Abstract
Introduction: Literature data present new studies about precancerous lesions of pelvic serous carcinoma that originate from the tubal secretory cells. It has long been thought that ovarian cancer cannot be prevented by prophylactic screening or surgery. In recent years, gynecologists have adapted to new principles and so, during routine hysterectomies in perimenopausal women for benign uterine pathologies, salpingo-oophorectomy is performed as a prophylactic approach. Aim: The purpose of our article was to draw attention to the association between abnormal fallopian tube pathology and the presence of serous ovarian neoplasia in perimenopausal women at risk. Case presentation: We report the case of a 45-year-old woman who had unspecific symptoms of abdominal pain and loss of appetite and weight. A pelvic magnetic resonance imaging was performed, and an ovarian mass was detected. Our case shows that the fallopian tube can be the primary point of origin for a pelvic disease, therefore prevention is possible with early computed tomography scan and annual ultrasound. The patient presented with a T1c staging post-surgery and her chances of survival could have decreased if she had postponed medical examination longer. We found a significant increase in the absolute number of tubal secretory cells in patients with ovarian neoplasia, which supports the assumption that serous tubal intraepithelial carcinoma lesions are found especially in the serous ovarian type. Conclusions: Our article is a strong suggestion that serous ovarian cancer originates from the fallopian tube and can potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube.
Keywords: high-grade serous ovarian cancer , STIC lesion , fallopian tube
Introduction
Women diagnosed with invasive high-grade serous ovarian cancer (HGSOC) have a limited time to undergo surgery and treatment, as their survival rate and prognosis are usually unfavorable. Early detection is the key to improving life quality, as well as their prognosis [1]. Several studies showed modifications in the fallopian tube, referred to as serous tubal intraepithelial lesion or STIL, and early markers for serous tubal intraepithelial carcinoma, referred to as STIC [2]. The presence of multiple lesions in the fallopian tube, associated with enlarged ovaries, with modifications on the ultrasound (US), may be an important predictor for the disease progression. The criteria for determining the fallopian tube origin are a tumor that originates from the fallopian tube mucosa, the histology of the tumor has tubal mucosa criteria, there is a transition from benign to malignant epithelium, and the size of the fallopian tube tumor is larger than the ovarian tumor. Nowadays, the definition of STIC tumors consists in the simultaneous presence of a fallopian and ovarian mass, detected either by US or during laparotomy [3]. Silverberg grading assigns three criteria to be discussed during an ovarian mass diagnosis, regarding its architecture: glandular, papillary or solid components, the presence of nuclear atypia, and mitosis. Unfortunately, rapid and early diagnosis remains a vital prognosis factor. Only 13% of women are diagnosed in early I or II stage, making their 5-year survival rate of 55%, while advanced stages have a survival rate of less than 15%. No effective prevention was found when considering transvaginal US or serum cancer antigen 125 (CA125) levels, or even breast cancer (BRCA) mutation testing. After the age of 40–45, bilateral salpingo-oophorectomy is considered to be the prophylactic and election surgery. As for the prevalence and mortality rates, ovarian cancer is considered one of the most aggressive cancers, with more than 2 000 000 cases diagnosed annually. The survival rates have improved in recent years for women who present for their annual check-up. According to recent studies, the 5-year survival rate is considered to be 47% [4].
Aim
Our paper aimed to draw attention to the association between abnormal fallopian tube pathology and the presence of serous ovarian neoplasia in perimenopausal women at risk.
Case presentation
A 45-year-old patient, known to have an abnormal Pap test result with high-grade squamous cell cervical dysplasia and right ovarian tumor diagnosed earlier the year before and having undergone, according to her declarations, left adnexectomy with benign results in 2013, was hospitalized in April 2023 for pain in the right iliac fossa, of moderate intensity. She declared weight loss, more than 10 kg in the last two months, and loss of appetite.
The pelvic magnetic resonance imaging (MRI) examination showed numerous masses with fluid content and peripheral contrast uptake, conglomerates at the mid-pelvic level, with difficulty in identifying the appendages, measuring between 17–84 mm, some showing liquid–liquid levels and discrete T1 hypersignal. The described lesions alternated with areas of tissue signal, present in the anterior section of the lesional conglomerate, with heterogeneous contrast uptake. The most voluminous liquid lesion described, located behind the uterus, presented a vegetative tissue inclusion, with diffuse restriction and contrast uptake, located on the left side wall. A right internal iliac adenopathy of 9 mm was noted. The conclusions were as follows: central tumor, including MRI result with mixed signal, liquid and tissue, corresponding to a possible lesion of mucinous origin. The endovaginal and abdominal US examination identified a uterus of normal size 40/50/45 mm, the right appendix with an irregular, inhomogeneous 10-cm mass, with mixed echostructure, and a 6-cm mass on the left side on the topography of the left ovary and fallopian tube.
The patient underwent extensive surgery that included median pubo-subxiphoid laparotomy. When the peritoneal cavity was opened, an average amount of 100 mL of intraperitoneal fluid was found and the fluid was sampled for peritoneal cytology. A 12-cm mass with mixed structure was also found in the right appendix, and a 6-cm cystic mass was detected in the left side. Right adnexectomy and left cyst excision were performed, with extemporaneous anatomopathological result of malignant right ovarian tumor. The patient underwent the surgery after signing an informed consent and our research was reviewed and approved by the Institutional Ethics Committee from Cuza Vodă Maternity Hospital of Iaşi, Romania.
An apparently normal size uterus was examined and total hysterectomy with bilateral adnexectomy, omentectomy and bilateral lymphadenectomy was performed. Post-operatively, the patient underwent anticoagulant treatment with Enoxaparin sodium 40 mg every 12 hours, Cefotaxime 1 g/12 hours, daily dressing, drain tube suppression on the fourth day after surgery and the patient was discharged in good general condition on the seventh postoperative day, with the resumption of physiological intestinal transit, physiological micturition, early mobilization and healing appearance of the postoperative wound.
We followed up with the patient’s results and performed three months postoperative examination. The anatomopathological result description consisted of the total hysterectomy piece with bilateral adnexectomy, omentectomy and lymphadenectomy.
The macroscopic analysis of the surgical parts showed a 4.5/3.5/3.6 cm cervix with a 3/1 cm vaginal fragment, smooth exocervix, with hemorrhagic suffusions, permeable endocervix for the stylet, diffusely thickened along the entire length, up to the maximum of 0.5 cm thickness.
The uterine body was sized 6/6.5/4.5 cm the uterine cavity was 3.5 cm long and the endometrium was 0.4 cm thick. The myometrium’s appearance was of adenomyosis and included a 0.4-cm nodular mass of compact appearance of whitish and elastic consistency. The right adnexa consisted of a fallopian tube of 4.5/0.8 cm. The right ovary was transformed into a cyst of 16/10.5/8.5 cm with uneven outer layer, multicystic, intact capsule, without external vegetation. The cross section revealed a multicystic appearance, with serous and serohemorrhagic content, with multiple yellow solid areas that had a maximum diameter of 2 cm and one of the cysts had a friable internal vegetation of 0.5 cm.
The left adnexa consisted of a fallopian tube of 6/0.7 cm attached to the ovary, with paratubal microcysts. A cyst-transformed ovary of 8/4/0.4 cm, fractured postoperatively together with the piece, with serosanguineous content, was found, without external vegetation, while the inner surface was lined with small, soft, whitish vegetations of 1–3 mm, representing >10% of the internal surface. Small white-yellow nodular areas of 5–6 mm were identified inside the ovary.
The 25/10/1 cm omentum piece was apparently without macroscopically visible pathological changes. The right iliac nodes with areas of adipose tissue, totaling a diameter of 5/2/0.6 cm, and the left iliac nodes, together with adjacent adipose tissue totaling 3/2/0.5 cm, with multiple lymph nodules per section, were noted.
The microscopic examination revealed bilateral ovarian tumors, with the histopathological appearance of high-grade invasive serous carcinoma, with solid and papillary tumor proliferation (Figures 1, 2, 3, 4, 5) marked nuclear pleomorphism, frequent atypical mitoses, invasive tumor necrosis not exceeding the capsule (Figures 3, 4).
Figure 1.
Tumor proliferation with solid and papillary architecture (HE staining, ×40). Arrow: remaining ovarian cortex. HE: Hematoxylin–Eosin
Figure 2.
– On the left side, inferior, tumoral proliferation with solid architecture with marked cellular pleomorphism (HE staining, ×200). Arrow: tumoral necrosis
Figure 3.
The arrow points tumor proliferation with solid architecture (HE staining, ×40)
Figure 4.
Tumor proliferation with solid architecture, papillary areas of necrosis (HE staining, ×100). It is pointed with the arrow
Figure 5.
The arrow points tumor proliferation with solid architecture and ovarian cortex remaining in the upper part (HE staining, ×40)
The left fallopian tube focusing the tumor invasion of the mucosa was present in the analyzed sections, supporting the theory of STIC lesions and ovarian cancer (Figure 2).
A suspicion-raising image of angioinvasion at the level of the left ovarian tumor was noted.
Non-specific chronic cervicitis with a focus of moderate dysplasia, with endocervical localization, was present in the cervix. A proliferative endometrium, rare aspects of adenomyosis and intramural nodular leiomyoma were the benign aspects in the corpus of the uterus. The omentum showed no histopathological changes. The nodes examined had no metastases, showed reactive changes and the peritoneal cytology was negative. The diagnosis set by the anatomopathologists was pT1C1N0Mx G3 high-grade bilateral ovarian serous carcinoma and high-grade squamous intraepithelial lesion (HSIL) cervical intraepithelial neoplasia (CIN) 2. We recommended our patient to go to the Regional Oncological Hospital of Iaşi for further follow-up of the disease.
The differential diagnosis of an ovarian unilateral mass, with minimum ascites, includes benign pathologies such as fibroma, dermoid cyst, cystadenofibroma, Meigs syndrome, appendicitis or pyelonephritis. Rare cases include metastatic diseases from other sites, such as the gastrointestinal tract or the breast.
Discussions
Ovarian cancer is one of the most severe types of pelvic cancer, with a high mortality rate [2]. A revealing theory in understanding the initiation of HGSOC was highlighted after the meticulous analysis of the ovaries and fallopian tubes, carried out for prophylactic purposes, in women at high risk of developing ovarian cancer, due to the presence of BRCA-type mutations, or in patients over 45 years of age having undergone hysterectomy with bilateral prophylactic opportunistic adnexectomy [4, 5]. Early cancerous lesions were detected in 10% of these women [1, 2, 3]. A large proportion of the lesions were initially present in the fallopian tube epithelium, rather than in the ovary, indicating that the fallopian tube epithelial cells were, most likely, precursors of this pathology, and later identified at the ovarian level [6]. The fallopian tube epithelium is composed of two types of constitutional cells, mainly secretory and ciliated. In premenopausal women, the secretory and ciliated cells are found in an alternate pattern. Early morphological changes were primarily observed in the secretory cells; thus, assuming that they have a type of precursor cells for HGSOC [7, 8], the most morphologically similar lesion to early-stage HGSOC is STIC. Nuclear changes, such as enlargement, atypia and reorganization with nucleolar enlargement, disorganization of polarity, pleomorphic cellularity, increased mitoses, and the failure to identify the ciliated cells are among the identified STIC lesion changes. STIC-type cellular changes show the presence of p53 and Ki67 in a proportion >10% [9, 10, 11].
Research initially focused solely on STIC lesion findings, as they were considered precursors to HGSOC, given their similar morphological and molecular characteristics [12, 13, 14]. However, the risk of ovarian cancer has been associated with early serous precursors (ESPs), markers that have a benign appearance, of diminished proliferation and do not meet the criteria of a STIC diagnosis. These ESPs include: STILs, that are characterized by less active Ki67 and much more discrete cellular atypia than STICs, defined as a single layer of more than 12 consecutive secretory cells with abnormal p53 labeling, abnormal growth of secretory cells (secretory cell outgrowth, SCOUT), defined as the presence of more than 30 secretory cells and secretory cell expansion (SCE), defined as a continuous run of >10 secretory cells, with normal p53 expression [15, 16]. It is not clear whether these secretory cell changes are precursors of STIC or if they are independent precursors of HGSOC. The cytotoxic effects of Phenformin were associated with ovarian cancer, while new molecules like paired box 8 (PAX8) and Wilms’ tumor 1 (WT1) have been considered for ovarian cancer diagnosis [17, 18, 19].
A major drawback in diagnosing such types of tumors lies in countries where the screening for gynecological cancers is not well set up. Increased economic efficiency in health care does not only mean finding ways of mechanically reducing hospital costs, as the primary goal aim is to improve healthcare by using the existing human, financial, material and time resources more effectively. Consequently, a parametric evaluation of treatment techniques and patient satisfaction is imperative, a medico-economic evaluation being complete only in these circumstances [20].
Around 90% of ovarian tumors have a response to epithelial transformed cells. In other rare cases they have germ cells or sex cord stromal tissues. The common subtypes are serous, mucinous, clear-cell and endometrioid.
Depending on the cytological modifications, there can be further differentiation between the same type of cancers, such as low or high-grade serous ovarian malignancy.
Histopathologically, HGSCOC is usually considered a solid mass of cells, differentiated by fenestrations, papillary, glandular or cribriform components and architecture, similar to the fallopian tube epithelium. It is often accompanied by large areas of necrosis, or areas that mimic other cancer types, such as endometrioid or transitional.
Genetics can reveal BRCA1 mutations and a large number of infiltrating lymphocytes. Other cellular characteristics are nuclear atypia, hyperchromatic and pleomorphic nuclei, with eosinophilic aspects, high mitotic index and psammoma aspects, associated with papillary tumor types. Dissemination is considered to be its direct expansion, not requiring blood or lymph. Dissemination occurs in the peritoneal cavity through the detachment of cells from the primary site. The cells can settle into nearby organs and rapidly determine secondary tumor nodules [4].
Conclusions
Ovaries are one of the leading organs associated with malignant genital tract lesions. Ovarian carcinomas represent about 90% of cancers that arise from the ovaries and are commonly diagnosed around menopausal age. Early detection of fallopian tube lesions during routine hysterectomies is important for preventing serous ovarian cancer. There is no reliable way to screen for ovarian cancer in women who do not have any signs or symptoms. The two tests widely used, in addition to a complete pelvic gynecological exam to screen for ovarian cancer, are the transvaginal US and the CA125 blood test, as part of the risk of ovarian malignancy algorithm (ROMA) score.
An annual routine US scan could potentially reduce the risk of advanced ovarian cancer, but in early forms, it has a high failure rate, due to the difficulty to recognize early signs. However, MRI scanning of the abdomino-pelvic region with intravenous contrast agent should be recommended in any suspected cases, in association with thorax computed tomography in cases of suspicious signs in the thoracic area, such as pleurisy or persistent cough. Identifying new and efficient therapies for HGSOC is essential to increase both progression-free survival rate and overall survival in our patients.
Conflict of interests
The authors declare that they have no conflict of interests.
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