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Mutation analysis of papillary tubal hyperplasia associated with ovarian atypical proliferative serous tumor and low-grade serous carcinoma

      We present a patient with ovarian atypical proliferative serous tumor and low-grade serous carcinoma, related to KRAS mutation. Bilateral fallopian tubes had papillary tubal hyperplasia, providing additional evidence that it is the putative precursor of low-grade serous tumors. Mutation analysis of papillary tubal hyperplasia has not been done in previous literature.

      Key words

      Ovarian cancer is the most lethal gynecologic malignancy and serous neoplasm is the most common subtype. According to histology, serous neoplasm includes atypical proliferative serous tumor (APST), low-grade (LG) serous carcinoma (SC), and high-grade (HG)-SC. Recent studies strongly suggest fallopian tube epithelium to be the origin of both LG- and HG-SC rather than the ovarian surface epithelium as previously believed.
      • Kurman R.J.
      • Shih I.M.
      Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm.
      • Kurman R.J.
      • Shih I.M.
      The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
      • Li J.
      • Abushahin N.
      • Pang S.
      • et al.
      Tubal origin of “ovarian” low-grade serous carcinoma.
      HG-SC originate from precursor tubal lesions designated serous tubal intraepithelial carcinomas (STICs).
      • Kurman R.J.
      • Shih I.M.
      The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
      Kurman et al
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      recently identified a fallopian tube lesion as the likely precursor of LG serous tumor, and designated it as papillary tubal hyperplasia (PTH). According to Kurman et al,
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      PTH, the putative precursor of LG serous neoplasm, is frequently associated with APST and noninvasive implants.
      Here we report a female patient with ovarian APST, LG-SC, and multiple noninvasive and invasive implantations over different sites. Bilateral fallopian tubes revealed PTH.

      Case Report

      A 48-year-old woman experienced abdominal fullness and poor appetite for 1 month. Her history was unremarkable except for hypertension. Physical examination showed abdominal distension.
      Abdominal sonography revealed massive ascites with suspicious omental cake formation, while computed tomography showed heterogeneous masses at bilateral adnexal regions, with multiple peritoneal lesions. No gastrointestinal tumor was found despite extensive endoscopic studies. Laboratory data showed elevated cancer antigen 125 at the level of 2888 U/mL. Cancer antigen 19-9 and carcinoembryonic antigen levels were within reference levels.
      Intraoperative examination of a frozen section was performed. The right ovarian tumor measured 7 × 5 cm and adhered to the posterior cul-de-sac. It was friable and cystic with papillary and solid components. Histologic features of frozen section favored an APST with focal micropapillary structures of the right ovary, with noninvasive and invasive omental implantations. The patient received debulking surgery, including hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and biopsy of the peritoneum and urinary bladder.
      Microscopically, the right ovary revealed a background of micropapillary serous borderline tumor with micropapillary, medusa branching, filigree patterns, cribriform confluent areas, and psammoma bodies (Figure 1). Foci of LG-SC with stromal invasions were present. Multiple noninvasive and invasive implants involved the left ovary, omentum, peritoneum and the serosa of the urinary bladder. Both fallopian tubes had tubal epithelial proliferations with papillary tufting, detached clusters and abundant psammoma bodies, suggestive of PTH (Figure 2). To perform mutation analysis, we used manual microdissection to harvest cells from selective areas of lesions with lesser calcification, where tumor cells occupied >50% of the overall cell population. Molecular studies revealed same KRAS mutations in the ovarian APST and LG-SC, but no mutation was detected in the PTH (Figure 3). The patient has received subsequent chemotherapy and regular follow-up.
      Figure thumbnail gr1
      Figure 1Histopathology of ovary
      A, Ovary revealed atypical proliferative serous tumor (APST) and low-grade (LG) serous carcinoma (SC). B, Area of APST. C, Area of micropapillary serous borderline tumor. D, Area of LG-SC with confluent pattern. (Hematoxylin-eosin stain; original magnifications: A, ×40; B to D, ×200.)
      Huang. Papillary tubal hyperplasia associated with ovarian APST and LG-SC. Am J Obstet Gynecol 2013.
      Figure thumbnail gr2
      Figure 2Histopathology of fallopian tube
      Fallopian tubes displayed papillary tubal hyperplasia with A, papillary tufting and B, psammoma bodies. C, High-power view of detached clusters. (Hematoxylin-eosin stain; original magnifications: A and B, ×100; C, ×400.)
      Huang. Papillary tubal hyperplasia associated with ovarian APST and LG-SC. Am J Obstet Gynecol 2013.
      Figure thumbnail gr3
      Figure 3KRAS mutation analysis
      Ovarian atypical proliferative serous tumor and low-grade serous carcinoma showed KRAS mutation (c.34G>C, pG12R). Papillary tubal hyperplasia revealed no mutation.
      Huang. Papillary tubal hyperplasia associated with ovarian APST and LG-SC. Am J Obstet Gynecol 2013.

      Comment

      LG-SC are thought to develop in a stepwise fashion from serous cystadenoma to APST, and eventually to invasive carcinomas.
      • Kurman R.J.
      • Shih I.M.
      The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
      • Shih I.M.
      • Kurman R.J.
      Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis.
      • Korner M.
      • Burckhardt E.
      • Mazzucchelli L.
      Different proportions of aneusomic cells in ovarian inclusion cysts associated with serous borderline tumors and serous high-grade carcinomas support different pathogenetic pathways.
      • Ho C.L.
      • Kurman R.J.
      • Dehari R.
      • Wang T.L.
      • Shih I.M.
      Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors.
      The tumor types of APST and LG-SC share similar molecular alterations, a finding that is supported by mutational analysis and gene expression studies.
      • Bonome T.
      • Lee J.Y.
      • Park D.C.
      • et al.
      Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary.
      • Dehari R.
      • Kurman R.J.
      • Logani S.
      • Shih I.M.
      The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis.
      More than 60% of LG-SC and APST have mutations of KRASBRAF, or ERBB2.
      • Kurman R.J.
      • Shih I.M.
      Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm.
      • Shih I.M.
      • Kurman R.J.
      Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis.
      • Singer G.
      • Oldt R.
      • Cohen Y.
      • et al.
      Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.
      • Nakayama K.
      • Nakayama N.
      • Kurman R.J.
      • et al.
      Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms.
      The whole exome sequence study also revealed frequently somatic activating mutations in BRAF and KRAS in LG-SC and APST.
      • Jones S.
      • Wang T.L.
      • Kurman R.J.
      • et al.
      Low-grade serous carcinomas of the ovary contain very few point mutations.
      In contrast, HG-SC is characterized by high levels of genetic instability and a very high frequency of TP53 gene mutations in >95% of cases.
      • Kurman R.J.
      • Shih I.M.
      Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm.
      • Kurman R.J.
      • Shih I.M.
      The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
      • Ahmed A.A.
      • Etemadmoghadam D.
      • Temple J.
      • et al.
      Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary.
      The traditional view on the origin of serous tumors has been that they were derived from the ovarian surface epithelium. Recent morphologic and molecular genetic studies have revealed that most HG-SC originate from the fallopian tubes.
      • Kurman R.J.
      • Shih I.M.
      The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
      • Kindelberger D.W.
      • Lee Y.
      • Miron A.
      • et al.
      Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.
      • Shaw P.A.
      • Rouzbahman M.
      • Pizer E.S.
      • Pintilie M.
      • Begley H.
      Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers.
      The precursor tubal lesions, designated STICs, were identified in 50-60% of cases of ovarian and primary peritoneal HG-SC.
      • Kindelberger D.W.
      • Lee Y.
      • Miron A.
      • et al.
      Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.
      • Przybycin C.G.
      • Kurman R.J.
      • Ronnett B.M.
      • Shih I.M.
      • Vang R.
      Are all pelvic (nonuterine) serous carcinomas of tubal origin?.
      In some cases, STICs shared identical TP53 mutations with the concomitant HG-SC
      • Kindelberger D.W.
      • Lee Y.
      • Miron A.
      • et al.
      Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.
      and closely related gene expression profile.
      • Marquez R.T.
      • Baggerly K.A.
      • Patterson A.P.
      • et al.
      Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon.
      Recently, studies from different groups also suggest that the fallopian tube is the likely origin of LG-SC.
      • Li J.
      • Abushahin N.
      • Pang S.
      • et al.
      Tubal origin of “ovarian” low-grade serous carcinoma.
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      The ovarian epithelial inclusions are mostly derived from the fallopian tube and are the origins of LG serous tumor.
      • Li J.
      • Abushahin N.
      • Pang S.
      • et al.
      Tubal origin of “ovarian” low-grade serous carcinoma.
      PTH is defined as “tubal proliferations that exhibit papillary tufting and detached clusters of bland epithelium frequently, but not always, associated with psammona bodies.”
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      According to Kurman et al,
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      PTH, the putative precursor of LG serous neoplasm, is frequently associated with APST and noninvasive implants. The fallopian-derived lesions expressed the immunophenotypes that were similar or identical to ovarian LG serous tumors.
      • Li J.
      • Abushahin N.
      • Pang S.
      • et al.
      Tubal origin of “ovarian” low-grade serous carcinoma.
      • Kurman R.J.
      • Vang R.
      • Junge J.
      • Hannibal C.G.
      • Kjaer S.K.
      • Shih I.M.
      Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
      The morphologic similarity among PTH, noninvasive epithelial implants, and APST is striking.
      Mutation analysis of PTH has not been recorded in previous literature. Our results showed KRAS mutation in ovarian serous tumors, but not in tubal PTH, which may imply tumorous progression associated with harboring activating oncogene mutation. It is crucial to have more results on mutation analysis among PTH, APST, and LG-SC, which will help us to better understand the pathogenesis of ovarian serous tumors.

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