- Email: [email protected]
Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma
Human Pathology (2011) 42, 743–748
www.elsevier.com/locate/humpath
Case study
Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma Arnold-Jan Kruse MD, PhD a,b,⁎, Brigitte Slangen MD, PhD a,b , Gerard A. Dunselman MD, PhD a,b , Tina Pirens MSc c , Frans C. H. Bakers MD d , Jan P. A. Baak MD, PhD, FRCPath, FIAC(Hon), Dr HonCausa(Antwerp) e,f,g , Koen Van de Vijver MD, PhD a,c a
GROW, School for Oncology and Developmental Biology, University of Maastricht/Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands b Department of Obstetrics and Gynaecology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands c Department of Pathology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands d Department of Radiology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands e Departments of Pathology, Stavanger University Hospital, Stavanger, The Netherlands f Gade Institute, University of Bergen, Bergen, Norway g Free University, Amsterdam, The Netherlands Received 30 April 2010; revised 9 August 2010; accepted 20 August 2010
Keywords: Endocervicosis; Mucinous cystadenocarcinoma; KRAS; Extraovarian
Summary Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous cystadenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear [1]. To our knowledge, this is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. Point mutation of KRAS is
the most common molecular genetic alteration in ovarian mucinous borderline tumors and ovarian mucinous carcinomas [2]. Mutational analysis shows an increasing frequency of KRAS mutations at codons 12 and 13 in ovarian mucinous carcinomas and its precursors [3,4]. To obtain insight into the etiology of extraovarian mucinous cystadenocarcinomas, KRAS mutational analysis was performed.
2. Case report ⁎ Corresponding author. Department of Obstetrics and Gynecology, Academisch Ziekenhuis Maastricht, 6202AZ Maastricht, The Netherlands. E-mail address: [email protected] (A. -J. Kruse). 0046-8177/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.08.017
A 40-year-old woman, with no prior history of malignancy, was evaluated for bowel obstruction in May 2004. A
744 laparoscopy was performed by the surgical unit, which showed a cystic mass in the left abdomen that originated from the lateral left retroperitoneum and extended to the sigmoid. The mass was not related to the kidney or spleen. During subsequent laparotomy, the cyst was dissected from the lateral abdominal wall; and the line of Toldt (the lateral peritoneal reflection along the outer edge of the ascending and descending colon) was opened. Subsequently, a subtotal resection of the sigmoid was performed. The surgeon decided to remove the ovary as well because it was not possible to separate the cystic mass from the ovary because of strong adhesions. Fig. 1 illustrates the relationship between the cystic mass, the sigmoid, and the left ovary. The specimen consisted of a part of the sigmoid that measured 26 cm in length. A unilocular cyst with a diameter of 5 cm and with an adjacent part of the left ovary was located 10.5 cm from the distal end. Macroscopically, the ovarian part showed no abnormalities and had no relationship with the cyst. This was confirmed by histopathological examination. At microscopy, a moderately differentiated extraovarian mucinous csytadenocarcinoma was present that
A. -J. Kruse et al. invaded the serosa, muscularis propria, and submucosa of the bowel wall (Fig. 2). The mucosa of the sigmoid was intact and showed no dysplastic features (Fig. 2A). Foci of benign mucin-secreting endocervical-type glands, the so-called endocervicosis, were identified either within or adjacent to the neoplastic components (Fig. 3A). In addition to this endocervicotic lesion, endocervical-type glands with variable degrees of architectural and cytologic atypia were present, showing a transition from the foci of endocervicosis to the invasive component (Fig. 3B, C). The epithelial lining of the cyst ranged from typical benign mucinous epithelium to areas with moderate architectural and cytologic atypia, but frankly malignant features were lacking. The underlying tissue contained 15 lymph nodes, of which 9 were tumor positive. A diagnosis of a primary extraovarian mucinous cystadenocarcinoma arising in endocervicosis was made. Further analysis of the adenocarcinoma cells by KRAS mutational analysis revealed them to be positive for a G N A mutation at position 2 of codon 12, leading to an amino acid substitution of Gly (GGC) for Asp (GAT), whereas the cells of the benign glands did not contain a mutation. Fig. 4 shows
Fig. 1 Illustration of the relationship between the cyst (triangle), the extraovarian tumor (arrow), the sigmoid, and the left ovary. Panel B is a magnified view outlined by the black square in panel A and shows the above-mentioned structures and their relationships in detail. Figs. 2 and 3 show microscopy images of the areas indicated by the black square and circle in panel B.
Neoplastic transformation of endocervicosis
745
Fig. 2 Extraovarian mucinous cystadenocarcinoma involving the sigmoid. The black square in Fig. 1B shows the site of the specimen. The mucosa (D; triangles) of the sigmoid was intact and showed no dysplastic features (D). Panels B, C, and D are magnified views of the areas in panel A and show a moderately differentiated mucinous adenocarcinoma that invaded the serosa (A, B; arrows), muscularis propria, and submucosa of the bowel wall (A, hematoxylin and eosin [HE] 25×; B-D, HE 100×).
sequencing traces for KRAS-codon 12, with the cancer mutant sequence (a) and the normal wild-type sequence indicated (b). Isolation of DNA was performed using standard procedures. KRAS mutational analysis was performed by direct sequence examination of a 169–base pair seminested polymerase chain reaction product. 5′-CTG TAT CAA AGA ATG GTC CTG CAC-3′ and 5′-AGG CCT GCT GAA AAT GAC TGA ATA-3′ were used as the outside primers, and 5′(bio)-AAA ATG ACT GAA TAT AAA CTT GTG G-3′ was used as the inside primer (Sigma-Aldrich, St Louis, MO). The patient was subsequently referred to the gynecologic oncologic unit for further treatment. The result of clinical examination was normal. The chest x-ray result was normal; and preoperative serum CA125 and CEA levels were 75.1 U/mL and 1.3 µg/L, respectively. A reexploration was performed in June 2004. There was no ascites. The uterus, fallopian tubes, right ovary, and the remainder of the left ovary were normal. The subdiaphragmatic surface and small bowel showed implants. The liver, stomach, appendix, large bowel, omentum, and peritoneal
surfaces were normal. There was no evidence of another source of the tumor. A staging procedure was performed: peritoneal washings, a total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies, and pelvic and paraaortic lymph node sampling. Implants of the small bowel and subdiaphragmatic surface with a maximum diameter of 2 cm were removed, and a complete debulking was performed. Histopathological examination of the omentum and peritoneal washings were tumor positive. All other specimens showed no evidence of a tumor. Thus, our patient had an International Federation of Gynecology and Obstetrics stage 3B extraovarian mucinous cystadenocarcinoma. Six cycles of carboplatin and paclitaxel were given uneventfully. Our patient was in clinical complete remission until January 2005, when she presented with abdominal pain, vomiting, and nausea. A bulky mass was palpable in the lower left side of the abdomen. Computed tomographic imaging demonstrated a nodular thickening of the anterior abdominal wall, which was suspicious of a recurrent tumor. Furthermore, computed tomographic imaging demonstrated liver metastases.
746
A. -J. Kruse et al.
Fig. 4 KRAS mutational analysis was performed on the extraovarian mucinous cystadenocarcinoma in the area depicted in Fig. 2C. Sequencing traces for KRAS-codon 12, with cancer mutant sequence (A) and normal wild-type sequence (B). A G N A mutation was demonstrated at position 2 of codon 12, leading to an amino acid substitution of Gly (GGC) into Asp (GAT).
supportive care. Three weeks later, the patient died of tumor progression.
3. Discussion
Fig. 3 Extraovarian mucinous cystadenocarcinoma between the lateral peritoneum of the pelvic wall and the sigmoid. The black circle in Fig. 1B shows the site of the specimen. Foci of benign mucin-secreting endocervical-type glands, so-called endocervicosis, were identified either within or adjacent to the neoplastic components (A). In addition to this endocervicotic lesions, endocervical-type glands with variable degrees of architectural and cytologic atypia were present, showing a transition from the foci of endocervicosis to the invasive component (B,C) (A-C, HE 100×).
The patient was advised to start with second-line systemic therapy; but she declined further treatment, instead choosing to go home and receive optimal
Despite the histologic and clinical resemblance between extraovarian mucinous cystadenocarcinomas and primary ovarian carcinomas, their specific etiology is not clear [1]. Nevertheless, many investigators prescribe similar therapy to patients with extraovarian mucinous cystadenocarcinomas as they would to a patient with advanced epithelial ovarian cancer. To our knowledge, this is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. Lesions of the müllerian system are characterized by müllerian differentiation and include those containing endometrioid (endometriosis), serous (endosalpingiosis), and mucinous (endocervicosis) epithelium [1]. Endocervicosis is characterized by the presence of benign glands lined by mucin-secreting endocervical-type epithelium and has
Neoplastic transformation of endocervicosis been documented in the cul-de-sac, vaginal apex, outer wall of the uterine cervix, and urinary bladder [5-7]. Extraovarian tumors arising in endometriosis have been described; but no such association has been described for endocervicosis and extraovarian mucinous cystadenocarcinomas, as in the present case [8]. The exact incidence of cancer originating in endocervicosis is unknown. For endometriosis, a malignant tumor has been documented to arise in 0.3% to 0.8% of cases [8]. Data are lacking as to whether these figures can be extrapolated to endocervicosis; and although this case linked endocervicosis with malignancy, there are no data at present to advise clinicians on the best management regimen for patients at risk of developing such cancers. A similar adenoma–borderline tumor–carcinoma sequence has been described for both extraovarian and ovarian mucinous cystadenocarcinomas [9]. This may be explained by the common embryologic heritage of the epithelial layer of the ovary and the peritoneum, as all müllerian structures derive from evagination of coelomic epithelium early in embryonic life. It has been postulated that the peritoneal mesothelium (also known as the secondary müllerian system) retains the potential for müllerian differentiation, with subsequent development of the same histologic spectrum as ovarian neoplasms [5]. Others have suggested that the presence of endocervicosis may be explained by developmentally misplaced mucinous epithelium of the cervix [10,11]. Research carried out by Signorile et al [11] sustains this theory, as they found misplacing of primitive endometrial tissue along the migratory pathway of fetal organogenesis in 4 of 36 fetuses. Irrespective of the hypothesis adhered to, the neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma supports a müllerian origin in the present case. Little is known regarding the molecular genetic characteristics of extraovarian mucinous cystadenocarcinomas. KRAS mutational analysis was performed, as point mutation of KRAS is the most common molecular genetic alteration in ovarian mucinous borderline tumors and ovarian mucinous carcinomas [2]. Mutational analysis showed an increasing frequency of KRAS mutations at codons 12 and 13 in ovarian mucinous carcinomas and its precursors [3,4]. Furthermore, similar KRAS mutation patterns in benign, borderline, and malignant mucinous areas within the same neoplasm have been noted, suggesting that KRAS mutation is an early event in mucinous tumorigenesis [2]. These data suggest that ovarian mucinous carcinomas arise via an adenoma–borderline tumor–carcinoma sequence with activation of the RAS-RAF signaling pathway by KRAS mutations [12]. Our case study showed that mutation of KRAS is also involved in the tumorigenesis of extraovarian mucinous cystadenocarcinomas and supports the hypothesis that these tumors have a similar peritoneal origin with the same activation of the RAS-RAF signaling pathway as in their ovarian counterparts. Endocervicosis is considered primarily as a benign lesion, and in only one case has a malignant tumor arising
747 in endocervicosis been previously documented. McCluggage et al [13] described a case of a primary adenocarcinoma of the vagina that arose within endocervicosis. One may question the histopathological diagnosis of endocervicosis in our case. Firstly, it is arguable that the endocervicotic lesion represents well-differentiated glands of the tumor near a less differentiated area of the tumor and therefore fails to establish transformation from benign to a malignant lesion. However, KRAS negativity would not be expected in a well-differentiated area of the tumor, as KRAS mutation is considered as an early event in tumorigenesis of these tumors. In our case, the endocervicotic area was KRAS negative, thus supporting the benign nature of this area. Secondly, it may be very difficult to distinguish between endocervicosis and endometriosis. Oliva et al [14] reported 2 clear cell carcinomas of the urinary bladder that were associated with benign müllerian-type epithelium that lacked endometrial stroma, but were associated focally with elastotic stroma, a subtle clue to the diagnosis of endometriosis. In the present case, there was no elastotic stroma. In addition, no other signs of endometriosis were present elsewhere in the peritoneum, thus favoring the diagnosis of endocervicosis. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous csytadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous adenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas.
Acknowledgments We thank Ms. M. Kunen, medical illustrator, for providing us with Fig. 1.
References [1] Clement PB. Diseases of the peritoneum. In: Kurman RJ, editor. Blaustein's pathology of the female genital tract. 5th ed. New York: Springer-Verlag; 2002. p. 745-73. [2] Kurman RJ, Visvanathan K, Roden R, Wu TC, Shih Iem. Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 2008;198:351-6. [3] Gemignani ML, Schlaerth AC, Bogomolniy F. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 2003;90:378-81. [4] Mok SC, Bell DA, Knapp RC. Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res 1993;53:1489-92. [5] Lauchlan SC. The secondary müllerian system. Obstet Gynecol Surv 1972;27:133-46. [6] Clement PB, Young RH. Endocervicosis of the urinary bladder: a report of six cases of a benign müllerian lesion that may mimic adenocarcinoma. Am J Surg Pathol 1992;16:533-42.
748 [7] Martinka M, Allaire C, Clement PB. Endocervicosis presenting as a painful vaginal mass: a case report. Int J Gynecol Pathol 1996;18: 274-6. [8] Mostoufizadeh M, Scully RE. Malignant tumors arising in endometriosis. Clin Obstet Gynecol 1980;23:951-63. [9] Fujii S, Konishi I, Okamura H, Mori T. Mucinous cystadenocarcinoma of the retroperitoneum: a light and electron microscopic study. Gynecol Oncol 1986;24:103-12. [10] Batt RE, Smith RA, Buck Louis GM, et al. Müllerianosis. Histol Histopathol 2007;10:1161-6. [11] Signorile PG, Baldi F, Bussani R, et al. Ectopic endometrium in human fetuses is a common event and sustain the theory of müllerianosis in
A. -J. Kruse et al. the pathogenesis of endometriosis, a disease that predisposes to cancer. J Exp Clin Cancer Res 2009;28:49. [12] Bell DA. Origins and molecular pathology of ovarian cancer. Mod Pathol 2005;18(suppl 2):S19-32. [13] McCluggage WG, Price JH, Dobbs SP. Primary adenocarcinoma of the vagina arising in endocervicosis. Int J Gynecol Pathol 2001;20: 399-402. [14] Oliva E, Amin M, Jimenez R, Young RH. Clear cell carcinoma of the urinary bladder. A report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol 2002;26: 190-7.
www.elsevier.com/locate/humpath
Case study
Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma Arnold-Jan Kruse MD, PhD a,b,⁎, Brigitte Slangen MD, PhD a,b , Gerard A. Dunselman MD, PhD a,b , Tina Pirens MSc c , Frans C. H. Bakers MD d , Jan P. A. Baak MD, PhD, FRCPath, FIAC(Hon), Dr HonCausa(Antwerp) e,f,g , Koen Van de Vijver MD, PhD a,c a
GROW, School for Oncology and Developmental Biology, University of Maastricht/Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands b Department of Obstetrics and Gynaecology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands c Department of Pathology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands d Department of Radiology, Maastricht University Medical Center, 6202AZ Maastricht, The Netherlands e Departments of Pathology, Stavanger University Hospital, Stavanger, The Netherlands f Gade Institute, University of Bergen, Bergen, Norway g Free University, Amsterdam, The Netherlands Received 30 April 2010; revised 9 August 2010; accepted 20 August 2010
Keywords: Endocervicosis; Mucinous cystadenocarcinoma; KRAS; Extraovarian
Summary Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous cystadenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear [1]. To our knowledge, this is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. Point mutation of KRAS is
the most common molecular genetic alteration in ovarian mucinous borderline tumors and ovarian mucinous carcinomas [2]. Mutational analysis shows an increasing frequency of KRAS mutations at codons 12 and 13 in ovarian mucinous carcinomas and its precursors [3,4]. To obtain insight into the etiology of extraovarian mucinous cystadenocarcinomas, KRAS mutational analysis was performed.
2. Case report ⁎ Corresponding author. Department of Obstetrics and Gynecology, Academisch Ziekenhuis Maastricht, 6202AZ Maastricht, The Netherlands. E-mail address: [email protected] (A. -J. Kruse). 0046-8177/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.08.017
A 40-year-old woman, with no prior history of malignancy, was evaluated for bowel obstruction in May 2004. A
744 laparoscopy was performed by the surgical unit, which showed a cystic mass in the left abdomen that originated from the lateral left retroperitoneum and extended to the sigmoid. The mass was not related to the kidney or spleen. During subsequent laparotomy, the cyst was dissected from the lateral abdominal wall; and the line of Toldt (the lateral peritoneal reflection along the outer edge of the ascending and descending colon) was opened. Subsequently, a subtotal resection of the sigmoid was performed. The surgeon decided to remove the ovary as well because it was not possible to separate the cystic mass from the ovary because of strong adhesions. Fig. 1 illustrates the relationship between the cystic mass, the sigmoid, and the left ovary. The specimen consisted of a part of the sigmoid that measured 26 cm in length. A unilocular cyst with a diameter of 5 cm and with an adjacent part of the left ovary was located 10.5 cm from the distal end. Macroscopically, the ovarian part showed no abnormalities and had no relationship with the cyst. This was confirmed by histopathological examination. At microscopy, a moderately differentiated extraovarian mucinous csytadenocarcinoma was present that
A. -J. Kruse et al. invaded the serosa, muscularis propria, and submucosa of the bowel wall (Fig. 2). The mucosa of the sigmoid was intact and showed no dysplastic features (Fig. 2A). Foci of benign mucin-secreting endocervical-type glands, the so-called endocervicosis, were identified either within or adjacent to the neoplastic components (Fig. 3A). In addition to this endocervicotic lesion, endocervical-type glands with variable degrees of architectural and cytologic atypia were present, showing a transition from the foci of endocervicosis to the invasive component (Fig. 3B, C). The epithelial lining of the cyst ranged from typical benign mucinous epithelium to areas with moderate architectural and cytologic atypia, but frankly malignant features were lacking. The underlying tissue contained 15 lymph nodes, of which 9 were tumor positive. A diagnosis of a primary extraovarian mucinous cystadenocarcinoma arising in endocervicosis was made. Further analysis of the adenocarcinoma cells by KRAS mutational analysis revealed them to be positive for a G N A mutation at position 2 of codon 12, leading to an amino acid substitution of Gly (GGC) for Asp (GAT), whereas the cells of the benign glands did not contain a mutation. Fig. 4 shows
Fig. 1 Illustration of the relationship between the cyst (triangle), the extraovarian tumor (arrow), the sigmoid, and the left ovary. Panel B is a magnified view outlined by the black square in panel A and shows the above-mentioned structures and their relationships in detail. Figs. 2 and 3 show microscopy images of the areas indicated by the black square and circle in panel B.
Neoplastic transformation of endocervicosis
745
Fig. 2 Extraovarian mucinous cystadenocarcinoma involving the sigmoid. The black square in Fig. 1B shows the site of the specimen. The mucosa (D; triangles) of the sigmoid was intact and showed no dysplastic features (D). Panels B, C, and D are magnified views of the areas in panel A and show a moderately differentiated mucinous adenocarcinoma that invaded the serosa (A, B; arrows), muscularis propria, and submucosa of the bowel wall (A, hematoxylin and eosin [HE] 25×; B-D, HE 100×).
sequencing traces for KRAS-codon 12, with the cancer mutant sequence (a) and the normal wild-type sequence indicated (b). Isolation of DNA was performed using standard procedures. KRAS mutational analysis was performed by direct sequence examination of a 169–base pair seminested polymerase chain reaction product. 5′-CTG TAT CAA AGA ATG GTC CTG CAC-3′ and 5′-AGG CCT GCT GAA AAT GAC TGA ATA-3′ were used as the outside primers, and 5′(bio)-AAA ATG ACT GAA TAT AAA CTT GTG G-3′ was used as the inside primer (Sigma-Aldrich, St Louis, MO). The patient was subsequently referred to the gynecologic oncologic unit for further treatment. The result of clinical examination was normal. The chest x-ray result was normal; and preoperative serum CA125 and CEA levels were 75.1 U/mL and 1.3 µg/L, respectively. A reexploration was performed in June 2004. There was no ascites. The uterus, fallopian tubes, right ovary, and the remainder of the left ovary were normal. The subdiaphragmatic surface and small bowel showed implants. The liver, stomach, appendix, large bowel, omentum, and peritoneal
surfaces were normal. There was no evidence of another source of the tumor. A staging procedure was performed: peritoneal washings, a total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies, and pelvic and paraaortic lymph node sampling. Implants of the small bowel and subdiaphragmatic surface with a maximum diameter of 2 cm were removed, and a complete debulking was performed. Histopathological examination of the omentum and peritoneal washings were tumor positive. All other specimens showed no evidence of a tumor. Thus, our patient had an International Federation of Gynecology and Obstetrics stage 3B extraovarian mucinous cystadenocarcinoma. Six cycles of carboplatin and paclitaxel were given uneventfully. Our patient was in clinical complete remission until January 2005, when she presented with abdominal pain, vomiting, and nausea. A bulky mass was palpable in the lower left side of the abdomen. Computed tomographic imaging demonstrated a nodular thickening of the anterior abdominal wall, which was suspicious of a recurrent tumor. Furthermore, computed tomographic imaging demonstrated liver metastases.
746
A. -J. Kruse et al.
Fig. 4 KRAS mutational analysis was performed on the extraovarian mucinous cystadenocarcinoma in the area depicted in Fig. 2C. Sequencing traces for KRAS-codon 12, with cancer mutant sequence (A) and normal wild-type sequence (B). A G N A mutation was demonstrated at position 2 of codon 12, leading to an amino acid substitution of Gly (GGC) into Asp (GAT).
supportive care. Three weeks later, the patient died of tumor progression.
3. Discussion
Fig. 3 Extraovarian mucinous cystadenocarcinoma between the lateral peritoneum of the pelvic wall and the sigmoid. The black circle in Fig. 1B shows the site of the specimen. Foci of benign mucin-secreting endocervical-type glands, so-called endocervicosis, were identified either within or adjacent to the neoplastic components (A). In addition to this endocervicotic lesions, endocervical-type glands with variable degrees of architectural and cytologic atypia were present, showing a transition from the foci of endocervicosis to the invasive component (B,C) (A-C, HE 100×).
The patient was advised to start with second-line systemic therapy; but she declined further treatment, instead choosing to go home and receive optimal
Despite the histologic and clinical resemblance between extraovarian mucinous cystadenocarcinomas and primary ovarian carcinomas, their specific etiology is not clear [1]. Nevertheless, many investigators prescribe similar therapy to patients with extraovarian mucinous cystadenocarcinomas as they would to a patient with advanced epithelial ovarian cancer. To our knowledge, this is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. Lesions of the müllerian system are characterized by müllerian differentiation and include those containing endometrioid (endometriosis), serous (endosalpingiosis), and mucinous (endocervicosis) epithelium [1]. Endocervicosis is characterized by the presence of benign glands lined by mucin-secreting endocervical-type epithelium and has
Neoplastic transformation of endocervicosis been documented in the cul-de-sac, vaginal apex, outer wall of the uterine cervix, and urinary bladder [5-7]. Extraovarian tumors arising in endometriosis have been described; but no such association has been described for endocervicosis and extraovarian mucinous cystadenocarcinomas, as in the present case [8]. The exact incidence of cancer originating in endocervicosis is unknown. For endometriosis, a malignant tumor has been documented to arise in 0.3% to 0.8% of cases [8]. Data are lacking as to whether these figures can be extrapolated to endocervicosis; and although this case linked endocervicosis with malignancy, there are no data at present to advise clinicians on the best management regimen for patients at risk of developing such cancers. A similar adenoma–borderline tumor–carcinoma sequence has been described for both extraovarian and ovarian mucinous cystadenocarcinomas [9]. This may be explained by the common embryologic heritage of the epithelial layer of the ovary and the peritoneum, as all müllerian structures derive from evagination of coelomic epithelium early in embryonic life. It has been postulated that the peritoneal mesothelium (also known as the secondary müllerian system) retains the potential for müllerian differentiation, with subsequent development of the same histologic spectrum as ovarian neoplasms [5]. Others have suggested that the presence of endocervicosis may be explained by developmentally misplaced mucinous epithelium of the cervix [10,11]. Research carried out by Signorile et al [11] sustains this theory, as they found misplacing of primitive endometrial tissue along the migratory pathway of fetal organogenesis in 4 of 36 fetuses. Irrespective of the hypothesis adhered to, the neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma supports a müllerian origin in the present case. Little is known regarding the molecular genetic characteristics of extraovarian mucinous cystadenocarcinomas. KRAS mutational analysis was performed, as point mutation of KRAS is the most common molecular genetic alteration in ovarian mucinous borderline tumors and ovarian mucinous carcinomas [2]. Mutational analysis showed an increasing frequency of KRAS mutations at codons 12 and 13 in ovarian mucinous carcinomas and its precursors [3,4]. Furthermore, similar KRAS mutation patterns in benign, borderline, and malignant mucinous areas within the same neoplasm have been noted, suggesting that KRAS mutation is an early event in mucinous tumorigenesis [2]. These data suggest that ovarian mucinous carcinomas arise via an adenoma–borderline tumor–carcinoma sequence with activation of the RAS-RAF signaling pathway by KRAS mutations [12]. Our case study showed that mutation of KRAS is also involved in the tumorigenesis of extraovarian mucinous cystadenocarcinomas and supports the hypothesis that these tumors have a similar peritoneal origin with the same activation of the RAS-RAF signaling pathway as in their ovarian counterparts. Endocervicosis is considered primarily as a benign lesion, and in only one case has a malignant tumor arising
747 in endocervicosis been previously documented. McCluggage et al [13] described a case of a primary adenocarcinoma of the vagina that arose within endocervicosis. One may question the histopathological diagnosis of endocervicosis in our case. Firstly, it is arguable that the endocervicotic lesion represents well-differentiated glands of the tumor near a less differentiated area of the tumor and therefore fails to establish transformation from benign to a malignant lesion. However, KRAS negativity would not be expected in a well-differentiated area of the tumor, as KRAS mutation is considered as an early event in tumorigenesis of these tumors. In our case, the endocervicotic area was KRAS negative, thus supporting the benign nature of this area. Secondly, it may be very difficult to distinguish between endocervicosis and endometriosis. Oliva et al [14] reported 2 clear cell carcinomas of the urinary bladder that were associated with benign müllerian-type epithelium that lacked endometrial stroma, but were associated focally with elastotic stroma, a subtle clue to the diagnosis of endometriosis. In the present case, there was no elastotic stroma. In addition, no other signs of endometriosis were present elsewhere in the peritoneum, thus favoring the diagnosis of endocervicosis. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous csytadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous adenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas.
Acknowledgments We thank Ms. M. Kunen, medical illustrator, for providing us with Fig. 1.
References [1] Clement PB. Diseases of the peritoneum. In: Kurman RJ, editor. Blaustein's pathology of the female genital tract. 5th ed. New York: Springer-Verlag; 2002. p. 745-73. [2] Kurman RJ, Visvanathan K, Roden R, Wu TC, Shih Iem. Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 2008;198:351-6. [3] Gemignani ML, Schlaerth AC, Bogomolniy F. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 2003;90:378-81. [4] Mok SC, Bell DA, Knapp RC. Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res 1993;53:1489-92. [5] Lauchlan SC. The secondary müllerian system. Obstet Gynecol Surv 1972;27:133-46. [6] Clement PB, Young RH. Endocervicosis of the urinary bladder: a report of six cases of a benign müllerian lesion that may mimic adenocarcinoma. Am J Surg Pathol 1992;16:533-42.
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