide N euroendocrine spectrum of disease. At one end are typical
In this article, we present the ten-year experience of the National Cancer Institute of Milan with welldifferentiated neuroendocrine lung carcinomas according to the criteria of Gould et al. 10.I 3-15
carcinoids, with a low incidence of metastases and excellent prognosis following surgical resection. At the other end are small-cell lung carcinomas (SCLC) that metastasize early. For the latter, surgery with or without chemotherapy is rarely curative and prognosis remains poor, with few long-term survivors. Welldifferentiated neuroendocrine carcinomas (WDNCs) For editorial comment see page 892 are intermediate between bronchial carcinoids and SCLCs. In 1944, Engalbreth-Holm1 first described two cases of bronchial carcinoid with histologic features different from those of typical carcinoid. Since then, many names have been given to this subtype of tumor: malignant carcinoid, 2 metastasizing bronchial adenoma, 3 carcinoid carcinoma," pleomorphic carcinoid,5 nonbenign carcinoid tumor,6 peripheral carcinoid,5 deeply invasive carcinoid,7 atypical carcinoid,8 Kulchitsky cell carcinoma grade 11,9 and, finall~ welldifferentiated neuroendocrine carcinoma. 10 However, WDNCs are misdiagnosed in more than 50 percent of patients or are not recognized. H •l2 *From the Department of OncolQgic Thoracic Surgery (Drs. Lequaglie, Cataloo, Muscolino, Preda, and Ravasi) and the Pathology Service (Dr. Patriarca), Istituto Nazionale Tumori, Milan, Ital~ Manuscript received October 1; revision accepted February 1. Reprint requeBts: Dr. uquaglie, Istituto NaziontJle 7Umoril' Via \enezian I, 20133 Milan, Italy
=
CAV cyclophosphamide, doxorubicin, and vincristine; crx
=
_ ; epi-DX=epirubicin; MTX=methotreute; SCLC=sDudI-eeD lung carcinoma; WDNC=weU-difJerentiated neuroendocriDe carcinoma.
MATERIALS AND METHODS
From November 1978 to January 1989, all available material from resected lung tumors was reviewed. Only WDNCs were included in this analysis. WDNCs were classiJied according to the criteria of Gould et al. IO.13-15 Histologically, these tumors showed an organoid pattern with trabeculae, ribbons, nests, and pseudoglandular structures. Pseudorosettes and peripheral palisading were occasionally evident. Necrosis was usually found in the center of solid nests. Mitoses ranged from 3 to 20 per 10 HPF ( X 250) (Fig 1). All patients were operated on in the Department ofOncologic Thoracic Surgery. The patients were studied retrospectively for age, sex, clinical presentation, history of smoking, preoperative diagnosis, location, type oftreatment, TNM stage according to the International Staging System, site of recurrence, treatment of recurrence, and survival. The cause of death was obtained from clinical records or death certificates. All living patients were contacted and interviewed with regard to their present health status. Foll~up was closed on January 19, 1990, after minimum of 12 months ofclinical foU~up. The probability of survival was calculated by the Kaplan-Meier method. Ie RESULTS
Nineteen patients with pulmonary WDNCs had resection. There were 18 men and one woman, aged 50 to 77 years (mean, 60.3 years). Sixteen patients were smokers: 13 had been smoking more than 15 cigarettes a day for 20 to 30 years. Ten patients were CHEST I 100 I 4 I OCTOBER, 1991
1053
Table I-Site of Firat &currmce and Suroivol (Cloeing DaIe,}an 19, 1990): WDNC Pathologic
Site of Recurrence
Free Disease Interval, mo
Survival, mo
T2,NO T2,NO T2,NO Tl,N2 T2,NO T2,Nl T2,NO T2,Nl Tl,Nl T2,NO
Brain Brain
35 11
60 16 34 21 S 21
Stage
FIGURE 1. Well-differentiated neuroendocrine carcinoma (x 250). The 6gure shows the most common features in WDNC: areas of tumor necrosis, peripheral palisading, and pleomorphism of nuclei with prominent nucleoli.
asymptomatic and their conditions were detected from an abnormal chest roentgenogram on check-up or during examination for other diseases or surgical procedures. In the remaining patients, the pulmonary symptoms that occurred most frequently were cough, fever, hemoptysis, and thoracic pain. Eleven tumors were located centrally in the main-stem or lobar bronchi and nine were located peripherally (one patient had two synchronous bilateral tumors). There were 13 (65 percent) right-side and 7 left-side tumors. Neither pleural effusions nor chest wall invasions were observed. Bronchoscopy was performed in all patients and showed neoplastic lesions in nine patients. Bronchoscopic biopsy specimens were positive for malignant tumors in three patients. Preoperative cytologic examinations of sputum and/or of bronchial brushings revealed malignant cells in five patients. Percutaneous aspiration needle biopsies were performed for only two patients with peripheral lesions and were positive for malignant neoplasms. For all patients, results of routine blood chemistry studies were unremarkable. All tumors were radically resected. There were 12 lobectomies, two right upper sleeve-lobectomies, three bilobectomies, one left pneumonectomy, and two segmentectomies of the right upper lobe (one patient had two synchronous WDNCs). There was neither operative mortality nor major complications. Table I-Pathologic Stage ofWDNC: 19 patieratI* Stage
II IlIa
TNM·
No. of Patients
Tl,NO,MO T2,NO,MO Tl,Nl,MO T2,Nl,MO Tl,N2,MO
*One patient with two stage I synchronous tumors. tTwo originally classi6ed as small cell carcinoma. *Two originally small cell carcinoma and six carcinoid. tOne originally small cell carcinoma.
1054
St 11*
1
2t It
3
Bone Lung
18
Brain Brain
3
Brain
21 23 11
103*
Brain
4
12*
Brain
7
Lung
18 22
*Alive.
The size of the tumors ranged from 0.8 to 8 cm in diameter. For nineteen patients, the initial histopathologic diagnoses were carcinoid (six patients), SCLC (six patients), and WDNC for the remaining seven patients. Table 1 reports the pathologic stages of the tumors: 16 tumors were stage I, three were stage II, and one was stage IlIa. Five patients had adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine [CAV] regimen), and one had only local and regional radiotherapy, because all these patients had been previously classified as having SCLC. Metastases were observed in ten patients (Table 2) despite adjuvant treatment of four. The brain was the first site of metastasis in seven patients. Two of the remaining three patients had local recurrences and the third had a recurrence in one rib at the site of thoracotomy three months later. Six patients with stage I disease had recurrences, five in the brain and one in one rib. Fifty percent of the N + patients had recurrences in the brain and all four died 18 to 22 months after surgery. Only two patients with recurrences are living, 12 and 103 months after the procedure, one 8 and the other 80 months after recurrence. The longest survivor among these patients had surgical resection of a solitary metastasis, and the other had
":R. 0
90
'i
80
•
70
~
:J
60
0
60
months
120
FIGURE 2. Stage I percentage curve of survival after resection in WDNC.
PlognoeIs 01 N8UfD811doc:rlIl8 CaICinoma 01 the Lung (1AquagIIe lit aI)
radio-chemotherapy (40 Gy plus methotrexate [MTX], epirubicin (epi-Dx), cyclophosphamide [CTX] at three-week intervals for eight cycles) for two brain lesions. They are now free of disease. Fifty-seven percent of the patients were alive at the end of the stud~ The percentage of survival for stage I after ten years was 68.1 percent (Fig 2). DISCUSSION
Bronchopulmonary neuroendocrine neoplasms cover a large range of tumors, including bronchial carcinoids, WDNCs, and SCLCs. Over the past 15 years, we have witnessed considerable progress in the understanding and knowledge of neuroendocrine lung tumors. The treatment of these tumors depends on the aggressiveness of each histotype. Unfortunately, correct preoperative diagnosis is not always possible. The recent recognition ofWDNCs as an entity and their specific histologic problems is one reason for errors in classifying these tumors (vide infra)!5 as for example, in the first 12 cases in our stud~ Six tumors were initially classified as bronchial carcinoids and the remaining six were diagnosed as SCLCs. The tumors classified as bronchial carcinoids were treated only by surgery; the six tumors classified as SCLCs were treated by surgery plus an adjuvant treatment: radiotherapy and/or chemotherap~ The final diagnosis ofthe reviewed specimens was WDNC. The limits of the diagnosis by biopsy specimen or cytologic study, because of poor material and neoplastic morphologic heterogeneity, should always be taken into account, especially since there is no general agreement on the subject. 17,18 The cytologic criteria for distinguishing WDNC are the arrangement in small epithelial aggregates with acinar or palisading structures, without the loose streaming of small densely hyperchromatic cells typical of SCLC. Indeed, compared with SCLC cells, WDNC cells are larger and without a background of diffuse nuclear debris. On the other hand, carcinoids are easily distinguished cytologically, being composed of extremely monomorphic nuclei, without mitosis and necrosis. Moreover, they tend to present as cohesive nests of cells. Even in surgical specimens, differential diagnosis ofWDNC from other tumors can be difficult. Sometimes the mitotic count is as high as in SCLC and differential diagnosis from the latter in these cases is based on the organoid pattern and the limited extension of the necrosis. Also, there are no crushing artifacts in WDNC. Differential diagnosis from typical carcinoids is based on increased cellularity, with disruption of the orderly pattern. Increased nuclearcytoplasmic ratios, moderate nuclear hyperchromasia with finely granular chromatin distribution and mitoses, which are very rare in typical carcinoids, are important for distinguishing WDNC.
All our cases satisfied the morphologic criteria of Gould et al. lO We also found that most patients are male (94.7 percent), and older than 55 years (14 patients), as did Bruschweiler and Megevand. 19 Smoking history was strongly correlated with WDNC: 84.2 percent of our patients smoked. This would suggest that the abuse of tobacco is probably an essential etiologic factor in this disease, as it is for SCLCs. This is in accord with Mills et aloo and McCaughan et al,21 but not with some others. 22 Forty-seven percent of patients had asymptomatic tumors and 45 percent had peripheral tumors. The management and prognosis ofWDNC are not well established, due in part to the relative rarity of the tumor. 8 Every case was treated as we usually treat non-SCLCs. Obviously, radical resection, including mediastinal lymph node dissection, was performed. We found lymph node involvement in 20 percent of the tumors. Other investigators reported lymph node metastases in 27 percent to 70 percent of WDNCs when systematic dissection was performed routinely.5,9,oo,21 There were only two local failures in ten patients with recurrences. These two are not surprising since they occurred in two patients with N + tumors, and is well known, these patients more frequently have local recurrences. The role of adjuvant therapy is not yet known. Five patients were given adjuvant chemotherapy, with a schedule similar to that applied in SCLC. Three of these patients died after recurrences. Some groups theorize that patients with WDNC who were treated with adjuvant chemotherapy as SCLCs do not respond to CAY regimen. 15 Others9,23
think that chemotherapy is the treatment of choice for patients with widespread disease, and that adjuvant therapy may well be indicated after surgery. In our stud~ pathologic stage seemed not to be related to the appearance of metastases. Six patients with stage I and 4 N + have had recurrences and only two stage I patients are living 12 and 103 months after the surgical procedure and 8 and 80 months after the recurrence. The brain, in our patients, was the first site of metastasis in seven of ten cases. Some investigators think there is a relationship between peripheral primary tumor and brain metastases. 24 We had six patients with central primary tumors. Four patients were not given therapy for the recurrence because of the disseminated disease.. Only two patients with brain metastases are living. The longest survivor among these patients had surgical resection of the solitary metastasis, and the other one had whole brain irradiation plus chemotherapy for two brain lesions. They are now free of disease. Similar observations have been reported by Gould et al. 10 In other studies, the most common sites for distant metastases were liver, bone, and brain. 5 ,22 The prognosis of WDNC seems to be somewhere between bronchial carcinoids CHEST I 100 I 4 I OCTOBER, 1991
1055
and SCLCS.5,8,14,20,25 An average of 65 percent of patients with WDNC were alive Bve years after surgical resection,21,25,26 in our group 57.8 percent. In conclusion, well-differentiated neuroendocrine lung carcinoma is more like SCLC than carcinoid tumor with regard to its clinical course, and especially, in our patients, in the neurotropism of the metastases. We think that surgery is curative, for non-SCLC, for more than halfofthe patients with localized disease. Finally, since ploidy and proliferative activity in lung cancer have been studied in the last decade, many groups have found a correlation between aneuploid lung cancers with high proliferative activity and shorter survival,27-29 particularly carcinoids and SCLCS.9 Therefore, a multimodal therap~ probably based on such tumor indices as DNA content, cell kinetics, or others, and investigations of tumor markers, is advisable. ACKNOWLEDGMENTS: The authors would like to thank Mrs. M. Stefani and Ms. S. McGrawth for the help in the preparation of the text.
13
14
15
16 17 18
REFERENCES 1 Engelbreth-Holm J. Benign bronchial adenomas. Acta Chir Scand 1944; 90:383 2 Mark EJ, Ramirez JF. Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. Arch Pathol Lab Med 1985; 109:263-69 3 McBurney ~ Kirklin ~ Woolner LB. Mestastasizing bronchial adenomas. Surg Gynecol Obstet 1953; 96:482-92 4 Lawson RM, Ramanathan L, Hurley G, Hinson K~ Lennox SC. Bronchial adenoma: review of an 18-year experience at the Brompton Hospital. Thorax 1976; 31:245-53 5 Warren H~ Faber LJ: Gould E\': Neuroendocrine neoplasms of the lung: a clinicopathologic update. J Thorac Cardiovasc Surg 1989; 98:321-32 6 Goodner JT, Berg ~ Watson W The nonbenign nature of bronchial carcinoids and cylindromas. Cancer 19fH; 14:539-46 7 Hajdu SI, Winawer SJ, Myers WPL. Carcinoid tumors: a study of204 cases. Am J Clin Patho11974; 61:521-28 8 Arrigoni MG, Woolner LB, Bernatz PEe Atypical tumors of the lung. J Thorac Cardiovasc Surg 1972; 64:413-21 9 Paladugu RR, Ben6eld JR, Pale HY, Ross RK, Teplitz RL. Bronchopulmonary Kulchitsky cell carcinomas: a new classification scheme for typical and atypical carcinoids. Cancer 1985; 55:1303-11 10 Gould VE, Linnoila HI, Memoli VA, Warren WHo Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 1983; 49:519-37 11 Lequaglie C, Patriarca C, Ongari M, Cataldo I, Muscolino, Alloisio M, et ale Neuroendocrine neoplasms of the bronchopulmonary tract (no-oat ceD). In: Montorsi M, Granelli J: eds. Thoracic surgery. Bologna: Monduzzi Editore SpA; 1988:15963 12 Lequaglie C, Patriarca C, Cataldo I, Preda F, Musoolino G,
1056
19 20 21 22 23 24
25 26 27 28 29
Alloisio M, et ale Bronchial carcinoid and well-differentiated neuroendocrine carcinoma: surgical treatment and long term results. In: Motta G, ed. Lung cancer: advanced concepts and present status. Genova: Cra6ca LP; 1989;389-96 Warren WH, Memoli VA, Gould VEe Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms, II: well-ditIerentiated neuroendocrine carcinomas. Ultrastroct Pathol 1984; 7: 185-99 Warren WH, Gould VE, Faber L~ Kittle CF, Memoli VA. Neuroendocrine neoplasms of the bronchopulmonary tract: a classification ofthe spectrum ofcarcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg 1985; 89: 819-25 Warren WH, Memoli VA, Jordan AG, Gould VEe Reevaluation of pulmonary neoplasms resected as small cell carcinomas: significance of distinguishing between well-ditIerentiated and small cell neuroendocrine carcinomas. Cancer 1990; 65:100310 Kaplan EL, Meier E Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:437-81 Jordan AG, Predmore L, Sullivan MM, Memoli VA. The cytodiagnosis of well-ditIerentiated neuroendocrine carcinoma: a distinct clinicophatologic entity. Acta Cytoll987; 31:464-70 Szyfelbein WM, Ross JS. Carcinoids, atypical carcinoids, and small-cell carcinomas of the lung: ditIerentiai diagnosis of 6neneedle aspiration biopsy specimens. Diagn Cytopatholl988; 4: 1-8 Broschweiler I, Megevand R. Carcinoides broncho-pulmonaires. Med Hyg 1988: 46:1969-72 MiDs SE, Walker AN, Cooper PH, Kron IL. Atypical tumor of the lung: a clinicopathologic study of 17 cases. Am J Surg Pathol 1982; 6:643-54 McCaughan BC, Martini N, Bains MS. Bronchial carcinoids: review of 124 cases. J Thorac Cardiovasc Surg 1985; 89:8-17 Grote TH, Macon WR, Davis B, Greco FA, Johnson DH. Atypical carcinoid of the lung: a distinct clinicopathologic entity. Chest 1988; 93:370-75 Allen MB, Shamash J, Kerr KM, Leitch AG. Hypercalcemia in atypical carcinoid tumors. Chest 1989; 96:1206-08 Tomlison BE, Perry RH, Stewart-Wynne EG. Influence on site of origin of lung carcinomas on clinical presentation and central nervous system metastases. J Neurol Neurosurg Psychiatry 1979; 42:82-8 Choplin RH, Kawamoto EH, Dyer 88, Geisinger KR, Mills SE, Pope TL. Atypical carcinoid of the lung: radiographic features. Am J Roentgenoll986; 146:665-68 Rea F, Binda R, Sprea6co G, Calabro F, Bonavina L, Cipriani A, et ale Bronchial carcinoids: a review of 60 patients. Ann Thorac Surg 1989; 47:412-14 Volm M, Mattern J, Vogt-Schaden M, Wayss K. Flow cytometric analysis of primary lung carcinomas and their lymph node metastases. Anticancer Res 1987; 7:71-6 Zimmerman P~ Hawson GAT, Bint MH, Parson PC. Ploidy as a prognostic determinant in surgically treated lung cancer. Lancet 1987; 2:530-33 Salvati F, Teodori L, Gagliardi L, Signora M, Aquilini M, Storiello G. DNA Bow cytometric studies of 66 human lung tumors analyzed before treatment: prognostic implications. Chest 1989; 96: 1092-98
Prognosis of NeuroeI adocrit Nt Carcinoma of the Lung (Lequaglie et aI)
