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Year : 2016  |  Volume : 59  |  Issue : 4  |  Page : 481-488
Secretory cell outgrowths, p53 signatures, and serous tubal intraepithelial carcinoma in the fallopian tubes of patients with sporadic pelvic serous carcinoma

1 Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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Date of Web Publication10-Oct-2016


Context: High-grade serous carcinomas of ovarian, tubal, and peritoneal origin are together referred as pelvic serous carcinoma. The fallopian tubes, ovarian surface epithelium, and the tuboperitoneal junctional epithelium are all implicated in pelvic serous carcinogenesis. Aims: The aim of this study is to identify putative precursor lesions of serous carcinoma including secretory cell outgrowths (SCOUTs), serous tubal intraepithelial carcinoma (STIC), and p53 signatures and assign its probable site of origin. Settings and Design: Prospective case-control study of consecutive specimen comprising 32 serous carcinomas and 31 controls (10 normal adnexa, 10 benign and 6 atypically proliferative surface epithelial tumors, and 5 other carcinomas). Subjects and Methods: Sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol along with immunohistochemistry for Bcl-2, p53, and Ki-67 was employed for evaluating invasive carcinoma and precursor lesions in cases versus controls. Results: SCOUT, p53 signatures, and STIC were most frequent in the serous carcinomas. p53 signatures and STIC were always seen in the fimbrial end. STICs were exclusively present in serous carcinomas, more common in ipsilateral tubes of cases with dominant ovarian mass. Multifocal p53 signatures with STIC were seen in 7 (21.9%) cases. STIC was present with or without an invasive carcinoma in 25% and in 6.25% of cases of pelvic serous carcinomas, respectively. The junctional epithelia did not show any lesion in any group. Conclusions: SEE-FIM protocol is recommended for evaluation of sporadicpelvic (ovarian/tubal/peritoneal) serous carcinoma. Based on the presence of STIC or invasive carcinoma, nearly 60% of all pelvic serous carcinomas are of fallopian tubal origin.

Keywords: Fallopian tube, p53 signature, secretory cell outgrowths, sectioning and extensively examining the fimbria protocol, serous carcinoma, serous tubal intraepithelial carcinoma

How to cite this article:
Mittal N, Srinivasan R, Gupta N, Rajwanshi A, Nijhawan R, Gautam U, Sood S, Dhaliwal L. Secretory cell outgrowths, p53 signatures, and serous tubal intraepithelial carcinoma in the fallopian tubes of patients with sporadic pelvic serous carcinoma. Indian J Pathol Microbiol 2016;59:481-8

How to cite this URL:
Mittal N, Srinivasan R, Gupta N, Rajwanshi A, Nijhawan R, Gautam U, Sood S, Dhaliwal L. Secretory cell outgrowths, p53 signatures, and serous tubal intraepithelial carcinoma in the fallopian tubes of patients with sporadic pelvic serous carcinoma. Indian J Pathol Microbiol [serial online] 2016 [cited 2023 Feb 7];59:481-8. Available from:

   Introduction Top

The traditional term "Epithelial ovarian carcinoma" is now referred to as high-grade pelvic serous carcinoma and includes serous epithelial ovarian carcinoma, tubal, and peritoneal carcinomas; they are an important cause of death in women from gynecologic malignancies world-wide and in India. [1],[2] A better understanding of the pathogenesis may help to evolve strategies for early detection and management. For decades, the ovarian surface epithelium (OSE) was implicated as the site of origin of these lethal neoplasms; however, recent evidence has clearly implicated the fallopian tubal fimbrial end in its pathogenesis. [3],[4],[5],[6] Detailed histological evaluation of risk-reduction prophylactic bilateral salpingo-oophorectomy specimens from BRCA positive women has revealed morphological evidence of the precursor lesion of high-grade serous epithelial carcinoma in the form of "serous tubal intraepithelial carcinomas" (STICs). STIC lesions display stratification, nuclear hyperchromasia and mitotic figures and are associated with p53 positivity and a high Ki-67/MIB-1 index. [7] Other putative precursor lesions include "p53 signatures" [8] and the secretory cell outgrowth (SCOUT). [9] A pathway of pelvic serous carcinogenesis integrating these lesions has been proposed by Jarboe et al.[7] In this study, we evaluated pelvic serous carcinomas with special attention to the distal fimbrial and OSE and the junctional epithelia including the tubo-peritoneal junction (TPJ) and the OSE-peritoneal junction in salpingo-oophorectomy specimen for identification of invasive and the putative precursor lesion of high-grade serous carcinoma. We compared the frequency and distribution of these lesions in serous carcinoma with atypically proliferative and benign surface epithelial tumors (SETs) as well as with normal controls to understand their role in serous carcinogenesis. We also assigned the site of probable origin based on the presence of these precursor lesions to identify the most common origin of pelvic serous carcinomas.

   Subjects and Methods Top

Case selection

The study was carried out after approval by the Institute Ethics Committee (vide letter No. 8691/PG-2Trg/2011/2783-84 dated 30.1.2013). This was a prospective study of 63 cases (53 surface epithelial ovarian neoplasms and 10 control group with normal ovaries) submitted for routine histopathological evaluation. Control specimen constituted hysterectomy and salpingo-oophorectomy performed for adenomyosis or leiomyomas.

Histopathological examination of the specimen and number of sections evaluated

The sectioning and extensively examining the fimbria (SEE-FIM) protocol [10] was employed for macroscopic evaluation of all salpingo-oophorectomy specimen. In breif the fimbrial end was transected and longitudinally sliced. The rest of the tube was serially transversely sliced. Thus, from each fimbrial end, 2-3 sections and from the rest of the tube 6-8 cross-sections were obtained for light microscopic evaluation. Adequate sections for routine histopathological evaluation of the neoplastic lesion were carried out and the tumor was appropriately categorized.


Immunohistochemistry was carried out using mouse monoclonal antibodies against Bcl-2 (Dako, Denmark AS, clone 124, 1:50 dilution), p53 (Novocastra, UK, clone NCL-L-p53-DO7; 1:30 dilution), and MIB-1 or Ki-67 (Novocastra, UK, clone NCL-L-Ki-67-MM1, 1:30 dilution) followed by EnVision staining (Dako, Denmark). One section each of tubal cross-section and distal fimbrial sections and the tumor was stained in all the cases included. Further a section representative of the OSE, cortical inclusion cysts and junctional epithelia (OSE-peritoneal junction and the tubal-peritoneal junction) wherever identified was also evaluated by all the three immunostains.

Evaluation of immunohistochemistry


Bcl-2 highlights the tubal secretory cells and shows cytoplasmic immunoreactivity. [11] A linear stretch of thirty fallopian tubal secretory cells was consistent with SCOUT. The number of SCOUTs was counted in the fallopian tubal sections and the SCOUT index, defined as the number of SCOUTs per cross-section was derived.


Nuclear positivity alone was considered as positive. A linear stretch of at least 12 positive nuclei in morphologically normal epithelium was defined as a "p53 signature" lesion. [10]

Ki-67 labeling index and categorization of lesions

The Ki-67 (MIB-1) labeling was performed on sections showing p53 signatures or p53 positivity and those with morphological evidence of nuclear stratification and atypia.

An algorithmic approach as proposed by Vang et al. [12] was applied for the diagnosis of p53 signature, STIC and lesions with intermediate features (serous tubal intraepithelial lesion [STIL]). STIC lesions showed morphological stratification with associated nuclear pleomorphism and atypia with p53 positivity and high Ki-67 index (≥10%). p53 signatures were lesions without any morphological abnormality but which displayed abnormal p53 positivity and low Ki-67 index (<10%). Lesions with intermediate features were categorized as STIL.

The following points were recorded for SCOUTs, p53 signature lesions and STIC lesions: (i) number of lesions in cross-sections and the fimbrial end of both right and left tube in different study groups; (ii) variation in their distribution in relation to tumour laterality - ipsilateral versus contralateral; (iii) in serous carcinomas, correlation to assigned site of origin and any difference in cases who did or did not receive neoadjuvant chemotherapy (NACT).

Statistical analysis

Data were analyzed using SPSS version 19.0 for MS-Windows (SPSS Inc., Chicago, IL, USA). The difference in the distribution of putative precursor lesions was analyzed within and between the different groups using ANOVA test with post hoc analysis or by nonparametric Kruskal-Wallis test. The value of P < 0.05 was considered statistically significant.

   Results Top

This was a prospective study of 63 cases (53 SET and 10 controls) broadly divided into four groups [Table 1]. The patients had no family history of ovarian or breast cancer. NACT consisting of cisplatin and paclitaxel (three cycles) was given in 18/32 cases (56.25%) of high-grade serous carcinomas as they were in an advanced stage to reduce the tumor burden before surgery; residual serous carcinoma was present in all these cases. The high-grade serous carcinomas were further assigned to a primary site of origin based on the earlier WHO criteria existing at the time when the study was undertaken. [13],[14] Thus, of 32 cases, 20 were of ovarian origin (bilateral in 8, right ovarian in 8 and left ovarian in 4 cases, respectively), 2 of tubal origin and 10 were of primary peritoneal origin.
Table 1: Group - wise distribution of cases included in the study (n=63)

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Nonneoplastic changes in the ovary, ovarian surface epithelium, fallopian tube and the junctional epithelia

Ovarian c ortical inclusion cysts [Figure 1]a were commonly seen in all categories (30-60% of cases) and there was no difference between groups. Transitional metaplasia [Figure 1]b in the peritoneal aspect of the tube was observed in just one case of serous carcinoma. Mesothelial hyperplasia [Figure 1]c was observed in the serosal aspect of the tube in eight cases in the serous neoplasm categories. Walthard cell nests [Figure 1]d in the serosal aspect of the tubal cross-sections and fimbriae, and dilated lymphatics [Figure 1]e in the tubal fimbriae were seen in 30-83% of cases. Papillary tubal hyperplasia [Figure 1]f was observed in 2/6 cases of atypical proliferative serous epithelial tumour (APSET) only.
Figure 1: Nonneoplastic changes in the ovaries and fallopian tubes documented. (a) Ovarian cortical epithelial inclusion cysts; (b) transitional metaplasia; (c) papillary mesothelial hyperplasia; (d) Walthard's cell nest with cystic change; (e) dilated lymphatics in tubal fimbria; (f) papillary tubal hyperplasia (a, c, d, e: H and E, ×100; b and f: H and E, ×200)

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The junctional epithelium was especially evaluated. The TPJ was identified as an abrupt transition from the tubal type serous epithelium to the flat mesothelium lining the serosal aspect of the tube [Figure 2]a. The OSE - peritoneal junction was more diffuse and is depicted in [Figure 2]b. A total of 23 TPJs were seen in 6/10 controls, 2/10 benign cases, 2/10 APSET, 12/32 serous carcinomas, and 1 case of clear cell carcinoma. There was no evidence of any proliferation or atypia morphologically in any of these TPJs. The OSE-peritoneal junction was appreciated in 26 cases including 12 cases of serous carcinoma and was morphologically unremarkable in all cases.
Figure 2: (a) Tubo-peritoneal junction; (b) ovarian surface epithelium-peritoneal junction (FT: Fallopian tube, OC: Ovarian cortex). Black solid arrows show the junctions respectively. Plain arrows show ovarian surface epithelium and blue arrows show peritoneal surface epithelium (a: H and E, ×200, b: H and E, ×40)

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Putative precursor lesions

Secretory cell outgrowths

SCOUTs [Figure 3]a were present in all groups and showed the highest prevalence in serous carcinomas (90.6% cases) followed by normal control group (70%), other carcinomas and benign epithelial neoplasms (60%) and was least common in the APSET (16.7%). The total number of SCOUTs in all the tubal cross-sections and the distal fimbria were also counted, and the differences among groups were statistically significant (P = 0.0089, ANOVA and Kruskal-Wallis test) [Figure 4]. Among serous carcinomas, there was no difference between those who did or did not receive NACT (P = 0.215). The distribution of SCOUTs in the various groups and the SCOUT index is shown in [Table 2]. SCOUTs were more common in the fimbrial end as compared to the proximal tube in general with the fimbria/proximal tube SCOUT ratio ranging from 2.1 to 3.2 in all groups except the atypical proliferative tumors. Further, the number of SCOUTs was highest in the serous carcinomas both in the proximal as well as distal fimbrial sections; the SCOUT index was nearly 4 times more and the fimbrial SCOUTs were 2.5 times more as compared to normal controls. The number of SCOUTs did not correlate to the assigned site of origin of the tumor, i.e., ovarian, tubal, or peritoneal origin (P = not significant).
Figure 3: Fallopian tubal fimbrial sections showing precursor lesions. (a) Secretory cell outgrowths as demonstrated by Bcl-2 positivity; inset shows H and E image; (b) p53 signature; (c) paired p53 and Ki- 67 (inset) stained sections demonstrating serous tubal intraepithelial lesion; (d) serous tubal intraepithelial carcinoma lesion showing p53 positivity and inset shows Ki-67 positive in 20% nuclei; (e) serous tubal intraepithelial carcinoma lesion overlying invasive serous carcinoma; (f) multifocal serous tubal intraepithelial carcinoma lesions (a and b: Immunoperoxidase with EnVision, ×400; c and f: Immunoperoxidase with EnVision, ×100, d and e: Immunoperoxidase with EnVision, ×200)

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Figure 4: Intergroup comparison of number of secretory cell outgrowths (P = 0.008, Kruskal-Wallis test). BSET: Benign surface epithelial tumor, APSET: Atypical proliferative surface epithelial tumor, SC: Serous carcinoma, OC: Other carcinoma

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Table 2: Frequency of secretory cell outgrowths in different groups and SCOUT fimbrial/proximal tube ratio

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p53 signature

p53 signatures consist of short stretches (≥12) of morphologically normal epithelium with p53 positive nuclei [Figure 3]b. The frequency and distribution of p53 signatures is summarized in [Table 3]. Thus, p53 signatures were seen always in the fimbrial end and were frequent in serous carcinomas (65.6%) as compared to control cases (30%). p53 signatures were not identified in nonserous carcinomas, atypical proliferative and benign tumors, the differences between groups were highly significant (ANOVA P = 0.003). In 32 high-grade serous carcinomas, 39 p53 signatures were seen right tubal fimbriae and 23 in the left fimbriae. In the control group, 4 p53 signatures were seen in the right tubal fimbrial end. There was no correlation of p53 signatures with the assigned site of origin of serous carcinoma (P = 0.607) [Table 3].
Table 3: Association of p53 signature to assigned site of origin of serous carcinoma (n=32)

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Serous tubal intraepithelial lesion and serous tubal intraepithelial carcinoma

STIL was observed in two cases of serous carcinoma, both presenting with dominant ovarian masses and one representative image with a continuous p53 positivity [Figure 3]c but with variable Ki-67 positivity [[Figure 3]c, inset]. There was no stratification and dysplasia was mild; this lesion was not observed in any other group. STIC was observed exclusively in the distal fimbrial end of high grade serous carcinomas in serous carcinoma and representative lesions are highlighted in [Figure 3]d-f. The epithelium showed stratification and significant atypia with strong p53 positivity. Ki-67 was usually high and ranged from 20% to 80%. Further, among serous carcinomas, 12/32 cases showed 34 STIC lesions in the fimbrial end (19 in right and 15 in left) [Table 4]. One case of serous carcinoma with assigned peritoneal origin showed three STICs and none was seen in the tubal origin serous carcinoma. Overall, the ovarian origin cases showed the highest STIC counts which was statistically significant (Yates'χ2 = 3.096; P = 0.04). Ipsilateral STIC was seen in 66.7% of cases with unilateral ovarian tumor and bilateral STIC in 42.8% of cases with bilateral ovarian tumor. There was no difference in STIC frequency between those who did or did not receive NACT (P = 0.11). Multifocal STIC was seen in seven cases [Figure 3]f. Invasive carcinoma without STIC was observed in 28.12% of cases, invasive tumor with STIC in 25% of cases [Figure 3]e and STIC alone in absence of invasive component [Figure 3]d was seen in 6.25% of cases of the serous carcinomas.
Table 4: Association of serous tubal intraepithelial carcinoma to assigned site of origin of serous carcinoma (n=32)

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Putative precursor lesions in junctional epithelia

The TPJ and OSE-peritoneum junctional epithelia and the OSE showed diffuse strong positivity for Bcl-2 and negativity for p53 and none of the precursor lesions, namely, SCOUT, p53, or STIC was identified in all cases evaluated.

Invasive carcinoma

Among 32 serous carcinomas, dominant ovarian masses were seen in 20 cases (unilateral in 12 cases, bilateral in 8 cases). The tumor mass involved the right ovary in 8 cases and the left ovary in 4 cases. In the remaining 12 cases, there was no dominant ovarian mass and the tubes and ovaries were normal sized and omental deposits forming omental cakes were seen, findings suggesting primary peritoneal carcinoma. The tubal involvement was carefully assessed. On macroscopic evaluation, right tube was grossly involved in 11 cases with luminal tumor in 2 cases, serosal deposits in 1 case and greyish white tumor nodules/deposits in the fimbriae in 8 cases. The left tube was grossly involved in 6 cases with 3 showing luminal tumor and 3 with fimbrial end tumor deposits. Bilateral tubal involvement in the form of fimbrial nodules measuring 0.5-0.6 cm in diameter was seen in three cases. On microscopy, neoplastic involvement of the tube was observed in the proximal tubal cross-sections as well as the fimbriae. Thus, 10/32 (31.25%) serous carcinoma showed luminal involvement by the invasive carcinoma with the invasion of the underlying smooth muscle and 11/32 (34.4%) serous carcinoma showed serosal tumor deposits. The fimbrial end showed invasive tumor in 16/32 (50%) cases. Bilateral involvement of fimbrial ends was seen in seven cases. In 20 cases presenting as a dominant ovarian mass, invasive carcinoma was identified in the tubal fimbrial end in 16 cases, 14 ipsilateral and 2 in contralateral tubes, respectively.

As per the prevailing the WHO criteria at the time of execution of the study, [13],[14] based on the gross and microscopic features, tumors were assigned a probable site of origin which was ovarian in 62.5% cases, tubal in 6.25% of cases, and peritoneal in 31.25% of cases [Table 5]. If invasive carcinoma and STIC was taken as presumptive of the distal tube as the site of origin of pelvic serous carcinoma, then the site of tumor origin was revised to ovarian in 21.9% of cases, tubal in 59.4% of cases, and peritoneal in 18.75% of cases [Table 5].
Table 5: Assignment of site of origin of pelvic serous carcinoma as per original WHO criteria versus revised criteria

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   Discussion Top

The identification of occult carcinomas in the fallopian tubal fimbria in prophylactic risk-reducing salpingo-oophorectomy specimen in BRCA positive women lead to the development of the SEE-FIM protocol for identifying occult neoplastic and precursor lesions of serous carcinoma. [7],[8] Studies over the last few years by Levanon et al. and subsequently by others have resulted in a paradigm shift in our understanding of the pathogenesis of serous ovarian carcinoma. [3],[4],[5],[6],[7],[8] Accordingly, the distal fimbrial end of the fallopian tube rather than the OSE is important in serous carcinogenesis. There are only a few studies [15],[16] which have evaluated sporadic pelvic serous carcinomas to document the involvement of the ovaries, tubes and the junctional epithelia by the putative precursor lesions; hence, this was the aim of our study.

Detailed evaluation of the OSE and the epithelium lining the cortical inclusion cysts wherever identified did not show any precursor lesion in the form of epithelial atypia or hyperplasia. Walthard cell nests, transitional metaplasia, and papillary tubal hyperplasia were also not significantly different between the groups. We concur with Rabban et al. that most of these findings are incidental and are not perhaps involved in serous carcinogenesis. [17]

The junctional epithelia including the TPJ or TPJ and the OSE-peritoneal junction have been proposed as potential sites of origin of serous carcinoma. [18],[19] However, the TPJ and the OSE-peritoneal junctions showed no atypia or any precursor lesion discussed in detail below and so, is unlikely to be of significance in serous carcinogenesis.

SCOUTs have been proposed to be the initial step in serous carcinogenesis. [7],[9] These cells show upregulation of Bcl-2, which may be used as a marker for this cell type. [11] We confirm the higher prevalence of SCOUTs in serous carcinomas compared to controls (90.6% in SC vs. 60% in controls) consistent with previous observations. [6],[20] The SCOUT index in our study was higher in both groups being 0.2 in controls and 0.78 in serous cancers as compared 0.03 and 0.25, respectively, reported earlier which would indicate a 4-fold increase in the number of SCOUTs in serous cancers as against an 8-fold increase previously reported. [9] An increase in SCOUT frequency with age has been observed. [20] SCOUTs were rare in women with mean age of 35 years [20] which is similar to our data wherein the lowest frequency of SCOUTs was seen benign tumor group with a mean age of 35 years. The prevalence of SCOUTs in both cross-section and the fimbrial end is in concordance with previous studies [9],[20] and so is the higher SCOUT counts in the fimbrial end as compared to the proximal tube (ratio of 2.12:1) consistent with a previous study. [9] Although, there are fallacies in deriving such counts as the numbers would depend on the number of sections examined, after adjustment for the same, Quick et al. did not find any significant difference between SCOUTs in the proximal versus distal fallopian tubes. [20] Further, we did not find any significant difference in the distribution of SCOUTs in the tubes with the laterality of ovarian involvement and the assigned site of origin of serous carcinoma.

In view of the fair interobserver variability (κ =0.39-0.453) for the identification of STIC lesions [5],[21] we employed the diagnostic algorithm for identification of precursor lesions proposed by Vang et al. which incorporates morphology and immunohistochemistry for p53 and Ki-67. [12] p53 immunostaining revealed an interrupted pattern of immunoreactivity in the fallopian tubal sections with anywhere from 3% to 30% nuclei being positive. Serous carcinomas showed the highest frequency (65.6% cases) as well as highest numbers [1],[2],[3],[4],[5],[6] of p53 signatures in the fimbrial end. p53 signatures were not seen in the benign, borderline tumors and other carcinomas but were seen in 30% of the control cases with extra-ovarian and extra-tubal nonneoplastic diseases. This was in concordance with a study by Lee et al. who found p53 signatures in 24% BRCA positive cases and in 33% cases of extra-ovarian conditions. [8]

STIL in transition was observed in two cases who presented as dominant ovarian masses. The low frequency of this intermediate lesion is similar to previous reports. [7],[22] STIC lesions were seen in 40.6% of cases of serous carcinomas and were not seen in any other carcinoma type consistent with previous studies who observed it in 50-58% cases. [15],[16] p53 signatures are also seen more frequently and tend to be multifocal in tubes with STIC. Multifocal p53 signatures with STIC were seen in 7 (21.9%) cases. Further, STIC were seen only in the fimbrial end of the fallopian tube in 100% of cases, similar to 92-93% reported previously. [15],[16] STIC lesions also tend to occur in the same side as the ovarian tumor (66.7% cases with unilateral ovarian tumor showed ipsilateral STIC and 42.8% with bilateral ovarian tumor showed bilateral STIC). STIC lesions tend to be present with an invasive carcinoma more often than isolated lesions which is in concordance with a previous study. [16] STIC lesions were present in 45%, 0% and 10% of cases and p53 signatures were present in 75%, 50%, and 50% of tumors assigned to "ovarian," tubal, or peritoneal origin. Leonhardt et al. found frequencies of p53 signature, tubal intraepithelial lesion in transition (TILT) and STIC lesions to be 18.2%, 9.1%, and 18.2%, respectively, in tubal carcinoma and 11.1%, 0%, and 33.3% in primary peritoneal serous carcinomas. [22] In a large series of primary peritoneal carcinomas, p53 signatures and STIC lesions were seen in 19.6% and 21.7% and it was concluded that there may be alternate pathways of carcinogenesis of primary peritoneal serous carcinomas. [23] It was also found that about 94% of these precursor lesions were located in the fimbrial end of the fallopian tube. It must be noted that STIC lesions with complete absence of p53 staining (0% labeling index) do exist and are believed to be due to p53 "null-type" mutations. [24],[25] We did not encounter any case with morphological atypia but lacking p53 positivity in this study. Most importantly, if the presence of an invasive carcinoma or a STIC lesion was presumptive of fallopian tubal origin of the pelvic serous carcinoma, then nearly 60% of cases were of fallopian tubal origin which reaffirms the previous studies on sporadic pelvic serous cancers wherein 64-75% cases were of primary tubal origin. [15],[16] This is reflected in the current WHO, TNM and FIGO classification of serous carcinoma wherein the tumors of the ovary, fallopian tube, and peritoneum are clubbed for purposes of staging. [26] Furthermore, as per the International Consortium for Cancer Reporting recommendations for reporting of ovary, fallopian tube, and primary peritoneal carcinoma, the histological sites of tumor involvement should be recorded as it is necessary for staging, and the primary site of origin of the tumor should be assigned. [27] The guidelines further make it mandatory for SEE-FIM protocol to be applied in all cases of high-grade serous carcinoma for documentation of STIC/invasive cancer in the tubal fimbria and if present, the tumor is assigned to be of tubal origin irrespective of where the greatest volume of the tumor is present. [27]

The management of high-grade pelvic serous carcinoma irrespective of the site of origin is the same with taxol and platinum-based chemotherapy in the adjuvant or neoadjuvant setting. A significant number of our patients with advanced stage serous carcinomas received three cycles of NACT and showed residual cancer in their histological specimen. Contrary to our expectations, none of the precursor lesions showed any statistical difference among those who did or did not receive NACT. In the Canadian experience, a slightly lower incidence of STIC was observed in women who received NACT as compared with those who did not (P = 0.042). [28]

None of our patients had any family history of breast or ovarian cancer. However, their BRCA genetic status is not known and it is speculative if the occurrence of the precursor lesions in such patients was related to altered BRCA expression either due to a genetic mutation or due to epigenetic mechanisms. Bilateral salpingo-oophorectomy is traditionally performed for risk-reduction in patients with BRCA mutations and also in the general population whenever hysterectomy is performed for other reasons. In view of the fact that the fallopian tube is the site of the precursor lesions of serous ovarian cancer, it has been proposed that in place of bilateral salpingo-oophorectomy, it should suffice to do bilateral salpingectomy to achieve risk reduction of ovarian cancer. [29] However, this is yet to be followed in general clinical practice.

   Conclusions Top

The fimbrial end of the fallopian tube is the site of invasive serous carcinoma as well as of putative precursor lesions including SCOUTs and p53 signatures, TILT and STIC making it the most common site of origin of pelvic serous carcinoma. Evaluation of distal fallopian tubes using the SEE-FIM protocol and judicious application of Bcl-2, p53, and Ki-67 immunohistochemistry is recommended for the detection of the precursor lesions in all cases of sporadic pelvic serous carcinoma.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.  Back to cited text no. 1
Murthy NS, Shalini S, Suman G, Pruthvish S, Mathew A. Changing trends in incidence of ovarian cancer - The Indian scenario. Asian Pac J Cancer Prev 2009;10:1025-30.  Back to cited text no. 2
Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 2008;26:5284-93.  Back to cited text no. 3
Gross AL, Kurman RJ, Vang R, Shih IE, Visvanathan K. Precursor lesions of high-grade serous ovarian carcinoma: Morphological and molecular characteristics. J Oncol 2010;2010:126295.  Back to cited text no. 4
Visvanathan K, Vang R, Shaw P, Gross A, Soslow R, Parkash V, et al. Diagnosis of serous tubal intraepithelial carcinoma based on morphologic and immunohistochemical features: A reproducibility study. Am J Surg Pathol 2011;35:1766-75.  Back to cited text no. 5
Vang R, Shih IE, Kurman RJ. Fallopian tube precursors of ovarian low- and high-grade serous neoplasms. Histopathology 2013;62:44-58.  Back to cited text no. 6
Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, et al. Serous carcinogenesis in the fallopian tube: A descriptive classification. Int J Gynecol Pathol 2008;27:1-9.  Back to cited text no. 7
Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007;211:26-35.  Back to cited text no. 8
Chen EY, Mehra K, Mehrad M, Ning G, Miron A, Mutter GL, et al. Secretory cell outgrowth, PAX2 and serous carcinogenesis in the fallopian tube. J Pathol 2010;222:110-6.  Back to cited text no. 9
Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006;30:230-6.  Back to cited text no. 10
Piek JM, van Diest PJ, Verheijen RH, Kenemans P. Cell cycle-related proteins p21 and bcl-2: Markers of differentiation in the human fallopian tube. Histopathology 2001;38:481-2.  Back to cited text no. 11
Vang R, Visvanathan K, Gross A, Maambo E, Gupta M, Kuhn E, et al. Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma. Int J Gynecol Pathol 2012;31:243-53.  Back to cited text no. 12
Benedet JL, Bender H, Jones H 3 rd , Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000;70:209-62.  Back to cited text no. 13
Lee KR, Tavassoli FA, Prat J, Deietel M, Gersell DJ, Karseadze AI, et al. Surface epithelial-stromal tumours. In: Tavassoli FA, Devilee P, editors. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. p. 119-20.  Back to cited text no. 14
Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007;31:161-9.  Back to cited text no. 15
Przybycin CG, Kurman RJ, Ronnett BM, Shih IE, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 2010;34:1407-16.  Back to cited text no. 16
Rabban JT, Crawford B, Chen LM, Powell CB, Zaloudek CJ. Transitional cell metaplasia of fallopian tube fimbriae: A potential mimic of early tubal carcinoma in risk reduction salpingo-oophorectomies from women With BRCA mutations. Am J Surg Pathol 2009;33:111-9.  Back to cited text no. 17
Seidman JD, Yemelyanova A, Zaino RJ, Kurman RJ. The fallopian tube-peritoneal junction: A potential site of carcinogenesis. Int J Gynecol Pathol 2011;30:4-11.  Back to cited text no. 18
Auersperg N. The origin of ovarian carcinomas: A unifying hypothesis. Int J Gynecol Pathol 2011;30:12-21.  Back to cited text no. 19
Quick CM, Ning G, Bijron J, Laury A, Wei TS, Chen EY, et al. PAX2-null secretory cell outgrowths in the oviduct and their relationship to pelvic serous cancer. Mod Pathol 2012;25:449-55.  Back to cited text no. 20
Carlson JW, Jarboe EA, Kindelberger D, Nucci MR, Hirsch MS, Crum CP. Serous tubal intraepithelial carcinoma: Diagnostic reproducibility and its implications. Int J Gynecol Pathol 2010;29:310-4.  Back to cited text no. 21
Leonhardt K, Einenkel J, Sohr S, Engeland K, Horn LC. p53 signature and serous tubal in-situ carcinoma in cases of primary tubal and peritoneal carcinomas and serous borderline tumors of the ovary. Int J Gynecol Pathol 2011;30:417-24.  Back to cited text no. 22
Horn LC, Kafkova S, Leonhardt K, Kellner C, Einenkel J. Serous tubal in situ carcinoma (STIC) in primary peritoneal serous carcinomas. Int J Gynecol Pathol 2013;32:339-44.  Back to cited text no. 23
Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, Soslow R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma - Evidence supporting the clonal relationship of the two lesions. J Pathol 2012;226:421-6.  Back to cited text no. 24
Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih IE, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: An immunohistochemical and nucleotide sequencing analysis. Mod Pathol 2011;24:1248-53.  Back to cited text no. 25
Kurman RJ, Carcangiu ML, Herringtin CS, Young RH, editors. WHO Classification of Tumors of Female Reproductive Organs. Lyon: International Agency for Research on Cancer; 2014. p. 14.  Back to cited text no. 26
McCluggage WG, Judge MJ, Clarke BA, Davidson B, Gilks CB, Hollema H, et al. Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: Recommendations from the International Collaboration on Cancer Reporting (ICCR). Mod Pathol 2015;28:1101-22.  Back to cited text no. 27
Mahe E, Tang S, Deb P, Sur M, Lytwyn A, Daya D. Do deeper sections increase the frequency of detection of serous tubal intraepithelial carcinoma (STIC) in the "sectioning and extensively examining the FIMbriated end" (SEE-FIM) protocol? Int J Gynecol Pathol 2013;32:353-7.  Back to cited text no. 28
Yoon SH, Kim SN, Shim SH, Kang SB, Lee SJ. Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: A meta-analysis. Eur J Cancer 2016;55:38-46.  Back to cited text no. 29

Correspondence Address:
Radhika Srinivasan
Research A Block, 4th Floor, Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.191789

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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