- Email: [email protected]
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma
Case Report
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma Sarah Glaze, MD, FRCSC,1 Jill Nation, MD, FRCSC,1 Martin Köbel, MD2 1
Division of Gynecologic Oncology, University of Calgary, Calgary AB
2
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary AB
Abstract Background: Ovarian carcinomas are currently managed as a single entity with no stratification for histological type. The foundation of treatment is a combination of surgery and chemotherapy. Women who are not candidates for up-front debulking surgery, either because of performance status or widespread disease, are often offered neoadjuvant chemotherapy in an effort to shrink their tumour and make resection possible. Case: A 76-year-old woman was treated with neoadjuvant platinumbased chemotherapy for advanced ovarian cancer. At interval debulking surgery, she was found to have a concurrent mucinous colorectal carcinoma that was essentially unaffected by her treatment. Conclusion: This case serves as an in vivo demonstration of the greater resistance to platinum-based treatments of mucinous carcinomas than of the “typical” high-grade serous ovarian cancer.
Résumé Contexte : À l’heure actuelle, les carcinomes ovariens sont pris en charge comme étant une seule entité, sans stratification en fonction du type histologique. Le traitement est fondé sur une combinaison de chirurgie et de chimiothérapie. Les femmes qui ne sont pas candidates à une chirurgie de réduction tumorale au stade initial, que ce soit en raison de l’indice de performance ou de la présence d’une maladie répandue, se voient souvent offrir une chimiothérapie néoadjuvante visant à provoquer le rétrécissement de la tumeur et à en rendre la résection possible. Cas : Une femme de 76 ans a été traitée au moyen d’une chimiothérapie néoadjuvante à base de platine en raison de la présence d’un cancer de l’ovaire avancé. Au moment de Key Words: Ovarian cancer, mucinous carcinoma, neoadjuvant chemotherapy Competing Interests: None declared. Received on December 7, 2011 Accepted on January 12, 2012
678 l JULY JOGC JUILLET 2012
la chirurgie de réduction tumorale d’intervalle, nous avons constaté la présence concomitante d’un carcinome colorectal mucineux qui n’avait essentiellement pas été affecté par le traitement. Conclusion : Ce cas fait figure de démonstration in vivo du fait que les carcinomes mucineux présentent une plus grande résistance aux traitements à base de platine que les cas « typiques » de cancer séreux de l’ovaire de haut grade histologique. J Obstet Gynaecol Can 2012;34(7):678–682
INTRODUCTION
W
ith the introduction of platinum-based chemotherapy more than 20 years ago, the median survival time of women with ovarian carcinoma has doubled.1 Carboplatin has remained the mainstay of adjuvant treatment despite countless clinical trials that have sought to improve on this standard.1,2 Traditionally, up-front debulking surgery was followed by adjuvant chemotherapy. The timing of surgery has now been questioned, with two randomized clinical trials showing similar outcomes but superior perioperative morbidity and lower costs when interval debulking follows neoadjuvant chemotherapy.3
Ovarian carcinomas are currently managed as a single entity with no stratification for histological type.4 By far the most common type of ovarian carcinoma is high-grade serous carcinoma, which accounts for two thirds of cases. Less common types are clear cell (12%), endometrioid (10%), mucinous (3%), and low-grade serous (3%) carcinomas.5 Recent improvements in histological classification allow a highly reproducible diagnosis based on morphology alone or with the use of ancillary immunohistochemistry.6,7
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma
Figure 1. High power image of residual ovarian tumour showing papillary architecture with marked nuclear atypia diagnostic for high-grade serous carcinomas. There are conspicuous psammoma bodies (*).
Figure 2. Low power view of ovarian tumour after neoadjuvant therapy. The tumour is almost entirely necrotic, with only small foci of residual tumour (ovTm) < 5 mm within a histiocytic response.
Figure 3. Medium power image of the colorectal tumour showing atypical epithelial formations floating within extracellular mucin (*). The extracellular mucin composes > 50% of the tumour area diagnostic for mucinous carcinoma.
Figure 4. Low power view of colorectal tumour after neoadjuvant therapy. The tumour (coTm) does not show any necrosis, but viable tumour invades the muscularis propria. Of note, the same section shows another focus of ovarian tumour metastatic to the peritoneum (ovTm).
JULY JOGC JUILLET 2012 l 679
Case Report
Figures 5 and 6. Medium power image of immunohistochemistry of the colorectal tumour showing neoplastic glands of the ovarian tumour invading the colorectal tumour (arrows), indicating the aggressive growth of the high-grade serous carcinoma compared with the mucinous carcinoma. Figure 5. ER nuclear expression in high-grade serous carcinoma, but no expression in mucinous colorectal carcinomas (ovarian mucinous carcinomas are also ER negative).
Figure 6. Complete absence of TP53 expression in the high-grade serous carcinomas (staining pattern indicative of null mutation16), while the mucinous colorectal carcinoma shows expression of occasional nuclei (wild type pattern).
Reproducible diagnosis sets the foundation for typespecific management. High-grade serous carcinomas are usually chemosensitive initially; most will demonstrate a 75% to 80% response rate.8 This is in contrast to special types such as clear cell or mucinous carcinomas,9,10 which show much lower response rates to platinum-based chemotherapy. It has been suggested that mucinous ovarian tumours be treated differently, possibly in a similar fashion to colorectal carcinomas.11–13 We present here the case of a woman with synchronous primary tumours of the ovary and colon treated with platinumbased neoadjuvant chemotherapy.
primary serous carcinoma of Müllerian origin. The patient was using anticoagulation medication and had a recently installed pacemaker, so the decision was made to proceed with three cycles of neoadjuvant chemotherapy with standard carboplatin and paclitaxel, followed by interval debulking surgery.
CASE
A previously healthy 76-year-old woman presented with a three-month history of fatigue, abdominal pain, and bloating. A CT scan revealed large volume ascites and a scattering of soft tissue nodules in keeping with peritoneal implants and a left pelvic mass measuring 5 cm × 2 cm. The imaged mass was intimately associated with the sigmoid colon, but was thought to represent the left ovary. Serum CA 125 was elevated at 1112 kU/L (normal ≤ 35.0 kU/L), but serum CEA was normal at 1.5 μg/L (normal ≤ 5.0 μg/L). A paracentesis was performed, and the cytology of the fluid obtained was consistent with a 680 l JULY JOGC JUILLET 2012
A preoperative CT scan showed considerable improvement in disease burden, with near absence of ascites, a decrease in the size of the metastatic deposits, and a greater than 80% shrinkage of the pelvic mass, which now measured 2 cm × 1 cm. The patient underwent a laparotomy for total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and resection of 9 cm of sigmoid colon for an obstructing lesion. Final pathology showed a high-grade serous carcinoma of the right ovary (Figure 1), which after neoadjuvant therapy was almost entirely necrotic (Figure 2). Metastatic deposits were present in the omentum and right fallopian tube. There was a second synchronous malignancy: a mucinous adenocarcinoma of the sigmoid colon (Figure 3) measuring 2 cm × 2 cm and invading the muscularis propria (Figure 4). One of 20 mesenteric lymph nodes was positive for metastatic mucinous adenocarcinoma. Resection margins were negative.
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma
The patient went on to receive six further cycles of carboplatin and paclitaxel chemotherapy (the latter was discontinued after four cycles because of severe neuropathy). She refused further adjuvant treatment for her colon cancer. Three months after completing treatment, sequential imaging revealed a parenchymal liver mass, consistent with metastatic disease from her colon cancer, which was radioablated. Six months after completion of chemotherapy, routine CT scan revealed worsening peritoneal disease and a new liver lesion. The patient declined further treatment and died six months later from metastatic mucinous colorectal carcinoma. DISCUSSION
Based on the assumption that cancers at the same site share essential biological properties, cancer is treated according to the primary tumour site, and there is very little substratification according to histological type or molecular alterations. This case illustrates the dramatic differences in response to chemotherapy of two molecularly different carcinomas treated under the same conditions within one patient. The ovarian high-grade serous carcinomas showed a marked reduction in size (the marker lesion, left ovary, shrank by more than 80% on imaging) and contained only a few viable tumour cells surrounded by necrosis (each tumour cell focus measured less than 1 mm). Although there were several additional peritoneal carcinoma foci, each of those foci measured less than 5 mm. Maximal residual tumour size of less than 5 mm after neoadjuvant chemotherapy has been associated with favourable outcome in ovarian carcinomas.14 Overall, this represents an excellent response of the high-grade serous carcinomas, a response usually seen in patients carrying a BRCA2 mutation.15 In contrast, the mucinous carcinoma of the colorectum was unaffected by platinum-based chemotherapy, and although not proven by biopsy or autopsy, the clinical scenario suggests that the mucinous carcinoma of the colorectum progressed under platinum-based chemotherapy and finally caused death. The more aggressive tumour (Figures 5 and 6) was controlled by cytotoxic chemotherapy, but the lack of treatment options for the low-grade mucinous carcinoma likely accounted for the unfavourable patient outcome. Of course, the neoplasms arose from two distinct sites and represent two distinct cell lineages (fallopian tube vs. colon), which may or may not have the same underlying oncogenic alterations. In this case, each tumour showed evidence of a different TP53 status: the high-grade serous carcinoma showed complete absence of p53 immunohistochemical staining, consistent with an underlying null mutation, while the colorectal mucinous carcinoma showed p53 wild-type staining pattern.16
We recently reviewed the similarities of mucinous carcinomas arising from the ovary and colon and found that they share more similarities with each other than with their more common counterparts, ovarian highgrade serous and colorectal adenocarcinoma usual type, respectively.10 For example, mucinous carcinomas share the expression of similar cell lineage markers and show a high frequency of KRAS mutations and defects in the mismatch repair pathway. Given the similarities between colorectal and ovarian mucinous carcinomas, we believe that responses to platinum-based chemotherapy for ovarian mucinous carcinomas would be similar to the results described here, particularly since several studies have shown a poor response rate of ovarian mucinous carcinomas to platinum-based chemotherapy.10 If mucinous carcinomas, irrespective of ovarian or colorectal origin, do not respond to platinum-based chemotherapy, the question of alternative treatment options arises. We do not think that a simple crossover of therapies from other organ systems, i.e., treating ovarian mucinous carcinomas with the colorectal 5-fluorouracil (5-FU) regimen, is as promising as recently suggested.11–13 Colorectal mucinous carcinomas do not respond well to 5-FU,10 so why should mucinous carcinomas of ovarian origin? We may consider combining rare tumour types from several sites if they share similar molecular alterations to overcome a rigid site-specific approach to adjuvant treatment. Including similar histological and molecular subtypes in a new multiple (anatomic) site trial design may offer a way to improve management of rare cancer types. In the case of mucinous ovarian or colorectal carcinomas, alterations in the MAPK pathway may come into focus; these are targetable with trastuzumab or BRAF inhibitors such as vemurafenib.17,18 A more stratified approach will potentially yield better treatment alternatives for rare or “special” types. ACKNOWLEDGEMENTS
The next-of-kin of the woman whose story is told in this case report has provided written consent for its publication. REFERENCES 1. McGuire WP III, Markman M. Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer 2003;89(Suppl 3):S3–S8. 2. Markman M. Role of chemotherapy in epithelial ovarian cancer. Minerva Ginecol 2011;63:287–97. 3. Hoskins PJ. Which is the better surgical strategy for newly diagnosed epithelial ovarian cancer: primary or interval debulking? Curr Opin Oncol 2011;23:501–6.
JULY JOGC JUILLET 2012 l 681
Case Report
4. Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 2008;5(12):e232. 5. Köbel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, et al. Differences in tumor type in low-stage versus highstage ovarian carcinomas. Int J Gynecol Pathol 2010;29:203–11. 6. Köbel M, Kalloger SE, Baker PM, Ewanowich CA, Arseneau J, Zherebitskiy V, et al. Diagnosis of ovarian carcinoma cell type is highly reproducible: a transCanadian study. Am J Surg Pathol 2010;34:984–93. 7. Kalloger SE, Köbel M, Leung S, Mehl E, Gao D, Marcon KM, et al. Calculator for ovarian carcinoma subtype prediction. Mod Pathol 2011;24:512–21. 8. Liu J, Matulonis UA. New advances in ovarian cancer. Oncology (Williston Park) 2010;24:721–8. 9. Anglesio MS, Carey MS, Köbel M, Mackay H, Huntsman DG; Vancouver Ovarian Clear Cell Symposium Speakers. Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynecol Oncol 2011;121:407–15. 10. Kelemen LE, Köbel M. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma. Lancet Oncol 2011;12:1071–80. 11. Bamias A, Psaltopoulou T, Sotiropoulou M, Haidopoulos D, Lianos E, Bournakis E, et al. Mucinous but not clear cell histology is associated with inferior survival in patients with advanced stage ovarian carcinoma treated with platinum-paclitaxel chemotherapy. Cancer 2010;116:1462–8.
682 l JULY JOGC JUILLET 2012
12. Pectasides D, Fountzilas G, Aravantinos G, Kalofonos HP, Efstathiou E, Salamalekis E, et al. Advanced stage mucinous epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol 2005;97:436–41. 13. Hess V, A’Hern R, Nasiri N, King DM, Blake PR, Barton DP, et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004;22:1040–4. 14. Sassen S, Schmalfeldt B, Avril N, Kuhn W, Busch R, Hofler H, et al. Histopathologic assessment of tumor regression after neoadjuvant chemotherapy in advanced-stage ovarian cancer. Hum Pathol 2007;38:926–34. 15. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011;306:1557–65. 16. Köbel M, Reuss A, Bois A, Kommoss S, Kommoss F, Gao D, et al. The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol 2010;222:191–8. 17. McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Köbel M, et al. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer 2009;9:433. 18. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16.
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma Sarah Glaze, MD, FRCSC,1 Jill Nation, MD, FRCSC,1 Martin Köbel, MD2 1
Division of Gynecologic Oncology, University of Calgary, Calgary AB
2
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary AB
Abstract Background: Ovarian carcinomas are currently managed as a single entity with no stratification for histological type. The foundation of treatment is a combination of surgery and chemotherapy. Women who are not candidates for up-front debulking surgery, either because of performance status or widespread disease, are often offered neoadjuvant chemotherapy in an effort to shrink their tumour and make resection possible. Case: A 76-year-old woman was treated with neoadjuvant platinumbased chemotherapy for advanced ovarian cancer. At interval debulking surgery, she was found to have a concurrent mucinous colorectal carcinoma that was essentially unaffected by her treatment. Conclusion: This case serves as an in vivo demonstration of the greater resistance to platinum-based treatments of mucinous carcinomas than of the “typical” high-grade serous ovarian cancer.
Résumé Contexte : À l’heure actuelle, les carcinomes ovariens sont pris en charge comme étant une seule entité, sans stratification en fonction du type histologique. Le traitement est fondé sur une combinaison de chirurgie et de chimiothérapie. Les femmes qui ne sont pas candidates à une chirurgie de réduction tumorale au stade initial, que ce soit en raison de l’indice de performance ou de la présence d’une maladie répandue, se voient souvent offrir une chimiothérapie néoadjuvante visant à provoquer le rétrécissement de la tumeur et à en rendre la résection possible. Cas : Une femme de 76 ans a été traitée au moyen d’une chimiothérapie néoadjuvante à base de platine en raison de la présence d’un cancer de l’ovaire avancé. Au moment de Key Words: Ovarian cancer, mucinous carcinoma, neoadjuvant chemotherapy Competing Interests: None declared. Received on December 7, 2011 Accepted on January 12, 2012
678 l JULY JOGC JUILLET 2012
la chirurgie de réduction tumorale d’intervalle, nous avons constaté la présence concomitante d’un carcinome colorectal mucineux qui n’avait essentiellement pas été affecté par le traitement. Conclusion : Ce cas fait figure de démonstration in vivo du fait que les carcinomes mucineux présentent une plus grande résistance aux traitements à base de platine que les cas « typiques » de cancer séreux de l’ovaire de haut grade histologique. J Obstet Gynaecol Can 2012;34(7):678–682
INTRODUCTION
W
ith the introduction of platinum-based chemotherapy more than 20 years ago, the median survival time of women with ovarian carcinoma has doubled.1 Carboplatin has remained the mainstay of adjuvant treatment despite countless clinical trials that have sought to improve on this standard.1,2 Traditionally, up-front debulking surgery was followed by adjuvant chemotherapy. The timing of surgery has now been questioned, with two randomized clinical trials showing similar outcomes but superior perioperative morbidity and lower costs when interval debulking follows neoadjuvant chemotherapy.3
Ovarian carcinomas are currently managed as a single entity with no stratification for histological type.4 By far the most common type of ovarian carcinoma is high-grade serous carcinoma, which accounts for two thirds of cases. Less common types are clear cell (12%), endometrioid (10%), mucinous (3%), and low-grade serous (3%) carcinomas.5 Recent improvements in histological classification allow a highly reproducible diagnosis based on morphology alone or with the use of ancillary immunohistochemistry.6,7
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma
Figure 1. High power image of residual ovarian tumour showing papillary architecture with marked nuclear atypia diagnostic for high-grade serous carcinomas. There are conspicuous psammoma bodies (*).
Figure 2. Low power view of ovarian tumour after neoadjuvant therapy. The tumour is almost entirely necrotic, with only small foci of residual tumour (ovTm) < 5 mm within a histiocytic response.
Figure 3. Medium power image of the colorectal tumour showing atypical epithelial formations floating within extracellular mucin (*). The extracellular mucin composes > 50% of the tumour area diagnostic for mucinous carcinoma.
Figure 4. Low power view of colorectal tumour after neoadjuvant therapy. The tumour (coTm) does not show any necrosis, but viable tumour invades the muscularis propria. Of note, the same section shows another focus of ovarian tumour metastatic to the peritoneum (ovTm).
JULY JOGC JUILLET 2012 l 679
Case Report
Figures 5 and 6. Medium power image of immunohistochemistry of the colorectal tumour showing neoplastic glands of the ovarian tumour invading the colorectal tumour (arrows), indicating the aggressive growth of the high-grade serous carcinoma compared with the mucinous carcinoma. Figure 5. ER nuclear expression in high-grade serous carcinoma, but no expression in mucinous colorectal carcinomas (ovarian mucinous carcinomas are also ER negative).
Figure 6. Complete absence of TP53 expression in the high-grade serous carcinomas (staining pattern indicative of null mutation16), while the mucinous colorectal carcinoma shows expression of occasional nuclei (wild type pattern).
Reproducible diagnosis sets the foundation for typespecific management. High-grade serous carcinomas are usually chemosensitive initially; most will demonstrate a 75% to 80% response rate.8 This is in contrast to special types such as clear cell or mucinous carcinomas,9,10 which show much lower response rates to platinum-based chemotherapy. It has been suggested that mucinous ovarian tumours be treated differently, possibly in a similar fashion to colorectal carcinomas.11–13 We present here the case of a woman with synchronous primary tumours of the ovary and colon treated with platinumbased neoadjuvant chemotherapy.
primary serous carcinoma of Müllerian origin. The patient was using anticoagulation medication and had a recently installed pacemaker, so the decision was made to proceed with three cycles of neoadjuvant chemotherapy with standard carboplatin and paclitaxel, followed by interval debulking surgery.
CASE
A previously healthy 76-year-old woman presented with a three-month history of fatigue, abdominal pain, and bloating. A CT scan revealed large volume ascites and a scattering of soft tissue nodules in keeping with peritoneal implants and a left pelvic mass measuring 5 cm × 2 cm. The imaged mass was intimately associated with the sigmoid colon, but was thought to represent the left ovary. Serum CA 125 was elevated at 1112 kU/L (normal ≤ 35.0 kU/L), but serum CEA was normal at 1.5 μg/L (normal ≤ 5.0 μg/L). A paracentesis was performed, and the cytology of the fluid obtained was consistent with a 680 l JULY JOGC JUILLET 2012
A preoperative CT scan showed considerable improvement in disease burden, with near absence of ascites, a decrease in the size of the metastatic deposits, and a greater than 80% shrinkage of the pelvic mass, which now measured 2 cm × 1 cm. The patient underwent a laparotomy for total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and resection of 9 cm of sigmoid colon for an obstructing lesion. Final pathology showed a high-grade serous carcinoma of the right ovary (Figure 1), which after neoadjuvant therapy was almost entirely necrotic (Figure 2). Metastatic deposits were present in the omentum and right fallopian tube. There was a second synchronous malignancy: a mucinous adenocarcinoma of the sigmoid colon (Figure 3) measuring 2 cm × 2 cm and invading the muscularis propria (Figure 4). One of 20 mesenteric lymph nodes was positive for metastatic mucinous adenocarcinoma. Resection margins were negative.
Type-Specific Response to Neoadjuvant Chemotherapy: Ovarian High-Grade Serous Carcinoma Versus Colorectal Mucinous Carcinoma
The patient went on to receive six further cycles of carboplatin and paclitaxel chemotherapy (the latter was discontinued after four cycles because of severe neuropathy). She refused further adjuvant treatment for her colon cancer. Three months after completing treatment, sequential imaging revealed a parenchymal liver mass, consistent with metastatic disease from her colon cancer, which was radioablated. Six months after completion of chemotherapy, routine CT scan revealed worsening peritoneal disease and a new liver lesion. The patient declined further treatment and died six months later from metastatic mucinous colorectal carcinoma. DISCUSSION
Based on the assumption that cancers at the same site share essential biological properties, cancer is treated according to the primary tumour site, and there is very little substratification according to histological type or molecular alterations. This case illustrates the dramatic differences in response to chemotherapy of two molecularly different carcinomas treated under the same conditions within one patient. The ovarian high-grade serous carcinomas showed a marked reduction in size (the marker lesion, left ovary, shrank by more than 80% on imaging) and contained only a few viable tumour cells surrounded by necrosis (each tumour cell focus measured less than 1 mm). Although there were several additional peritoneal carcinoma foci, each of those foci measured less than 5 mm. Maximal residual tumour size of less than 5 mm after neoadjuvant chemotherapy has been associated with favourable outcome in ovarian carcinomas.14 Overall, this represents an excellent response of the high-grade serous carcinomas, a response usually seen in patients carrying a BRCA2 mutation.15 In contrast, the mucinous carcinoma of the colorectum was unaffected by platinum-based chemotherapy, and although not proven by biopsy or autopsy, the clinical scenario suggests that the mucinous carcinoma of the colorectum progressed under platinum-based chemotherapy and finally caused death. The more aggressive tumour (Figures 5 and 6) was controlled by cytotoxic chemotherapy, but the lack of treatment options for the low-grade mucinous carcinoma likely accounted for the unfavourable patient outcome. Of course, the neoplasms arose from two distinct sites and represent two distinct cell lineages (fallopian tube vs. colon), which may or may not have the same underlying oncogenic alterations. In this case, each tumour showed evidence of a different TP53 status: the high-grade serous carcinoma showed complete absence of p53 immunohistochemical staining, consistent with an underlying null mutation, while the colorectal mucinous carcinoma showed p53 wild-type staining pattern.16
We recently reviewed the similarities of mucinous carcinomas arising from the ovary and colon and found that they share more similarities with each other than with their more common counterparts, ovarian highgrade serous and colorectal adenocarcinoma usual type, respectively.10 For example, mucinous carcinomas share the expression of similar cell lineage markers and show a high frequency of KRAS mutations and defects in the mismatch repair pathway. Given the similarities between colorectal and ovarian mucinous carcinomas, we believe that responses to platinum-based chemotherapy for ovarian mucinous carcinomas would be similar to the results described here, particularly since several studies have shown a poor response rate of ovarian mucinous carcinomas to platinum-based chemotherapy.10 If mucinous carcinomas, irrespective of ovarian or colorectal origin, do not respond to platinum-based chemotherapy, the question of alternative treatment options arises. We do not think that a simple crossover of therapies from other organ systems, i.e., treating ovarian mucinous carcinomas with the colorectal 5-fluorouracil (5-FU) regimen, is as promising as recently suggested.11–13 Colorectal mucinous carcinomas do not respond well to 5-FU,10 so why should mucinous carcinomas of ovarian origin? We may consider combining rare tumour types from several sites if they share similar molecular alterations to overcome a rigid site-specific approach to adjuvant treatment. Including similar histological and molecular subtypes in a new multiple (anatomic) site trial design may offer a way to improve management of rare cancer types. In the case of mucinous ovarian or colorectal carcinomas, alterations in the MAPK pathway may come into focus; these are targetable with trastuzumab or BRAF inhibitors such as vemurafenib.17,18 A more stratified approach will potentially yield better treatment alternatives for rare or “special” types. ACKNOWLEDGEMENTS
The next-of-kin of the woman whose story is told in this case report has provided written consent for its publication. REFERENCES 1. McGuire WP III, Markman M. Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer 2003;89(Suppl 3):S3–S8. 2. Markman M. Role of chemotherapy in epithelial ovarian cancer. Minerva Ginecol 2011;63:287–97. 3. Hoskins PJ. Which is the better surgical strategy for newly diagnosed epithelial ovarian cancer: primary or interval debulking? Curr Opin Oncol 2011;23:501–6.
JULY JOGC JUILLET 2012 l 681
Case Report
4. Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 2008;5(12):e232. 5. Köbel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, et al. Differences in tumor type in low-stage versus highstage ovarian carcinomas. Int J Gynecol Pathol 2010;29:203–11. 6. Köbel M, Kalloger SE, Baker PM, Ewanowich CA, Arseneau J, Zherebitskiy V, et al. Diagnosis of ovarian carcinoma cell type is highly reproducible: a transCanadian study. Am J Surg Pathol 2010;34:984–93. 7. Kalloger SE, Köbel M, Leung S, Mehl E, Gao D, Marcon KM, et al. Calculator for ovarian carcinoma subtype prediction. Mod Pathol 2011;24:512–21. 8. Liu J, Matulonis UA. New advances in ovarian cancer. Oncology (Williston Park) 2010;24:721–8. 9. Anglesio MS, Carey MS, Köbel M, Mackay H, Huntsman DG; Vancouver Ovarian Clear Cell Symposium Speakers. Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynecol Oncol 2011;121:407–15. 10. Kelemen LE, Köbel M. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma. Lancet Oncol 2011;12:1071–80. 11. Bamias A, Psaltopoulou T, Sotiropoulou M, Haidopoulos D, Lianos E, Bournakis E, et al. Mucinous but not clear cell histology is associated with inferior survival in patients with advanced stage ovarian carcinoma treated with platinum-paclitaxel chemotherapy. Cancer 2010;116:1462–8.
682 l JULY JOGC JUILLET 2012
12. Pectasides D, Fountzilas G, Aravantinos G, Kalofonos HP, Efstathiou E, Salamalekis E, et al. Advanced stage mucinous epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol 2005;97:436–41. 13. Hess V, A’Hern R, Nasiri N, King DM, Blake PR, Barton DP, et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004;22:1040–4. 14. Sassen S, Schmalfeldt B, Avril N, Kuhn W, Busch R, Hofler H, et al. Histopathologic assessment of tumor regression after neoadjuvant chemotherapy in advanced-stage ovarian cancer. Hum Pathol 2007;38:926–34. 15. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011;306:1557–65. 16. Köbel M, Reuss A, Bois A, Kommoss S, Kommoss F, Gao D, et al. The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol 2010;222:191–8. 17. McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Köbel M, et al. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer 2009;9:433. 18. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16.