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ORIGINAL ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 610-616
Prevalence of precursor lesions (P53 signature, SCOUT, STIL, STIC) in fallopian tubes resected for non-neoplastic causes


Department of Pathology, Moti Lal Nehru Medical College, Prayagraj, Uttar Pradesh, India

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Date of Submission29-May-2021
Date of Decision17-Aug-2021
Date of Acceptance24-Aug-2021
Date of Web Publication26-May-2022
 

   Abstract 


Background: High-grade pelvic serous carcinoma is a common cause of death in women worldwide and India. Recent evidence has clearly implicated the changes in the mucosa of the fimbrial end of the fallopian tube in its pathogenesis. Objective: 1) To study histopathology features of surgically resected specimens of fallopian tubes received with non-neoplastic lesions of the uterus and ovary for the presence of any precursor lesions [secretory cell outgrowth (SCOUT), serous tubal intraepithelial lesion (STIL), p53 signatures, and serous tubal intraepithelial carcinoma (STIC)]. 2) To confirm the findings with immunohistochemistry. 3) To correlate the prevalence of precursor lesions with clinical parameters and benign lesions of the uterus and ovaries. Materials and Methods: Assessment of histopathological changes in 100 specimens of distal fallopian tubes was done using the sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol. H and E stain followed by immunohistochemistry for Bcl-2, p53, and Ki-67. The statistical significance of the difference in the mean values of precursor areas was evaluated by an unpaired t-test. Results: Among 100 specimens taken on H and E, precursor lesions were suspected in 49% of the cases. SCOUT, suspicious for STIC, suspicious for STIC with areas of SCOUT, and unequivocal for STIC with areas of SCOUT were seen in 8%, 4%, 33%, and 4% of the cases, respectively. However, on IHC, SCOUTS were confirmed in 45% of the cases, p53 signature in 2%, STIL in 9%, and STIC in 4% of the cases. Conclusion: Sectioning and extensive examination of the fimbrial end (SEE-FIM) should be routinely done as it provides the opportunity to detect the early malignant changes. It may help in evolving the strategies for early detection, management, and reducing mortality.

Keywords: Fallopian tubes, fimbrial, non-neoplastic, precursor lesions

How to cite this article:
Tewari S, Misra V, Kumar V, Mishra RR, Yadav K, Paridhi, Sangma H. Prevalence of precursor lesions (P53 signature, SCOUT, STIL, STIC) in fallopian tubes resected for non-neoplastic causes. Indian J Pathol Microbiol 2022;65:610-6

How to cite this URL:
Tewari S, Misra V, Kumar V, Mishra RR, Yadav K, Paridhi, Sangma H. Prevalence of precursor lesions (P53 signature, SCOUT, STIL, STIC) in fallopian tubes resected for non-neoplastic causes. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:610-6. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/610/345879





   Introduction Top


High-grade pelvic serous carcinoma is a common cause of death in women from gynecologic malignancies worldwide and India.[1],[2] Recent evidence has clearly implicated the changes in the mucosa of the fimbrial end of the fallopian tubal in its pathogenesis.[3],[4] Sectioning and extensive examination of the fimbrial end (SEE-FIM) has revealed that the fallopian tube is the site of origin of most of the serous carcinomas. Recent publications also highlight the fallopian tube as a likely site-of-origin of primary pelvic serous carcinomas (PPSC) detected in the fallopian tube, ovary, or peritoneum.[4],[5],[6]

Serous tubal intraepithelial carcinoma (STIC) is the earliest morphologically recognizable form of pelvic (nonuterine) high-grade serous carcinoma.[7],[8],[9] STIC lesions display stratification, nuclear hyperchromasia, mitotic figures and are associated with p53 mutant type and a high Ki-67/MIB-1 index.[9] Other putative precursor lesions include “p53 signatures”[10] and the secretory cell outgrowth (SCOUT).[11] These precursor lesions may also be seen in sporadic cases of serous carcinomas.

The pathologists are now regularly examining all tubal tissue from surgical specimens and evaluating them with immunohistochemistry and therefore, numerous other lesions ranging from those with normal-appearing tubal epithelium with p53 mutant type [”p53 signature”][9],[10],[12],[13] to lesions displaying cytologic atypia that fall short of STIC,[9],[13],[14],[15] have been documented. The latter have been referred to by some as “tubal intraepithelial lesion in transition,”[9] or “serous tubal intraepithelial lesion” (STIL) as the nature of this lesion and its association to STIC has not been clearly established.


   Materials and Methods Top


The study was carried out after approval by the Institute Ethics Committee. The study design was prospective, encompassing 200 cases of fallopian tube specimens received as a part of hysterectomy with salpingo-oophorectomy, salpingo-oophorectomy specimens, or salpingectomy specimens in the Department of Pathology during a period of 1.5 years. The relevant clinical details were collected from the case records.

The resected samples that were received in the department were fixed in 10% formalin. Sectioning and extensive examination of the fimbria were done using the SEE-FIM protocol. In brief, the fimbrial end was transected and longitudinally sliced. The rest of the tube was serially transversely sliced. Thus, the whole of each fimbrial end in 6–8 sections and from the rest of the tube, 3–4 cross-sections were obtained for light microscopic evaluation by hematoxylin and eosin-stained sections. Immunostaining for Bcl-2, p53, and Ki-67 was also done.

Evaluation of hematoxylin and eosin

The lining epithelium of a normal fallopian tube show alternating pseudo-stratified ciliated and secretory cells. The secretory cell is considered to be the precursor of the former, undergoing ciliation under hormonal control. Diagnosis of SCOUT,[11] serous tubal intraepithelial carcinoma (STIC)[3] and serous tubal intermediate lesions (STIL)[3] on H and E and immunohistochemistry has been discussed in [Table 1].{Table 1}

Immunohistochemistry

  1. Sections of 3–4 micron thick were cut from paraffin block and mounted on poly-L-Lysine coated slides. The tissue sections were allowedto be fixed.
  2. The sections were dewaxed, washed in alcohol, and antigen retrieval carried out in antigen retriever pressure cooker (Tris buffer PH 10.0) for 30 mi at 106–110°C.
  3. Endogenous peroxidase activity was blocked by using peroxidase block on the tissue for 35 min.
  4. The slides were washed by PBS briefly and incubated with mouse monoclonal primary antibody (prediluted type) for 60 min.
  5. The slides were then extensively washed with PBS and incubated with secondary antibody (HRP- polymer, anti-mouse, and rabbit) for 45 min.
  6. The slides were washed by PBS and incubated with DAB chromogen for 8–10 min.
  7. The slides were counterstained with hematoxylin and mounted.


Primary antibody used for Bcl-2[17]: Bio SB Mouse Monoclonal Anti-Bcl-2, prediluted, clone BSB-5, Bio SB Inc., 69 Santa Felicia Dr., Santa Barbara, CA 93117, USA.

Primary antibody used for p53[17]: Bio SB Rabbit Monoclonal Anti-p53, prediluted, clone D07, Bio SB Inc., 69 Santa Felicia Dr., Santa Barbara, CA 93117, USA.

Primary antibody used for Ki-67[17]: Bio SB Rabbit Monoclonal Anti-Ki67, prediluted, clone EP5, Bio SB Inc., 69 Santa Felicia Dr., Santa Barbara, CA 93117, USA.

Evaluation of immunohistochemistry

Bcl-2

Bcl-2 highlights the tubal secretory cells and shows cytoplasmic immunoreactivity.[15] A linear stretch of 30 fallopian tubal secretory cells was consistent with SCOUT.[17] SCOUTs were counted in 10 high power field (hpf) per section showing continuous cytoplasmic Bcl-2 positivity in 30 cells or more.

p53

A linear stretch of at least 12 positive nuclei in the morphologically normal epithelium was defined as a “p53 signature” lesion.[17] p53 was considered mutant type if the focus showed >80% cells with moderate to strong nuclear expression (nuclear positive) or 0% labeling index (i.e., completely negative/null type).[18] Cases without either of these two patterns were considered wild type (negative) for p53. In cases without histologic atypia (i.e., not suspicious for STIC), the denominator for the calculation of the percentage of p53 mutant cells was based on a minimum length of 12 cells. It should be noted that the 0% labeling index pattern of a “mutant” p53 stain can only be recognized for foci showing histologic atypia (i.e., STIC or suspicious for STIC) as it is not possible to localize the area with a 0% labeing index in cases without histologic atypia (i.e., not suspicious for STIC).[16],[19]

Ki-67 labeling index and categorization of lesions

The Ki-67 (MIB-1) labeling was performed on sections showing p53 signatures or p53 mutant type and those with morphological evidence of nuclear stratification and atypia[17]. [Figure 1].{Figure 1}

An algorithmic approach as proposed by Vang et al.[16] was also 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 mutant type and high Ki-67 index (≥10%). p53 signatures were lesions without any morphological abnormality but which displayed p53 mutant type and low Ki-67 index (<10%). Lesions with intermediate features were categorized as STIL. Diagnostic criteria for precursor lesions on H and E and IHC based on Vang protocol along with positive criteria for immunohistochemistry have been discussed in [Table 1] and [Table 2].{Table 2}

Statistics

Mean (S.D.) of SCOUTs, p53 signatures, and Ki-67 labeling areas/10 hpf were calculated in all the sections in cases diagnosed as not suspicious for STIC (A), suspicious for STIC (B), and unequivocal for STIC (C) on H and E stained sections [Figure 2].{Figure 2}

The statistical significance of the difference in the mean values of precursor areas of two sets (A Vs B, A Vs C, B Vs C) was evaluated by an unpaired t-test. Statistical calculations were performed using Graph Pad software. P value <0.05 was taken as a critical level of significance. Method for mean values have been discussed in [Table 2].


   Results Top


A total of 200 specimens of the fallopian tube along with associated disorders of uterus, cervix, or ovary were included in the present study. Out of 200 cases, only 136 cases (68%) had attached ovary also. In the rest 64 cases (32%), the fallopian tube was received either alone or with uterus and cervix only.

The age of the patients included in this study ranged from 18 years to 73 years with a mean (SD) age of 41.3 (9.9) years. Maximum numbers of cases were found in the age group of 36 to 45 years (43.5%).

In the present study, we found precursor lesions in 49 specimens on morphology. None of these cases were associated with any occult malignancy. Based on the histological criteria described in the materials and method, the lesions on histology were labeled as SCOUT, suspicious for STIC, and unequivocal for STIC. The maximum number of precursor lesions was in the age group of 35–45 years.

  • A total of 8 out of 49 (16.3%) cases were identified with areas of SCOUT but were not suspicious for STIC.


  • A total of 33 out of 49 (67.34%) cases were identified as suspicious for STIC and also showed an area of SCOUT.

  • A total of 4 out of 49 (8.16%) cases were identified as Unequivocal for STIC along with SCOUT.
  • A total of 4 out of 49 (8.16%) cases were identified as suspicious for STIC.


Immunohistochemical examination for the presence of SCOUT, p53 signature, and Ki-67 (MIB-1) labeling index was done. Due to some technical and financial reasons, immunohistochemistry (IHC) for SCOUT, p53 signature, and Ki-67 (MIB-1) labeling index could be done only in 59 cases of normal histology, 37 cases which were suspicious for STIC, and 4 cases which were unequivocal for STIC on histology. Therefore, H and E and IHC correlation could only be done for the 100 specimens.

Among 100 specimens taken, on H and E, precursor lesions were suspected in 49% of the cases. SCOUT, suspicious for STIC, suspicious for STIC with areas of SCOUT, and unequivocal for STIC with areas of SCOUT were seen in 8%, 4%, 33%, and 4% of the cases, respectively. However, on IHC, out of these 100 cases, SCOUTS were confirmed in 45% of the cases, p53 signature in 2%, STIL in 9%, and STIC in 4%.

  • Eight cases of the fallopian tube with normal histology showed the presence of SCOUT.
  • Mean (S.D.) of SCOUT areas in cases not suspicious for STIC, suspicious for STIC, and unequivocal for STIC were 0.69 (1.90), 5.72 (2.6), and 5.75 (2.75), respectively.
  • Two cases of the fallopian tube with normal histology showed a p53 signature.
  • Mean (S.D.) of p53-signature area in cases not suspicious for STIC, suspicious for STIC, and unequivocal for STIC were 0.1 (0.54), 0.56 (1.14), and 2.5 (1.73), respectively.
  • Mean (S.D.) of Ki-67 labeling index cases not suspicious for STIC, suspicious for STIC, and unequivocal for STIC were 1.26 (0.64), 9.21 (3.24), and 28.64 (2.64), respectively.
  • In cases diagnosed as not suspicious for STIC (A), suspicious for STIC (B), and unequivocal for STIC (C) on H and E stained sections showed that P value was significant for mean values of p-53 signature, Ki-67 labeling index in sets A vs B, A vs C, and B Vs C. However, P- value was significant for mean values of SCOUT in A vs B and A vs C but not B vs C.


We have used the same protocol as used by Vang et al.[16] in which we have divided the patients into three main groups on the basis of changes in H and E stained sections. Then, these lesions were further classified on the basis of IHC (Bcl-2, p53, and Ki-67) into STIC, STIL, p53 signature, or normal/reactive groups. When we put up the IHC results in this algorithmic chart, the final diagnosis changed in 39% of the lesions.

On H and E, out of 100 cases, 4 (4%) cases were grouped into unequivocal for STIC [Figure 3], 37 (37%) cases were grouped into suspicious for STIC, and the rest 59 (59%) cases were grouped into not suspicious for STIC.{Figure 3}

After putting the findings of IHC (Bcl-2, p53, and Ki-67), into the algorithm of Vang et al.[16] [Figure 4], the final diagnosis was as follows: -{Figure 4}

  • Out of four cases of unequivocal for STIC, one case (25%) was confirmed as STIC, and the rest three were downgraded asserous tubal intraepithelial lesion (STIL).
  • Out of 37 cases of suspicious for STIC, 3 cases (8.1%) were upgraded as STIC, 6 cases (16.2%) remained as STIL, and the rest 28 cases (75.6%) were reverted to normal/reactive lesions.
  • Out of 59 cases of not suspicious for STIC, 2 (3.3%) cases were identified as p53 signature, and the rest 57 (96.6%) cases were confirmed as normal/reactive.
  • On H and E, out of 15 cases of serous cystadenoma of the ovary, none of the cases were grouped into unequivocal for STIC, 6 (40%) cases were grouped into suspicious for STIC, and the rest 9 (60%) cases were grouped into not suspicious for STIC.


After putting the findings of IHC (Bcl-2, p53, and Ki-67), into the algorithm of Vang et al.,[16] fthe inal diagnosis of cases of serous cystadenoma of ovary was as follows: -

  • Out of 6 cases of suspicious for STIC, 3 cases (50%) were upgraded as STIC, and the rest 3 cases (50%) were reverted to normal/reactive lesions.
  • Out of 9 cases of not suspicious for STIC, all 9 (100%) cases were confirmed as normal/reactive.
  • All three cases upgraded as STIC showed mutant type p53 and a high Ki-67 index.
  • All the three cases downgraded as normal/reactive lesions were p53 wild type with low Ki-67 index.


We also found that this algorithm is useful in confirming the final diagnosis made on IHC. Thus, discordance was maximum in the cases which were morphologically diagnosed as suspicious for precursor lesions. These findings were similar to the reports of Vang et al.,[16] who also found the maximum discordance in suspicious for precursor lesion group.


   Discussion Top


A study by Nishida et al.[20] was the first that focused on the correlation between precursor lesions and benign diseases. p53 signature, SCOUT, and tubal intraepithelial lesion in transition (TILT) were seen in 9.7%, 21.1%, and 3.2% of the cases, respectively. None of the cases were associated with STIC. However, in the present study, out of the 100 cases that were taken up, on H and E 49% cases were suspected of precursor lesions. On immunohistochemistry on these 100 cases, p53 signatures, SCOUT, STIL, and STIC were confirmed in 2%, 45%, 9%, and 4% of the cases, respectively. These results were higher in frequency except for p53 signatures than observed by Nishida et al.[20] Most common association of SCOUT was observed by Nishida et al.[20] was with leiomyoma which is similar to our study. They observed SCOUT in 22% of ectopic tubal pregnancy cases which is in contrast to our study where none of the ectopic tubal gestation cases were associated with precursor lesions. p53 expression was most frequently seen in benign ovarian tumors followed by leiomyoma, whereas in our study, p53 was most commonly associated with leiomyoma followed by adenomyosis and benign ovarian tumors. However, this is in contrast with a study by Leonhardt et al.[21] where none of the serous borderline ovarian tumor taken as control was associated with any precursor lesion. Similarly, in a study by Kar et al.[22] none of the fallopian tubes from benign ovarian tumors which were taken as control showed the presence of precursor lesions.

Ida et al.[23] observed p53 in 19% of the cases. They studied the incidence of p53 mutant type in 113 fallopian tubes removed for benign gynecological and obstetric causes. They, however, did not comment upon the relationship between benign gynecological cause of surgery and the occurrence of p53 lesions. In the present study, both p53 signature and SCOUT were most commonly seen in patients with leiomyoma followed by adenomyosis. None of the cases of ectopic tubal gestation were associated with precursor lesions. Salpingitis was seen in 25% of STIC cases but none of STIL cases. STIC was most commonly associated with serous cystadenoma of the ovary (50%) and adenomyosis (50%).

Chen et al.[11] included 25 fallopian tubes from non-neoplastic cases in their study as a control. They identified SCOUTs in 12%, 18%, and 83% of the fallopian tubes from non-neoplastic cases, BRCA-positive healthy cases, ovarian HGSC cases, respectively. Quick et al.[24] identified SCOUTs in 23% of fimbria.

Out of 37 cases diagnosed as suspicious for STIC on H and E, only 9 were confirmed as precursor lesions on IHC in our study. This is in consistent with study by Vang et al.[16] They found maximum interobserver variability and poor reproducibility on IHC in STIL lesion. Out of 4 cases diagnosed as STIC on morphology, only 1 was confirmed as STIC, whereas 3 were downgraded to STIL. Carlson et al.[25] highlighted that the diagnosis of STIC is not optimally reproducible based only on morphologic assessment. Therefore, a combination of morphology and immunohistochemistry is recommended for the definite diagnosis of precursor lesions. All 45 cases of SCOUT diagnosed on H and E were confirmed on immunohistochemistry. P53 signature was diagnosed in 2 cases classified as not suspicious for STIC on morphology. This shows that immunohistochemistry reflects the changes at the molecular level as these early changes can be missed on morphology. Moreover, reactive changes can be misleading and confirmation of findings by immunohistochemistry is required. According to new WHO guidelines for p53 mutant type, unequivocal cytoplasmic positivity has been added as a positive criteria.[18] However, none of the cases in our study showed p53 cytoplasmic positivity.

In the present study which included only non-neoplastic cases, we observed a high frequency of SCOUT cases (45%; 45 out of 100 cases) which is consistent with a study by Nishida et al.[20] It is difficult to compare the present study with other studies[11],[21],[22] which included non-neoplastic cases as control groups, and the sample size was relatively small in these studies. Thus, further work is necessary using a larger population of patients. We believe including a larger sample size will provide a better assessment. Moreover, the age difference between our cases and those used in other studies may also cause these inconsistencies.

In the present study, SCOUT, p53 signatures, and increased Ki 67 index were found even in normal-looking fallopian tubes or with benign pathologies. This advocates that processing fallopian tubes in detail with multiple sections from fimbria by SEE-FIM technique should be a routine practice to determine these lesions early and efficiently. To the best of our knowledge, there is only one such study in the literature[20] and none in India where the suspected precursor lesions in the fallopian tube have been correlated with the corresponding benign uterine and ovarian lesions.

Mittal et al.[17] studied the changes in the fallopian tube of sporadic cases of serous ovarian carcinoma of the ovary without confirming BRCA status. They suggested the fimbrial end of the fallopian tube as the site of invasive serous carcinoma and precursor lesions including SCOUTs and p53 signatures, tubal intraepithelial lesion in transition (TILT), and STIC making it the most common site of origin of pelvic serous carcinoma. They also observed that the assessment of distal fallopian tubes using the SEE-FIM protocol and application of Bcl-2, p53, and Ki-67 immunohistochemistry should be done for the detection of the precursor lesions in all cases of sporadic pelvic serous carcinoma.

The main drawback of the present study was the small number of cases in which IHC was done. Moreover, due to the ongoing COVID-19 pandemic, patients who showed precursor lesions could not be followed up for BRCA mutation testing. A study on a larger group of patients with cytogenetic testing and proper follow-up may further help in the correlation of premalignant changes in fallopian tubes of patients with non-neoplastic lesions.


   Conclusion Top


Sectioning and extensive examination of the fimbrial end of the fallopian tube (SEE-FIM) should be routinely done so as it provides the opportunity to detect these early malignant changes. Identification of these changes may help in proper follow-up of the patients to reduce the risk of morbidity and mortality. It may further help in evolving the strategies for early detection and management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Vatsala Misra
Department of Pathology, Moti Lal Nehru Medical College, Prayagraj, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_529_21

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