JOURNAL OF PATHOLOGY, VOL.
162: 189-190 (1990)
EDITORIAL CARCINOID TUMOURS OF THE APPENDIX ARE DIFFERENT
In the pathological literature, appendiceal carcin- whereas ENCs have a more uniform distribution oid tumours are usually described with other midgut along its length.' Moreover, numbers of both carcinoid tumours because of their similar mor- appendiceal carcinoid tumours and SNCs rise to a phology and staining characteristics. This classifi- peak in early adulthood, unlike numbers of appencation has tended to obscure clinical and other diceal ENCs, which are maximal in childhood and then decline through life.' Previous work has estabdifferences which set appendiceal tumours apart. First, in most parts of the gastrointestinal (GI) lished that in carcinoids at other sites there is a direct tract the incidence of carcinoid tumours is roughly connection between subepithelial tumour and proportional to the number of neuroendocrine cells hyperplastic ENCs, but such a connection has present,' but the incidence in the appendix is some not been demonstrated in appendiceal carcinoid orders of magnitude higher than expected.2 More- tumours." Also, the intimate association of SNCs, over, the distribution of carcinoids within the but not ENCs, with S100-positive cells and nerves in appendix is unusual, with many more tumours at the lamina propria is reflected in the association the tip than at the base. Second, the peak incidence between neuroendocrine cells and S 100-positive of appendiceal carcinoid tumours is in the third and 'sustentacular' cells in appendiceal carcinoid fourth decades, some 20 years earlier than carcin- tumours.6 Apparently against the origin of carcinoid oids from other parts of the GI tract.2 Third, other carcinoid tumours behave as low-grade carcinomas, tumours from SNCs is the demonstration of yet over 95 per cent of appendiceal carcinoids are increased numbers of ENCs adjacent to carcinoid benign despite apparent neural invasion3 and most tumours," which was interpreted as evidence of probably regress with time.4Fourth, despite similar pre-existing ENC hyperplasia. This is not the only reactions with silver and other immunohistochemi- explanation and comparison with another odd cal stain^,^ most appendiceal but not ileal carcinoids lesion of the appendix is instructive. contain S 100-positive 'sustentacular' cells around Neurogenous hyperplasia of the appendix is a and within the islands of neuroendocrine c e k 6 common condition previously attributed to subFinally, there is now good evidence to suggest that acute inflammation, but more recently suggested to in most parts of the GI tract carcinoid tumours arise be a primary proliferative lesion.'* Appendices confrom epithelial neuroendocrine cells (ENCs) in a taining neurogenous hyperplasia12 as well as those background of neuroendocrine cell hyperpla~ia.~containing carcinoid turnours' I have increased However, the evidence for a similar mechanism numbers of ENCs adjacent to the lesions. Moreoccurring in the appendix is not conclusive and there over, in neurogenous hyperplasia ENC numbers is still debate as to whether appendiceal carcinoid decrease with distance from the lesion,'* suggesting tumours arise from ENCs or from subepithelial that the hyperplasia is due to a local factor. neuroendocrine cells (SNCs) which are found deep The similarities do not stop there. Neurogenous within the lamina p r ~ p r i a . ' .If~the latter is correct, it hyperplasia shows large clusters of S 100-positive may explain some of the other anomalies. cells associated with variable numbers of neuroEvidence in favour of an origin from SNCs has endocrine cells which on occasions mimic microcome from recent work on the distribution of carcinoids.' Conversely, carcinoid tumours consist neuroendocrine cells within the appendix. This of islands of neuroendocrine cells surrounded by has shown that most SNCs, like most carcinoid S1 00-positive cells with S 100-positive cell clusters tumours, are concentrated at the tip of the appendix identical to those seen in neurogenous hyperplasia 0022-3417/90/110189-02 $05.00 0 1990 by John Wiley & Sons, Ltd.
190
EDITORIAL
present nearby in 75 per cent.7 Finally, both lesions occur predominantly at the tip of the appendix and eventually regress to leave fibrous t i s s ~ e . ~ . ’ ~ Such similarities prompt speculation that these lesions are different facets of the same proliferative process affecting the SNC-mucosal nerve complex. Owing to some stimulus, possibly obstruction,’- and perhaps via autocrine growth factors, there is hyperplasia of both nerves and neuroendocrine cells. When neural tissue predominates, there is neurogenous hyperplasia; when neuroendocrine cells predominate, a carcinoid tumour develops. If correct, this implies that most appendiceal carcinoid tumours are probably hyperplastic lesions rather than true neoplasms, which would explain their benign nature, their relative abundance, and their tendency to regress. Moreover, what was thought to be neural invasion is just the normal association of hyperplastic neuroendocrine cells and nerves. The exceptions which might prove the rule are the mucinous carcinoids of the appendix. These tumours behave more aggressively than typical carcinoids’ and are the one type of neuroendocrine tumour of the appendix which has been seen to arise directly from thecrypt epithe1i~m.I~ Moreover, they do not appear to be associated with S 100-positive cells (personal observation). At the moment, these findings do not have any direct clinical relevance but it is possible that the presence of S 100-positive sustentacular cells in a carcinoid tumour may be a marker of a benign course, analogous to proliferations of the adrenal medulla.I4 Finally, it should be mentioned that SNCs occur elsewhere in the GI tract and may give rise to occasional tumours at those sites. Also, the mechanism described does not exclude some carcinoid tumours of the appendix developing via ENC hyperplasia, nor neoplastic transformation of hyperplastic SNCs. However, this theory may go some of the way to explaining why carcinoid
tumours of the appendix are just that little bit different. PAULA. V. SHAW Department of His topath ology Leicester Ro-val InJrmary Leicester LE1.5 W W , U.K.
REFERENCES I . Sjolund K, Sanden G, Hakanson R. Sundler R. Endocrine cells in human intestine: an immunocytochemical study. Gastroenrerologr 1983:85: 1120-1130. 2 Godwin JD. Carcinoid tumors. An analysis of 2837 cases. Cancer 1975: 36:560-569. 3. Moertel CG. Weiland LH. Nagorney DM. Dockerty MB. Carcinoid tumors of the appendix: treatment and prognosis. N Engl J Med 1987; 317: 1699-1701. 4. Berge T. Linell F. Carcinoid tumours. Frequency in a defined population during a I2 year period. Arm Parhol Microbiol Scand Sect A 1976; &I: 322-330. 5. Chejfec G.. Fdlkmer S , Askensten U. Grimelius L. Gould VE. Neuroendocrine tumours of the gastrointestinal tract. Parhol Res Pracr 1988; 183: 143-154. 6. Lundqvist M, Wilander E. Subepithelial neuroendocr~necells and carcinoid tumours of the human small intestine and appendix. A comparative immunohistochemical study with regard to serotonin. neuron specific enolase and Sl00 protein reactivity. J Parhol 1986, 148: 141-147. 7. Aubock L. Hofler H. Extraepithelial intraneural endocrine cells as starting points for gastrointestinal carcinoids. Virchows Arch A (ParholAnar] 1983;401: 17-33. 8 Rode J . Dhillon AP, Papadaki L, Griffiths D. Neurosecretory cells of the lamina propria of the appendix and their possible relationship to carcinoids. Hbropathology 1982; 6 69-79. 9. Kinsey WL. Shaw PAV. On the histogenesis of carcinoid tumours: evidence from the distribution of neuroendocrine cells in the normal appendix. J Patholl990: 161: 356A. 10. Lundqvist M,. Wilander E. A study of the histopathogenesis of carcinoid tumors of the small intestine and appendix. Cancer 1987; 60: 201-206. I I . Cross S S , Hughes AD, Williams GT. Williams ED. Endocrine cell hyperplasla and appendiceal carcinoids. J Parhol1988; 156 325-329. 12. Stanley MW, Cherwitz D, Hagen K, Snover DC. Neuromas of the appendix. A light microscopic, immunohistochemical and electron microscopic study of 20 cases. A m J Surg Parhol1986; 1 0 801-81 5. 13. Lewin KJ. Ulich T, Yang K. Layfield L. The endocrine cells of the GI tract and their tumors. Part 11. In: Sommers SC, Rosen PR, Fechner RE, eds. Pathology Annual, Volume 21, Part 2. Norwalk. CT: Appleton-Century-Crofts, 1986; 181-21 5. 14. Lloyd RV, Blaivas M. Wilson BS. Distribution of chromogranin and SlO0 protein in normal and abnormal adrenal medullary tissues. Arch Parhol Lab Med 1985; 109: 633-635.
162: 189-190 (1990)
EDITORIAL CARCINOID TUMOURS OF THE APPENDIX ARE DIFFERENT
In the pathological literature, appendiceal carcin- whereas ENCs have a more uniform distribution oid tumours are usually described with other midgut along its length.' Moreover, numbers of both carcinoid tumours because of their similar mor- appendiceal carcinoid tumours and SNCs rise to a phology and staining characteristics. This classifi- peak in early adulthood, unlike numbers of appencation has tended to obscure clinical and other diceal ENCs, which are maximal in childhood and then decline through life.' Previous work has estabdifferences which set appendiceal tumours apart. First, in most parts of the gastrointestinal (GI) lished that in carcinoids at other sites there is a direct tract the incidence of carcinoid tumours is roughly connection between subepithelial tumour and proportional to the number of neuroendocrine cells hyperplastic ENCs, but such a connection has present,' but the incidence in the appendix is some not been demonstrated in appendiceal carcinoid orders of magnitude higher than expected.2 More- tumours." Also, the intimate association of SNCs, over, the distribution of carcinoids within the but not ENCs, with S100-positive cells and nerves in appendix is unusual, with many more tumours at the lamina propria is reflected in the association the tip than at the base. Second, the peak incidence between neuroendocrine cells and S 100-positive of appendiceal carcinoid tumours is in the third and 'sustentacular' cells in appendiceal carcinoid fourth decades, some 20 years earlier than carcin- tumours.6 Apparently against the origin of carcinoid oids from other parts of the GI tract.2 Third, other carcinoid tumours behave as low-grade carcinomas, tumours from SNCs is the demonstration of yet over 95 per cent of appendiceal carcinoids are increased numbers of ENCs adjacent to carcinoid benign despite apparent neural invasion3 and most tumours," which was interpreted as evidence of probably regress with time.4Fourth, despite similar pre-existing ENC hyperplasia. This is not the only reactions with silver and other immunohistochemi- explanation and comparison with another odd cal stain^,^ most appendiceal but not ileal carcinoids lesion of the appendix is instructive. contain S 100-positive 'sustentacular' cells around Neurogenous hyperplasia of the appendix is a and within the islands of neuroendocrine c e k 6 common condition previously attributed to subFinally, there is now good evidence to suggest that acute inflammation, but more recently suggested to in most parts of the GI tract carcinoid tumours arise be a primary proliferative lesion.'* Appendices confrom epithelial neuroendocrine cells (ENCs) in a taining neurogenous hyperplasia12 as well as those background of neuroendocrine cell hyperpla~ia.~containing carcinoid turnours' I have increased However, the evidence for a similar mechanism numbers of ENCs adjacent to the lesions. Moreoccurring in the appendix is not conclusive and there over, in neurogenous hyperplasia ENC numbers is still debate as to whether appendiceal carcinoid decrease with distance from the lesion,'* suggesting tumours arise from ENCs or from subepithelial that the hyperplasia is due to a local factor. neuroendocrine cells (SNCs) which are found deep The similarities do not stop there. Neurogenous within the lamina p r ~ p r i a . ' .If~the latter is correct, it hyperplasia shows large clusters of S 100-positive may explain some of the other anomalies. cells associated with variable numbers of neuroEvidence in favour of an origin from SNCs has endocrine cells which on occasions mimic microcome from recent work on the distribution of carcinoids.' Conversely, carcinoid tumours consist neuroendocrine cells within the appendix. This of islands of neuroendocrine cells surrounded by has shown that most SNCs, like most carcinoid S1 00-positive cells with S 100-positive cell clusters tumours, are concentrated at the tip of the appendix identical to those seen in neurogenous hyperplasia 0022-3417/90/110189-02 $05.00 0 1990 by John Wiley & Sons, Ltd.
190
EDITORIAL
present nearby in 75 per cent.7 Finally, both lesions occur predominantly at the tip of the appendix and eventually regress to leave fibrous t i s s ~ e . ~ . ’ ~ Such similarities prompt speculation that these lesions are different facets of the same proliferative process affecting the SNC-mucosal nerve complex. Owing to some stimulus, possibly obstruction,’- and perhaps via autocrine growth factors, there is hyperplasia of both nerves and neuroendocrine cells. When neural tissue predominates, there is neurogenous hyperplasia; when neuroendocrine cells predominate, a carcinoid tumour develops. If correct, this implies that most appendiceal carcinoid tumours are probably hyperplastic lesions rather than true neoplasms, which would explain their benign nature, their relative abundance, and their tendency to regress. Moreover, what was thought to be neural invasion is just the normal association of hyperplastic neuroendocrine cells and nerves. The exceptions which might prove the rule are the mucinous carcinoids of the appendix. These tumours behave more aggressively than typical carcinoids’ and are the one type of neuroendocrine tumour of the appendix which has been seen to arise directly from thecrypt epithe1i~m.I~ Moreover, they do not appear to be associated with S 100-positive cells (personal observation). At the moment, these findings do not have any direct clinical relevance but it is possible that the presence of S 100-positive sustentacular cells in a carcinoid tumour may be a marker of a benign course, analogous to proliferations of the adrenal medulla.I4 Finally, it should be mentioned that SNCs occur elsewhere in the GI tract and may give rise to occasional tumours at those sites. Also, the mechanism described does not exclude some carcinoid tumours of the appendix developing via ENC hyperplasia, nor neoplastic transformation of hyperplastic SNCs. However, this theory may go some of the way to explaining why carcinoid
tumours of the appendix are just that little bit different. PAULA. V. SHAW Department of His topath ology Leicester Ro-val InJrmary Leicester LE1.5 W W , U.K.
REFERENCES I . Sjolund K, Sanden G, Hakanson R. Sundler R. Endocrine cells in human intestine: an immunocytochemical study. Gastroenrerologr 1983:85: 1120-1130. 2 Godwin JD. Carcinoid tumors. An analysis of 2837 cases. Cancer 1975: 36:560-569. 3. Moertel CG. Weiland LH. Nagorney DM. Dockerty MB. Carcinoid tumors of the appendix: treatment and prognosis. N Engl J Med 1987; 317: 1699-1701. 4. Berge T. Linell F. Carcinoid tumours. Frequency in a defined population during a I2 year period. Arm Parhol Microbiol Scand Sect A 1976; &I: 322-330. 5. Chejfec G.. Fdlkmer S , Askensten U. Grimelius L. Gould VE. Neuroendocrine tumours of the gastrointestinal tract. Parhol Res Pracr 1988; 183: 143-154. 6. Lundqvist M, Wilander E. Subepithelial neuroendocr~necells and carcinoid tumours of the human small intestine and appendix. A comparative immunohistochemical study with regard to serotonin. neuron specific enolase and Sl00 protein reactivity. J Parhol 1986, 148: 141-147. 7. Aubock L. Hofler H. Extraepithelial intraneural endocrine cells as starting points for gastrointestinal carcinoids. Virchows Arch A (ParholAnar] 1983;401: 17-33. 8 Rode J . Dhillon AP, Papadaki L, Griffiths D. Neurosecretory cells of the lamina propria of the appendix and their possible relationship to carcinoids. Hbropathology 1982; 6 69-79. 9. Kinsey WL. Shaw PAV. On the histogenesis of carcinoid tumours: evidence from the distribution of neuroendocrine cells in the normal appendix. J Patholl990: 161: 356A. 10. Lundqvist M,. Wilander E. A study of the histopathogenesis of carcinoid tumors of the small intestine and appendix. Cancer 1987; 60: 201-206. I I . Cross S S , Hughes AD, Williams GT. Williams ED. Endocrine cell hyperplasla and appendiceal carcinoids. J Parhol1988; 156 325-329. 12. Stanley MW, Cherwitz D, Hagen K, Snover DC. Neuromas of the appendix. A light microscopic, immunohistochemical and electron microscopic study of 20 cases. A m J Surg Parhol1986; 1 0 801-81 5. 13. Lewin KJ. Ulich T, Yang K. Layfield L. The endocrine cells of the GI tract and their tumors. Part 11. In: Sommers SC, Rosen PR, Fechner RE, eds. Pathology Annual, Volume 21, Part 2. Norwalk. CT: Appleton-Century-Crofts, 1986; 181-21 5. 14. Lloyd RV, Blaivas M. Wilson BS. Distribution of chromogranin and SlO0 protein in normal and abnormal adrenal medullary tissues. Arch Parhol Lab Med 1985; 109: 633-635.
