Malignancy and the Terminology of Carcinoids
The term “carcinoid”13 has recently been criticized by several authors on the grounds that it is archaic,6, 14 outmoded,15, 16 or even a misnomer.3, 6, 8, 9, 17–19 The term “carcinoid” in this article is consistent with its use in an earlier series of articles.3–5, 7–9, 20–23, 25, 29
It is clear that submucosal lesions of GI carcinoids, often larger than primary lesions in the mucosa, are a sure indication of malignancy that results from an invasion of intramucosal primary lesions into the submucosa.20, 21
Even primary intramucosal lesions of GI microcarcinoids, ≤ 1 mm, or minute carcinoids, ≤ 5 mm, may also prove to be malignant based on histologic evidence of invasion into surrounding tissues and vascular channels.22 Moreover, they provide clear evidence of malignancy in both animal models with complete serial sections20, 21 and human materials,22 whereas small submucosal GI carcinoids of ≤ 10 mm have unexpectedly high metastatic rates calculated as 10.0% (105/1045)3 and 10.6% (114/1074).22
It is noteworthy that when early GI carcinoids and early gastric carcinomas, with invasion confined to the mucosa, are compared for evidence of malignancy, calculation revealed a metastatic rate of 13.1% (49/374) for the former and 22.5% for the latter (49/218; P < 0.01). When the lesions were restricted to a tumor of ≤ 20 mm, however, the metastatic rates proved to be identical, 9.8% versus10.3%.23
Conversely, verification of the benign nature of GI carcinoids, especially in early stages, has proved extremely difficult. Hence, the term “endocrinocarcinoma”,3, 5, 22, 24, 25 which covers both the carcinoid group and variant group (Fig. 1), was proposed to obtain further understanding of the background of malignancy of GI carcinoids.
In the pancreas, which does not have a layered structure, consideration should be given to the possibility of an identical malignant nature, one aspect of which may be represented by metastatic rates. The metastatic rate in the pancreatic carcinoid series was significantly higher (66.7%;104/156) than that of the overall total average of 35.7% (4045/11,343; P < 0.01) and somewhat lower, though statistically identical, than that in the ileum (76.1%) and the ileocecum (66.9%) in the high-metastasis group. To obtain a more detailed evaluation of metastases, the calculation of metastatic rates was based on controlled use of tumors of ≤ 20 mm (Table 6). This, however, resulted in statistically insignificant P values between metastatic rates for the pancreatic carcinoid series (31.3%; 5/16), the ileum (51.2%; 155/303), and the total average (21.4%; 821/3829).
The average tumor size of pancreatic carcinoids (68.6 mm) was largest of all, almost equal to that of the ovary (68.2 mm), far greater than the ileocecum (46.5 mm), and even the total average (30.2 mm). This suggests that pancreatic tumors may be difficult to detect in earlier stages without aid of image diagnosis such as ultrasonography, computed tomography, and magnetic resonance imaging, which are apparently useful in early detection of tumor nodules in the pancreas.26–28
In the 1961 publication of a large series of 138 cases containing typical carcinoid syndrome, no detailed description of carcinoid syndrome in patients with pancreatic carcinoids was included in the report.12 However, a recently published evaluation of 748 cases with carcinoid syndrome (8.4%; 748/8876) includes 19 cases with this syndrome in the pancreas (17.8%; 19/107), exhibiting a significant statistical difference (P < 0.01) between both series.29 To date, numerous articles dealing with this particular syndrome have appeared,2, 10, 29–31 and it has now been confirmed that the first case of a pancreatic carcinoid is associated with this syndrome.1
Several unique and distinctive cases of pancreatic carcinoids exist. One such case is that of a 54-year old female with carcinoid syndrome who survived for > 5 years after a laparotomy, performed without removal of a lesion measuring 58 mm in diameter and accompanied by both hepatic and nodal metastases. Successful treatment with somatostatin analogues resulted in satisfactory prognosis and disappearance of the syndrome.32 A further case concerns a 55-year old man with carcinoid syndrome who survived 4 years and 11 months after a left pancreatectomy caused the syndrome to disappear. A recurrence of the lesion found in his liver with carcinoid syndrome after 4 years and 1 month was successfully treated by a liver transplant, but the patient died 10 months later of hepatic and bone metastases.33
It is worth noting that all Grimelius argyrophilia, argyrophil cell type and argentaffin cell type indicated a ratio (%) that was virtually identical to that of the total average (84.8% vs. 85.4%; 59.1% vs. 58.5%; 22.7% vs. 22.3%).
Immunohistochemical analyses revealed that carcinoids in both the pancreas and other representative sites were multisecretory. In pancreatic carcinoids, however, serotonin (5-HT) was far more dominant than other active hormonal substances, and it was suggested that neither gastrin nor somatostatin should be overlooked in immunohistochemical analyses.
At 92.9% and 100.0%, respectively, serotonin and NSE exhibited a high rate of immunohistochemical positivity in the carcinoid group. Although the former was significantly higher (P < 0.01%) than the total average (54.9%), the latter was not significantly different from the total average (87.8%). Both serotonin and NSE are without doubt necessary routine examinations as is chromogranin, which showed a high positivity rate of 90.9% identical to the total average (88.2%).
It was pointed out that there existed a close correlation between postoperative survival rates and histologic patterns of carcinoids.3, 5, 7, 9, 10–12 In the current series of pancreatic carcinoids, however, histologic patterns were recorded in a relatively small number of only 18 cases, insufficient for the purpose of statistically evaluating the correlation with postoperative outcomes. The cumulative 5YSR calculated on the basis of the Kaplan–Meier method (Fig. 2) was extremely low for the pancreatic carcinoid series (28.9% ± 16.7%; n = 46), significantly different from that for the appendiceal series (89.7% ± 2.0%; n = 565) but not so for the small intestine series (82.1% ± 3.3%; n = 368). Despite extremely low 5YSR for the pancreatic carcinoid series, a margin of as much as 16.7% in the rate may exist, theoretically increasing the 5YSR to a possible 45.6%. In a previous study,3 the 5YSR in this particular carcinoid series was calculated as 43.2% ± 20.9% (n = 40), but one would expect the analysis of a larger and more effective number of cases to yield a much more precise and stable value for 5YSR in the pancreatic carcinoid series.
In the current study, several attempts have been made to compare various clinicopathologic aspects of the pancreatic carcinoid series with the carcinoid series of other representative sites. Abundant information is available in a monograph, containing a collection of carcinoids and their variant neoplasms in the systemic sites of both digestive and extradigestive organs.25
Compared with other representative sites, statistical evaluation of 156 cases of pancreatic carcinoids revealed that this series of neoplasms is characterized by a high metastatic rate (66.7%), a large average tumor size (68.6 mm), a relatively high incidence of carcinoid syndrome (23.3%), a high detection rate of immunohistochemical serotonin (92.9%) and NSE (100.0%), and a very low 5-year survival rate (28.9%).