- Email: [email protected]
The role of Ki-67 in predicting biological behavior of goblet cell carcinoid tumor in appendix
The American Journal of Surgery (2011) 202, 400 – 403
Clinical Science
The role of Ki-67 in predicting biological behavior of goblet cell carcinoid tumor in appendix Eric Liu, M.D.a, Dana A. Telem, M.D.a, Richard R.P. Warner, M.D.b, Andrew Dikman, M.D.c, Celia M. Divino, M.D., F.A.C.S.a,* a
Division of General Surgery, Department of Surgery, bDivision of Gastroenterology, Department of Medicine, and Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
c
KEYWORDS: Appendix; Goblet cell carcinoid tumor; Ki-67; Correlation; Patient survival; Prognosis
Abstract BACKGROUND: The aim of this study was to examine the role of Ki-67, a cellular proliferation marker, in the prognosis of goblet cell appendiceal carcinoid tumor. METHODS: Twelve goblet cell appendiceal carcinoid tumors were stained with MIB-1, a monoclonal antibody of Ki-67, to assess their cell proliferation and correlations with clinical and histologic parameters. RESULTS: Among 12 patients studied, the mean MIB-1 index was 24%, with tumors ranging from .5 to 5.0 cm in size. No correlation was observed between tumor size and MIB-1 index. Two patients had metastatic disease on presentation (MIB-1 index 10% and 60%). All patients received surgical intervention according to extent of tumor invasion regardless of their MIB-1 index values. Median follow-up was 54 months, with a 75% follow-up rate and 1 death from metastasis. The overall survival rate was 76%, with a disease-specific survival rate of 87%. CONCLUSIONS: Ki-67 had no prognostic significance for goblet cell carcinoid tumors and should not be used solely to determine treatment and surgical approach. © 2011 Elsevier Inc. All rights reserved.
Carcinoid tumors are rare neoplasms that are considered to have more indolent clinical courses than adenocarcinoma. They account for up to 57% of all appendiceal tumors and are usually discovered incidentally during routine appendectomy.1 Among appendiceal carcinoid tumors, goblet cell carcinoid (GCC) tumors are a unique subgroup of mixed endocrine and exocrine neoplasms constituting ⬍5% of all primary appendiceal tumors.2 GCC tumors, also known as mucinous carcinoid, adenocarcinoid, or crypt cell carcinoma, were originally described This project was funded in part by the Carcinoid Cancer Foundation (White Plains, NY). * Corresponding author. Tel.: 212-241-5499; fax: 212-534-2654. E-mail address: [email protected] Manuscript received June 18, 2010; revised manuscript August 18, 2010
0002-9610/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2010.08.036
by Gagne et al3 in 1969.4 In 1974, Subbuswamy et al5 provided the term “goblet cell appendiceal carcinoid” on the basis of the similarity of tumor morphology with the normal crypt of the intestinal epithelium, containing goblet, enterochromaffin, and Paneth cells.1,4,6 Arising from the stem cell of the crypt base, GCC tumors stain positive for the same immunohistochemical markers as classical appendiceal carcinoid tumors. However, GCC tumors also produce mucin, consistent with adenocarcinoma.7 The aggressiveness of GCC tumors is thought to be intermediate between typical carcinoid tumors and adenocarcinoma.1–7 Hence, the clinical behavior of GCC tumors is unpredictable, and controversies exist regarding their clinical course and appropriate treatment. Ki-67, an immunohistochemical marker, has recently been used in the workup and surveillance of carcinoid
E. Liu et al.
Ki-67 and appendiceal carcinoid tumor behavior
tumors. It is a nuclear protein antigen associated with chromatin during cell proliferation and not with deoxyribonucleic acid repairs.8,9 Using MIB-1, a highly specific monoclonal antibody to Ki-67, on formalin-fixed paraffin-embedded pathologic sections, cell growth fraction can be measured as a proliferation index.9 We have previously shown that Ki-67 correlates with long-term survival in patients with appendiceal carcinoid tumors (unpublished data). This finding was confirmed in a recently reported study of 82 patients with neuroendocrine tumors by Singh et al.10 The purpose of this study was to determine whether Ki-67 is valuable in predicting the behavior of GCC tumors.
Methods Following approval by The Mount Sinai School of Medicine Institutional Review Board, a retrospective chart review with prospective follow-up was performed. Through the hospital’s electronic medical records and pathology department databases, 53 patients with carcinoid tumors involving the appendix who underwent operative intervention and pathologic specimen review at The Mount Sinai Medical Center from 1991 to 2010 were identified. Of the 62 patients with appendiceal carcinoid tumors, 12 with GCC tumors (19%) were identified. Pathology review and confirmation of GCC tumors was performed by board-certified pathologists specialized in gastrointestinal malignancies. Medical records were reviewed with respect to patient demographics, medical history, presenting symptoms, type of surgical intervention, outcomes, and tumor characteristics, with an emphasis on Ki-67 proliferative index. Follow-up was obtained through electronic patient records or telephone interviews with patients or immediate family members. MIB-1 was used to assess the tumor cell growth fraction by immunostaining the paraffin sections, and stored pathologic specimens were stained retrospectively. The MIB-1 labeling index was defined as the percentage of positive tumor cell nuclei: MIB-1 labeling index (%) ⫽ number of cells with positive nuclear staining/total number of tumor cells ⫻ 100. The proliferative indexes were compared with clinical and histologic parameters such as age, gender, tumor size, presence of lymph node metastasis, disease-free interval, and survival. All staining was performed and evaluated at The Mount Sinai Medical Center by a single board-certified pathologist specialized in carcinoid pathology. Kaplan-Meier survival curves were used to analyze the overall survival and disease-specific survival in patients. All statistical analysis was performed using GraphPad Prism for Windows version 4 (GraphPad Software, San Diego, CA). P values ⬍ .05 were considered statistically significant.
401
Results Demographics Of the 12 patients, 9 were women and 3 were men, with a mean age of 59 years (range, 40 –98 years). Preoperative diagnoses were available for 9 patients and included acute appendicitis (n ⫽ 1), chronic appendicitis (n ⫽ 1), perforated appendicitis (n ⫽ 2), diverticulitis complicated by colovesicular fistula (n ⫽ 1), partial small bowel obstruction (n ⫽ 1), adenocarcinoma of the right colon (n ⫽ 1), Crohn’s ileitis (n ⫽ 1), and a bilateral kidney obstruction (in the setting of lymphoma and bladder lymphosarcoma). No patient presented with carcinoid syndrome.
Tumor characteristics Tumor size ranged from .5 to 5.0 cm, with 2 tumors having unspecified sizes. For MIB-1 proliferative index, the mean value was 24% (range, 0% to ⬎80%). No direct correlation was observed between tumor size and MIB-1 index. Three tumors were confined to the lumen of the appendix, and their MIB-1 indexes were ⬎80%, 0%, and 0%. However, most of the tumors spread beyond the muscularis propria of the appendix to the serosa and the periappendiceal fat at the time of diagnosis (neural invasion presented in patient 12), with their mean MIB-1 index being 28.6%. In addition, there were also 2 tumors presenting with lymph node metastases at time of diagnosis, and their MIB-1 indexes were 10% and 60%. No correlation could be drawn from tumor aggressiveness and MIB-1 proliferative index. Immunohistochemical staining was positive in 9 of 12 GCC tumors for ⱖ1 of the classical carcinoid markers: chromogranin A, synaptophysin, and neuron-specific enolase. Furthermore, 5 tumors also presented with adenocarcinomatous feature: 1 with strongly positive mucin staining, 3 with mucinous adenoma of the appendix, and 1 with adenocarcinoma of the right colon.
Management and follow-up Table 1 demonstrates management and outcomes by patient age, tumor characteristics, and tumor biology. In the 12 patients, 10 appendectomies were performed, and 8 of these patients required more extensive resection. Three patients proceeded to more extensive operations without having appendectomy first. In patient 5, right hemicolectomy was performed because of synchronous adenocarcinoma of right colon. In patient 7, laparoscopic ileocolic resection was done because of Crohn’s ileitis. In patient 11, laparoscopic low anterior resection was performed in addition to appendectomy because of diverticulitis complicated by colovesicular fistula. Overall, the extent of surgical resection was not guided by MIB-1 index in patients with GCC tumors.
402
The American Journal of Surgery, Vol 202, No 4, October 2011
Table 1
Tumor biology, tumor characteristics, management, and outcomes of patients with GCC tumors
Mitotic Tumor Size MIB-1 Figures Age Patient (y)/Sex (cm) Index (per 10 hpf) Clinical and Pathologic Characteristics 1
47/F
2
2
52/F
.7
3
98/F
.5
⬎80% NA
4
80/F
5.0
0%
0
5
66/F
4.5
40%
3
6
61/M
NA
35%
0
7 8
41/F 53/M
⬎5
.5
0% 10%
0 0
9
56/F
2.2
60%
8
10
40/M
1
0%
0
11
65/F
12
54/F
.5 NA
10%
0
30%
1
0% ⬍2 75%
0
Management
Tumor involved periappendiceal fat and Appendectomy and right hemicolectomy showed lymphovascular invasion; metastasis on presentation, and 3 of 13 lymph nodes were positive Tumor had transmural infiltration Appendectomy and right hemicolectomy Patient had synchronous mucinous Appendectomy adenoma of appendix Patient had perforated appendix with Appendectomy synchronous mucinous adenoma of appendix Tumor showed serosal involvement and Right hemicolectomy synchronous adenocarcinoma of right colon Tumor showed transmural infiltration Appendectomy and ileocolic resection GCC tumor Ileocolic resection Tumor showed transmural infiltration Appendectomy and right and involved with periappendiceal hemicolectomy fat Tumor had metastasized to lymph Appendectomy and total nodes on presentation abdominal hysterectomy/bilateral salpingo-oophorectomy Tumor showed transmural infiltration Appendectomy and right and serosal involvement hemicolectomy Patient had synchronous mucinous Appendectomy and lower cystadenoma of the appendix anterior resection Appendectomy and right Perforated appendix with tumor hemicolectomy invaded through muscularis propria and mesoappendix with lymphovascular and neural involvement; resection margin and lymph nodes (0/13) were uninvolved; strongly positive for mucin
Outcome No follow-up
AWND DFOC (natural cause) No follow-up
AWND
AWND AWND AWND
DOD (after development of metastases) No follow-up AWND AWND
AWND ⫽ alive with no disease; DFOC ⫽ died of other cause; DOD ⫽ died of disease.
Follow-up was possible in 9 patients (75%), with a median follow-up time of 54 months. There were 2 deaths reported in our patients: patient 2 (MIB-1 ⬎ 80%) died of an unrelated condition, and patient 9 (MIB-1 60%) died of metastatic disease. At the median follow-up time, the overall survival rate of our patients was 76%, and diseasespecific survival was 87%.
Comments The expression of the Ki-67 proliferation marker protein has been used to measure mitotic activity during cell proliferation because of its close association with the chromatins in the nucleolus.8,9,11,12 Although its exact function is not well un-
derstood, its correlations with known tumor prognostic factors (ie, tumor size, tumor aggressiveness, lymph node metastasis, and patient survival) have been studied. As demonstrated in pancreatic and gastrointestinal neuroendocrine tumors, Ki-67 proliferative index displayed positive correlations with tumor size and metastatic disease at the time of diagnosis, whereas decreases in patient survival were observed.8,9,11,13,14 To our knowledge, this is the only study exclusively examining the correlation between Ki-67 with known prognostic factors in GCC tumors of the appendix. Consistent with the literature,15 all of our patients were diagnosed incidentally. None of the patients had preoperative diagnoses of GCC carcinoma. The mean MIB-1 index was 24 ⫾ .27%, and the results were comparable with those of previous studies.1,2,4,6,16 –18 The MIB-1 proliferative index was significantly higher than the classical appendiceal
E. Liu et al.
Ki-67 and appendiceal carcinoid tumor behavior
carcinoid value of 1.9.4 With some tumors without grossly defined mass, the MIB-1 index failed to correlate with GCC tumor size. In addition, most GCC tumors invaded beyond the muscularis propria of the appendix, with 2 tumors presenting with lymph node metastases. The MIB-1 index did not demonstrate clear relationships with tumor aggressiveness and lymph node metastasis at the time of diagnosis. In our study, MIB-1 index exhibited a wide range of values, from 0% to ⬎80%. According to recent studies,2,17 a histopathologic classification was proposed to stratify GCC tumors on the basis of tumor cell differentiation and the proliferation index, Ki-67. The groups of GCC tumors consist of (1) typical GCC tumors (MIB-1 index, 11%), (2) adenocarcinoma ex GCC with signet ring cell type (MIB-1 index, 16%), and (3) poorly differentiated carcinoma cell type (MIB-1 index, 80%). These histologic classifications have been shown to have predictive value for patient survival. The typical GCC tumor is associated with the highest survival rate, and the poorly differentiated carcinomas have the lowest survival rate. Operative procedures were guided by the extent of tumor invasion and comorbidity of the patients, regardless of MIB-1 index. The patients, who underwent more extensive resection other than an appendectomy, had tumor invasion beyond the muscularis propria of the appendix with invasion to the surrounding structures. This is consistent with previous studies,19 –21 in which management was customized to individual patients and comorbidities as indicated.21 With the exception of patient 3, the 5-year survival of the patients in our study was 83%, which is comparable with previous studies.1,20 The MIB-1 index did not play a role in predicting patient survival. Another finding of this study was a 3:1 female predominance. The demographic difference could be due to the sampling of a rare malignancy. The same female predominance was seen by van Eeden et al4 and Tang et al,17 whereas male predominance was seen by Kanthan et al16 and Bucher et al.19 Overall, equal representation in both sexes should be demonstrated when enough patients are included in the study population. Although this study represents one of the larger series of patients with GCC tumors with prospective follow-up, it did have several limitations. The sample size and retrospective study design limit the applicability of clinical findings. However, our results clearly demonstrate the lack of correlation between MIB-1 and the behavior of GCC tumors. This is consistent with known characteristics of GCC tumors, unlike typical appendiceal carcinoid tumors.
Conclusions Although sample size limits conclusions, this study demonstrates a lack of correlation between Ki-67 and tumor prognostic factors in GCC tumors. Management of GCC tumors should continue to be carefully planned and
403 tailored to individual patients because of the unpredictability of this malignancy.
References 1. Toumpanakis C, Standish RA, Baishnab E, et al. Goblet cell carcinoid tumors (adenocarcinoid) of the appendix. Dis Colon Rectum 2007;50: 315–22. 2. Wang H, Dhall D. Goblet or signet ring cells: that is the question. Adv Anat Pathol 2009;16:247–54. 3. Gagne F, Fortin P, Dufour V, et al. Tumours of the appendix associating histologic features of carcinoid and adenocarcinoma. Ann Anat Pathol (Paris) 1969;14:393– 406. 4. van Eeden S, Offerhaus GJA, Hart AAM, et al. Goblet cell carcinoid of the appendix: a specific type of carcinoma. Histopathology 2007; 51:763–73. 5. Subbuswamy SG, Gibbs NM, Ross CF, et al. Goblet cell carcinoid of the appendix. Cancer 1974;34:338 – 44. 6. Alsaad KO, Serra S, Perren A, et al. CK19 and CD99 immunoexpression profile in goblet cell (mucin-producing neuroendocinre tumors) and classical carcinoids of the vermiform appendix. Int J Surg Pathol 2007;15:252–7. 7. Pham TH, Wolff B, Abraham SC, et al. Surgical and chemotherapy treatment outcomes of goblet cell carcinoid: a tertiary cancer center experience. Ann Surg Oncol 2006;13:370 – 6. 8. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 2005;89:151– 60. 9. Vilar E, Salazar R, Pérez-García J, et al. Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer 2007;14:221–32. 10. Singh S, Rowsell C, Ingber N, et al. The role of Ki-67 in the prognosis and management of neuroendocrine (NET) patients in a multidisciplinary cancer center [abstract 266]. Presented at: Gastrointestinal Cancers Symposium of American Society of Clinical Oncology; Orlando, FL; January 2010. 11. Brown DC, Gatter KC. Ki67 protein: the immaculate deception? Histopathology 2002;40:2–11. 12. Gerdes J, Lemke H, Baisch H, et al. Cell cycle analysis of a cell proliferation-associated Human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710 –5. 13. Kloppel G, Perren A, Heitz P. The gastroenteropancreatic neuroendocrine cell system and its tumors. Ann N Y Acad Sci 2004;1014: 13–27. 14. Kawahara M, Kammori M, Kanauchi H, et al. Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumors. Eur J Surg Oncol 2002;28:140 – 6. 15. Li CC, Hirokawa M, Qian ZR, et al. Expression of E-cadherin, -catenin, and Ki-67 in goblet cell carcinoids of the appendix: an immunohistochemical study with clinical correlation. Endocr Pathol 2002;13:47–58. 16. Kanthan R, Saxena A, Kanthan SC. Goblet cell carcinoid of the appendix: immunophenotype and ultrastructural study. Arch Pathol Lab Med 2001;125:386 –90. 17. Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol 2008;32:1429 – 43. 18. Alsaad KO, Serra S, Chetty R. Combined goblet cell carcinoid and mucinous cytadenoma of the vermiform appendix. World J Gastroenterol 2009;15:3431–3. 19. Bucher P, Gervaz P, Ris F, et al. Surgical treatment of appendiceal adenocarcinoid (goblet cell carcinoid). World J Surg 2005;29: 1436 –9. 20. Pahlavan PS, Kanthan R. Goblet cell carcinoid of the appendix. World J Surg Oncol 2005;3:36. 21. Byrn JC, Wang JL, Divino CM, et al. Management of goblet cell carcinoid. J Surg Oncol 2006;94:396 – 402.
Clinical Science
The role of Ki-67 in predicting biological behavior of goblet cell carcinoid tumor in appendix Eric Liu, M.D.a, Dana A. Telem, M.D.a, Richard R.P. Warner, M.D.b, Andrew Dikman, M.D.c, Celia M. Divino, M.D., F.A.C.S.a,* a
Division of General Surgery, Department of Surgery, bDivision of Gastroenterology, Department of Medicine, and Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
c
KEYWORDS: Appendix; Goblet cell carcinoid tumor; Ki-67; Correlation; Patient survival; Prognosis
Abstract BACKGROUND: The aim of this study was to examine the role of Ki-67, a cellular proliferation marker, in the prognosis of goblet cell appendiceal carcinoid tumor. METHODS: Twelve goblet cell appendiceal carcinoid tumors were stained with MIB-1, a monoclonal antibody of Ki-67, to assess their cell proliferation and correlations with clinical and histologic parameters. RESULTS: Among 12 patients studied, the mean MIB-1 index was 24%, with tumors ranging from .5 to 5.0 cm in size. No correlation was observed between tumor size and MIB-1 index. Two patients had metastatic disease on presentation (MIB-1 index 10% and 60%). All patients received surgical intervention according to extent of tumor invasion regardless of their MIB-1 index values. Median follow-up was 54 months, with a 75% follow-up rate and 1 death from metastasis. The overall survival rate was 76%, with a disease-specific survival rate of 87%. CONCLUSIONS: Ki-67 had no prognostic significance for goblet cell carcinoid tumors and should not be used solely to determine treatment and surgical approach. © 2011 Elsevier Inc. All rights reserved.
Carcinoid tumors are rare neoplasms that are considered to have more indolent clinical courses than adenocarcinoma. They account for up to 57% of all appendiceal tumors and are usually discovered incidentally during routine appendectomy.1 Among appendiceal carcinoid tumors, goblet cell carcinoid (GCC) tumors are a unique subgroup of mixed endocrine and exocrine neoplasms constituting ⬍5% of all primary appendiceal tumors.2 GCC tumors, also known as mucinous carcinoid, adenocarcinoid, or crypt cell carcinoma, were originally described This project was funded in part by the Carcinoid Cancer Foundation (White Plains, NY). * Corresponding author. Tel.: 212-241-5499; fax: 212-534-2654. E-mail address: [email protected] Manuscript received June 18, 2010; revised manuscript August 18, 2010
0002-9610/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2010.08.036
by Gagne et al3 in 1969.4 In 1974, Subbuswamy et al5 provided the term “goblet cell appendiceal carcinoid” on the basis of the similarity of tumor morphology with the normal crypt of the intestinal epithelium, containing goblet, enterochromaffin, and Paneth cells.1,4,6 Arising from the stem cell of the crypt base, GCC tumors stain positive for the same immunohistochemical markers as classical appendiceal carcinoid tumors. However, GCC tumors also produce mucin, consistent with adenocarcinoma.7 The aggressiveness of GCC tumors is thought to be intermediate between typical carcinoid tumors and adenocarcinoma.1–7 Hence, the clinical behavior of GCC tumors is unpredictable, and controversies exist regarding their clinical course and appropriate treatment. Ki-67, an immunohistochemical marker, has recently been used in the workup and surveillance of carcinoid
E. Liu et al.
Ki-67 and appendiceal carcinoid tumor behavior
tumors. It is a nuclear protein antigen associated with chromatin during cell proliferation and not with deoxyribonucleic acid repairs.8,9 Using MIB-1, a highly specific monoclonal antibody to Ki-67, on formalin-fixed paraffin-embedded pathologic sections, cell growth fraction can be measured as a proliferation index.9 We have previously shown that Ki-67 correlates with long-term survival in patients with appendiceal carcinoid tumors (unpublished data). This finding was confirmed in a recently reported study of 82 patients with neuroendocrine tumors by Singh et al.10 The purpose of this study was to determine whether Ki-67 is valuable in predicting the behavior of GCC tumors.
Methods Following approval by The Mount Sinai School of Medicine Institutional Review Board, a retrospective chart review with prospective follow-up was performed. Through the hospital’s electronic medical records and pathology department databases, 53 patients with carcinoid tumors involving the appendix who underwent operative intervention and pathologic specimen review at The Mount Sinai Medical Center from 1991 to 2010 were identified. Of the 62 patients with appendiceal carcinoid tumors, 12 with GCC tumors (19%) were identified. Pathology review and confirmation of GCC tumors was performed by board-certified pathologists specialized in gastrointestinal malignancies. Medical records were reviewed with respect to patient demographics, medical history, presenting symptoms, type of surgical intervention, outcomes, and tumor characteristics, with an emphasis on Ki-67 proliferative index. Follow-up was obtained through electronic patient records or telephone interviews with patients or immediate family members. MIB-1 was used to assess the tumor cell growth fraction by immunostaining the paraffin sections, and stored pathologic specimens were stained retrospectively. The MIB-1 labeling index was defined as the percentage of positive tumor cell nuclei: MIB-1 labeling index (%) ⫽ number of cells with positive nuclear staining/total number of tumor cells ⫻ 100. The proliferative indexes were compared with clinical and histologic parameters such as age, gender, tumor size, presence of lymph node metastasis, disease-free interval, and survival. All staining was performed and evaluated at The Mount Sinai Medical Center by a single board-certified pathologist specialized in carcinoid pathology. Kaplan-Meier survival curves were used to analyze the overall survival and disease-specific survival in patients. All statistical analysis was performed using GraphPad Prism for Windows version 4 (GraphPad Software, San Diego, CA). P values ⬍ .05 were considered statistically significant.
401
Results Demographics Of the 12 patients, 9 were women and 3 were men, with a mean age of 59 years (range, 40 –98 years). Preoperative diagnoses were available for 9 patients and included acute appendicitis (n ⫽ 1), chronic appendicitis (n ⫽ 1), perforated appendicitis (n ⫽ 2), diverticulitis complicated by colovesicular fistula (n ⫽ 1), partial small bowel obstruction (n ⫽ 1), adenocarcinoma of the right colon (n ⫽ 1), Crohn’s ileitis (n ⫽ 1), and a bilateral kidney obstruction (in the setting of lymphoma and bladder lymphosarcoma). No patient presented with carcinoid syndrome.
Tumor characteristics Tumor size ranged from .5 to 5.0 cm, with 2 tumors having unspecified sizes. For MIB-1 proliferative index, the mean value was 24% (range, 0% to ⬎80%). No direct correlation was observed between tumor size and MIB-1 index. Three tumors were confined to the lumen of the appendix, and their MIB-1 indexes were ⬎80%, 0%, and 0%. However, most of the tumors spread beyond the muscularis propria of the appendix to the serosa and the periappendiceal fat at the time of diagnosis (neural invasion presented in patient 12), with their mean MIB-1 index being 28.6%. In addition, there were also 2 tumors presenting with lymph node metastases at time of diagnosis, and their MIB-1 indexes were 10% and 60%. No correlation could be drawn from tumor aggressiveness and MIB-1 proliferative index. Immunohistochemical staining was positive in 9 of 12 GCC tumors for ⱖ1 of the classical carcinoid markers: chromogranin A, synaptophysin, and neuron-specific enolase. Furthermore, 5 tumors also presented with adenocarcinomatous feature: 1 with strongly positive mucin staining, 3 with mucinous adenoma of the appendix, and 1 with adenocarcinoma of the right colon.
Management and follow-up Table 1 demonstrates management and outcomes by patient age, tumor characteristics, and tumor biology. In the 12 patients, 10 appendectomies were performed, and 8 of these patients required more extensive resection. Three patients proceeded to more extensive operations without having appendectomy first. In patient 5, right hemicolectomy was performed because of synchronous adenocarcinoma of right colon. In patient 7, laparoscopic ileocolic resection was done because of Crohn’s ileitis. In patient 11, laparoscopic low anterior resection was performed in addition to appendectomy because of diverticulitis complicated by colovesicular fistula. Overall, the extent of surgical resection was not guided by MIB-1 index in patients with GCC tumors.
402
The American Journal of Surgery, Vol 202, No 4, October 2011
Table 1
Tumor biology, tumor characteristics, management, and outcomes of patients with GCC tumors
Mitotic Tumor Size MIB-1 Figures Age Patient (y)/Sex (cm) Index (per 10 hpf) Clinical and Pathologic Characteristics 1
47/F
2
2
52/F
.7
3
98/F
.5
⬎80% NA
4
80/F
5.0
0%
0
5
66/F
4.5
40%
3
6
61/M
NA
35%
0
7 8
41/F 53/M
⬎5
.5
0% 10%
0 0
9
56/F
2.2
60%
8
10
40/M
1
0%
0
11
65/F
12
54/F
.5 NA
10%
0
30%
1
0% ⬍2 75%
0
Management
Tumor involved periappendiceal fat and Appendectomy and right hemicolectomy showed lymphovascular invasion; metastasis on presentation, and 3 of 13 lymph nodes were positive Tumor had transmural infiltration Appendectomy and right hemicolectomy Patient had synchronous mucinous Appendectomy adenoma of appendix Patient had perforated appendix with Appendectomy synchronous mucinous adenoma of appendix Tumor showed serosal involvement and Right hemicolectomy synchronous adenocarcinoma of right colon Tumor showed transmural infiltration Appendectomy and ileocolic resection GCC tumor Ileocolic resection Tumor showed transmural infiltration Appendectomy and right and involved with periappendiceal hemicolectomy fat Tumor had metastasized to lymph Appendectomy and total nodes on presentation abdominal hysterectomy/bilateral salpingo-oophorectomy Tumor showed transmural infiltration Appendectomy and right and serosal involvement hemicolectomy Patient had synchronous mucinous Appendectomy and lower cystadenoma of the appendix anterior resection Appendectomy and right Perforated appendix with tumor hemicolectomy invaded through muscularis propria and mesoappendix with lymphovascular and neural involvement; resection margin and lymph nodes (0/13) were uninvolved; strongly positive for mucin
Outcome No follow-up
AWND DFOC (natural cause) No follow-up
AWND
AWND AWND AWND
DOD (after development of metastases) No follow-up AWND AWND
AWND ⫽ alive with no disease; DFOC ⫽ died of other cause; DOD ⫽ died of disease.
Follow-up was possible in 9 patients (75%), with a median follow-up time of 54 months. There were 2 deaths reported in our patients: patient 2 (MIB-1 ⬎ 80%) died of an unrelated condition, and patient 9 (MIB-1 60%) died of metastatic disease. At the median follow-up time, the overall survival rate of our patients was 76%, and diseasespecific survival was 87%.
Comments The expression of the Ki-67 proliferation marker protein has been used to measure mitotic activity during cell proliferation because of its close association with the chromatins in the nucleolus.8,9,11,12 Although its exact function is not well un-
derstood, its correlations with known tumor prognostic factors (ie, tumor size, tumor aggressiveness, lymph node metastasis, and patient survival) have been studied. As demonstrated in pancreatic and gastrointestinal neuroendocrine tumors, Ki-67 proliferative index displayed positive correlations with tumor size and metastatic disease at the time of diagnosis, whereas decreases in patient survival were observed.8,9,11,13,14 To our knowledge, this is the only study exclusively examining the correlation between Ki-67 with known prognostic factors in GCC tumors of the appendix. Consistent with the literature,15 all of our patients were diagnosed incidentally. None of the patients had preoperative diagnoses of GCC carcinoma. The mean MIB-1 index was 24 ⫾ .27%, and the results were comparable with those of previous studies.1,2,4,6,16 –18 The MIB-1 proliferative index was significantly higher than the classical appendiceal
E. Liu et al.
Ki-67 and appendiceal carcinoid tumor behavior
carcinoid value of 1.9.4 With some tumors without grossly defined mass, the MIB-1 index failed to correlate with GCC tumor size. In addition, most GCC tumors invaded beyond the muscularis propria of the appendix, with 2 tumors presenting with lymph node metastases. The MIB-1 index did not demonstrate clear relationships with tumor aggressiveness and lymph node metastasis at the time of diagnosis. In our study, MIB-1 index exhibited a wide range of values, from 0% to ⬎80%. According to recent studies,2,17 a histopathologic classification was proposed to stratify GCC tumors on the basis of tumor cell differentiation and the proliferation index, Ki-67. The groups of GCC tumors consist of (1) typical GCC tumors (MIB-1 index, 11%), (2) adenocarcinoma ex GCC with signet ring cell type (MIB-1 index, 16%), and (3) poorly differentiated carcinoma cell type (MIB-1 index, 80%). These histologic classifications have been shown to have predictive value for patient survival. The typical GCC tumor is associated with the highest survival rate, and the poorly differentiated carcinomas have the lowest survival rate. Operative procedures were guided by the extent of tumor invasion and comorbidity of the patients, regardless of MIB-1 index. The patients, who underwent more extensive resection other than an appendectomy, had tumor invasion beyond the muscularis propria of the appendix with invasion to the surrounding structures. This is consistent with previous studies,19 –21 in which management was customized to individual patients and comorbidities as indicated.21 With the exception of patient 3, the 5-year survival of the patients in our study was 83%, which is comparable with previous studies.1,20 The MIB-1 index did not play a role in predicting patient survival. Another finding of this study was a 3:1 female predominance. The demographic difference could be due to the sampling of a rare malignancy. The same female predominance was seen by van Eeden et al4 and Tang et al,17 whereas male predominance was seen by Kanthan et al16 and Bucher et al.19 Overall, equal representation in both sexes should be demonstrated when enough patients are included in the study population. Although this study represents one of the larger series of patients with GCC tumors with prospective follow-up, it did have several limitations. The sample size and retrospective study design limit the applicability of clinical findings. However, our results clearly demonstrate the lack of correlation between MIB-1 and the behavior of GCC tumors. This is consistent with known characteristics of GCC tumors, unlike typical appendiceal carcinoid tumors.
Conclusions Although sample size limits conclusions, this study demonstrates a lack of correlation between Ki-67 and tumor prognostic factors in GCC tumors. Management of GCC tumors should continue to be carefully planned and
403 tailored to individual patients because of the unpredictability of this malignancy.
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