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Invasive Lobular Carcinoma Metastases to the Female Genital Tract. A Review of Case Reports and Case Series

A peer-reviewed version of this preprint was published in:
Diagnostics 2025, 15(18), 2356. https://doi.org/10.3390/diagnostics15182356

Submitted:

18 August 2025

Posted:

20 August 2025

You are already at the latest version

Abstract
Invasive lobular carcinoma (ILC) is the most common special type of breast carcinoma, accounting for 5-15% of all breast carcinoma cases. It exhibits several unique features in morphology, clinical behavior, radiological features, molecular characteristics, and metastatic pattern. The latter differs from that of invasive breast carcinoma of no special type with ILC metastases to the peritoneum, gastrointestinal tract, and female genital tract being more frequent. We herewith review the demographic, clinicopathological, and therapeutic aspects of ILC metastases to the female genital tract and discuss separately the differential diagnosis and prognosis for each anatomic location of the female genital tract.
Keywords: 
breast carcinoma
;  
invasive lobular carcinoma
;  
female genital tract
;  
metastasis
;  
diagnosis
Subject: 
Medicine and Pharmacology  -   Pathology and Pathobiology

1. Introduction

Invasive lobular carcinoma (ILC) is the commonest special subtype of invasive breast carcinoma, accounting for 5-15% of breast carcinomas [1], thus being second in frequency only to invasive breast carcinoma of no special type (IBCNST) [2]. It was first described by Foote and Stewart in 1941 [2]. Its morphological, immunohistochemical, clinical, radiological, and molecular characteristics differ from those of IBCNST. It may remain undetectable or present as a palpable tumor [3]. In imaging studies, it may be detected with difficulty and tumor size may occasionally be underestimated, resulting in positive surgical margins [4]. The metastatic pattern also differs from that of IBC NST, with ILC metastases to the peritoneum, gastrointestinal tract, and female genital tract (FGT) being more frequent [5,6,7,8]. ILC lacks E-cadherin immunopositivity and displays an aberrant β-catenin immunostaining [9]. Its molecular profile is characterized by deleterious mutations in CDH1 paired with allelic loss of the remaining allele [4].
Histologically, ILC is characterized by small cells with a discohesive growth pattern forming single-cell files, and a minimal stromal response. Signet-ring-like cells may sometimes be found [4]. Apart from the classic variant, several histological variants have been described, including alveolar [10], tubulolobular [11], solid [12], trabecular [10], signet-ring [13], pleomorphic [14], and mixed [15]. Another three rare variants (ILC with extracellular mucin production, ILC with papillary features, and ILC with tubular elements) have recently been described [3].
ILC treatment usually includes hormonal therapy, since it is commonly positive for estrogen (ER) and progesterone receptors (PR) [3]. It displays a poor response to neoadjuvant chemotherapy when compared to IBCNST [3].
We herewith review case reports and case series describing ILC metastases to the FGT.

2. Materials and Methods

2.1. Search Strategy

A literature review was conducted using PubMed, Scopus, and Web of Science to identify all published cases in the English language of ILC metastasis to the FGT. The research utilized the following terms: “lobular carcinoma” AND “metastasis” AND “female genital tract OR ovary OR ovarian OR vulva OR vagina OR endometrium OR endometrial OR uterus OR uterine."We did not set any additional limitations while performing the search.

2.2. Inclusion and Exclusion Criteria

Two authors [MGS, KS] performed the literature review and collected data. Discrepancies were corrected in consensus. In cases where consensus could not be reached, the principal investigator (NK) resolved the discrepancy.
The timeline for the selected studies ranged from October 1993 to April 2024.
Both single case reports as well as case series (studies reporting at least two cases) on ILC metastasis to the FGT were included in the review. At the same time, we excluded narrative or systematic reviews, meta-analyses, opinion pieces, and other articles that did not present original research findings.
Papers available only as abstracts or those with text appearing too brief or noninformative were excluded from the present review.
The clinicopathological and treatment parameters analyzed included age (median and range), clinical presentation, primary tumor size, ER, PR, and HER-2 status both in primary focus and in the metastasis, tumor stage, location of metastatic involvement, metastases in organs or locations other than the FGT, surgical and neoadjuvant or adjuvant treatment, time interval to metastasis, median follow-up, outcome, and tumor grade (Tables 2–4).
In addition, cases with insufficient or too much aggregated data, as well as manuscripts in languages other than English, were excluded.
After applying inclusion and exclusion criteria, 54 manuscripts describing 61 cases of ILC with metastasis to the female genital tract [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69] remained for data extraction.

2.3. Statistical Analysis

As detailed patient characteristics were available in the studied case reports, it was feasible to perform statistical analysis. Specifically, the descriptive characteristics for the quantitative data that were expressed as median and Quartile 1 (Q1) to Quartile 3 (Q3), range and for completeness reasons via mean±standard deviation (SD), and for the qualitative data was reported the frequency of occurrence and the relevant percentage. It was also possible to evaluate overall survival (OS) via the Kaplan – Meier estimator and perform comparisons of OS with various characteristics via the log-rank method. The statistical analysis was performed using the R language for statistical analysis (version 4.4.0), and the significance level (p-value) was set to 0.05 when applicable tests were two-sided.The Materials and Methods should be described with sufficient details to allow others to replicate and build on the published results. Please note that the publication of your manuscript implicates that you must make all materials, data, computer code, and protocols associated with the publication available to readers. Please disclose at the submission stage any restrictions on the availability of materials or information. New methods and protocols should be described in detail while well-established methods can be briefly described and appropriately cited.

3. Results

3.1. Patients’ Characteristics

In total, 61 patients were reported in the studied case reports and case series. The mean patient age was 57.4±12.2 years (min: 32, max: 86). The detailed descriptive statistics for patient characteristics are depicted in Table 1.

3.2. Demographic and Clinicopathological Features

Metastasis of ILC to the female genital tract ILC metastasis to the FGT is uncommon. We were able to retrieve 54 manuscripts describing a total of 61 cases of ILC FGT secondaries. Primary tumor size was mentioned in 22/61 (36%) [17,18,21,22,23,25,28,32,34,36,39,40,41,43,50,53,58,59,63,65,66] cases. The mean tumor size was 36.5 mm (range 9–100 mm). The metastatic site was mentioned in all cases. Some of the patients had more than one FGT metastatic site. The most common metastatic site was the uterine corpus in 30/61 (49.2%) [20,24,27,28,30,35,36,38,39,40,41,43,44,45,46,47,49,50,51,53,54,55,56,59,61,62,64,65,66] patients, followed by the uterine cervix in 25/61 (41%) [21,22,24,27,28,30,31,32,34,35,39,44,46,50,53,54,58,59,62,65,66], and the ovary in 22/61 (36%) [28,29,30,35,36,38,42,44,48,51,53,54,57,63,65,66,67] patients. In 9/61 (14.7%) [16,20,26,27,52,60,68] cases, the metastatic site was an endometrial polyp; in 8/61 (13.1%) [17,23,27,33,37,38,44,45,52,59] a uterine leiomyoma, and in the vulva in 4/61 (6.5%) [18,25,37,42]. Less common metastatic sites were an ovarian granulosa cell tumor [19], the vagina [54], and an ovarian fibroma [69]. Metastases to sites other than the FGT were documented in 21/61 (34.4%) [18,20,21,23,36,37,38,40,41,42,43,44,45,46,49,57,59,62,63,64,66,67]. Metastatic spread to the bones was found in 12/21 (57.1%) [18,20,23,38,41,43,49,59,62,63,64,66] patients. Other metastatic sites were the pancreas [21], stomach [21,37,47,67], liver [36,38], pleura [37], peritoneum [37,42,43], lymph nodes [42,43,46], gallbladder [43], omentum [44], orbit [49], large bowel [57], and appendix [57].
Symptoms were mentioned in 60/61 (98.4%) [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69] cases. Bleeding from the genitalia was the commonest symptom in 24/60 (40%) [17,20,21,24,26,28,33,35,37,41,43,44,49,52,53,54,55,56,58,60,61,64,65,68] cases followed by abdominal pain in 6/60 (10%) [19,22,57,59,60,69] patients, a mass in 5/60 (8.3%) [18,23,25,51] cases, abdominal distention in 3/60 (5%) [44,63,69] cases, abdominal discomfort in 3/60 (%) [39,67] patients. Less common symptoms included abdominal fullness [29], loss of appetite [29], urinary incontinence [38], polyuria [39], abdominal bloating [42,57], abdominal compression [45], postcoital bleeding [46], vaginal fullness and discomfort [51], altered bowel habits [57], and right shoulder pain [66] in 1/60 (1.7%) of patients each. Finally, 14/60 (23.3%) [16,27,30,31,32,34,36,40,47,48,49,50,51,62] patients were asymptomatic. In 42 cases, the FGT metastasis was metachronous, while in 12 cases, it was concomitant. The interval to metastasis ranged from 2 to 360 months (mean 65.6 months). The detailed demographic and clinicopathological features of the cases are shown in Table 2.

3.3. Histological Findings

No information regarding the subtype of ILC was available, apart from one case of ILC with extracellular mucin production [69], which is a very rare subtype with around forty cases in the English literature [70,71].

3.4. Estrogen Receptors (ER) /Progesterone Receptors (PR) /HER-2 Status

Concerning hormonal and HER-2 status, 36/61 (59%) [18,20,21,23,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,50,54,55,56,58,59,63,65,66,68] cases reported ER and PR in the primary focus and 34/61 (55.7%) [18,19,20,21,23,26,27,28,29,32,35,37,39,40,41,42,44,45,46,47,48,50,52,56,57,58,59,62,63,64,66,68] in the metastatic setting. HER-2 status was reported in 24/61 (39.3%) [29,30,32,34,35,37,38,39,40,41,43,44,45,47,50,54,55,56,58,59,63,65,66,68] in the in the primary focus and 12/61 (19.7%) [28,29,32,35,46,47,52,58,62,64] in the metastatic location. ER, PR, and Her-2 status of the cases and the histological grade are shown in Table 3.

3.5. Treatment

Surgical treatment information was available in 51/61 (83.6%) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,52,54,55,56,57,58,59,61,62,63,64,65,66,67,68] cases. In 32/51 (62.7%) [17,20,21,22,23,25,26,27,28,29,30,31,35,39,40,42,44,47,49,54,55,56,57,58,61,62,65,66,67,68] cases, surgical treatment consisted of a modified radical mastectomy. Breast-conserving surgery was performed in 9/51 (17.6%) [18,32,34,36,41,45,46,48,53] cases, hysterectomy and bilateral salpingo-oophorectomy in 5/51 [23,36,39,59,63] (9.8%), breast biopsies in 3/51 (5.9%) [33,43,44]. Omentectomy was performed in 2/51 (3.9%) [36,63] cases. Endometrial and cervical biopsies were performed in 2/51 (3.9%) [34,49] cases, cervical biopsy in 1/51 (1.9%) [34], and partial vulvectomy in 1/51 (1.9%) [18] cases. Additionally, two manuscripts reported that surgical treatment was performed without any additional detail concerning the type of intervention [52,64]. In cases with metachronous FGT metastasis, second-line treatment was reported in 43/49 (87.7%) [16,19,20,21,22,23,25,27,28,29,30,31,32,33,35,37,38,40,41,42,44,45,46,47,48,49,52,53,54,55,56,57,58,60,61,62,64,65,66,68] cases. Surgical treatment consisted in hysterectomy and bilateral salpingo-oophorectomy in 22/43 (51.2%) [16,21,26,28,29,30,32,35,38,41,42,45,48,49,52,53,54,55,58,60,64,65,66,68] patients, bilateral oophorectomy in 2/43 (4.6%) [19,57], pancreatoduodenectomy in 1/43 (2.3%) [21], wide tumor excision in 1/43 (2.3%) [25], omentectomy in 4/43 (9.3%) [29,30,48,64], pelvic lymph node sampling in 1/43 (2.3%) [29], pelvic lymphadenectomy in 2/43 (4.6%) [30,32], excision of an endometrial polyps in 2/43 (4.6%) [33,37], appendectomy in 2/43 (4.6%) [42,57], endometrial biopsy in 1/43 (2.3%) [47], peritoneal biopsies in 2/43 (4.6%) [48,64], partial colectomy in 1/43 (2.3%) [52], anterior resection in 1/43 (2.3%) [57]. Biopsy of the metastatic lesion was performed in 5/43 (11.6%) cases [20,46,56,61,62].
Information regarding adjuvant treatment was provided in 50/61 (83.6%) [17,19,20,21,22,23,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,52,53,54,55,56,57,58,59,62,63,64,65,66,67,68] cases. Chemotherapy either in the adjuvant or neoadjuvant setting was offered in 43/50 (86%) [17,19,20,22,23,25,27,28,29,31,33,34,35,36,38,40,41,42,43,44,45,46,47,48,49,52,53,54,55,56,57,58,59,62,63,64,65,66,67,68] cases and radiotherapy in 27/50 (54%) [19,20,22,27,28,29,31,32,34,35,42,44,45,46,47,48,49,52,53,54,55,57,58,62,65,67,68] cases. In two cases, patients refused chemotherapy [30,50], and in another two, radiotherapy [30,66]. The most common regimen used consisted of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF regimen). In contrast, the second most common regimen consisted of adriamycin, cyclophosphamide (AC regimen), and paclitaxel administered in four [20,25,31,42] and three cases [54,58,63], respectively. Hormonal treatment was provided to 48/50 (96%) [17,19,20,21,22,23,25,26,27,28,29,30,31,32,34,35,36,37,38,39,40,41,42,43,44,45,46,47,49,52,53,54,55,56,57,58,59,62,63,64,65,66,67,68] patients. Among 43 cases with metachronous metastasis, 13 received additional chemotherapy [21,25,30,32,40,42,44,46,47,48,54,56,66,67], one received targeted therapy [65], two received additional radiotherapy [23,41], and 13 received additional hormonal treatment [19,21,23,32,35,41,42,45,52,58,64,65,68].

3.6. Outcome

Follow-up information was available in 40/61 (65.6%) [17,18,19,21,22,23,25,28,30,31,32,34,35,36,37,38,39,40,41,42,43,45,47,48,50,51,52,53,54,58,60,62,63,64,66,67,68] cases. Briefly, 16/40 (40%) [17,19,32,35,36,37,38,39,45,48,52,53,58,60,64,67,68] patients were alive without evidence of disease, 9/40 (22.5%) [18,23,25,30,34,41,42,47,51] were alive with disease, and 10/40 (25%) [21,28,31,40,43,51,54,66] died of disease in a period of time that ranges from 1 to 308 months. In 2/40 (5%) [22,50] cases, patients were lost to follow-up. Treatment and follow-up data are shown in Table 4.

3.5. Patient Survival

Patient survival time information was available for 31 patients. Of these patients, 10 were deceased due to their disease; the restricted mean survival time was 186±30.7 months.
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Figure 1. Kaplan Meier estimator for the patient overall survival. The shaded area corresponds to the 95% confidence interval.
Figure 1. Kaplan Meier estimator for the patient overall survival. The shaded area corresponds to the 95% confidence interval.
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Further analysis was based on the evaluation of the role of all recorded characteristics in patient survival. The results are depicted in Table 5. Notably, a negative ER on a secondary tumor was found to be linked to worst patient survival (HR: 0.13, 95% CI: 0.02-0.8, p=0.01); see Figure 2.

4. Discussion

Extragenital metastases to the FGT are relatively uncommon. Concernng specific locations of secondaries, One study reported that, among 149 metastatic neoplasms to the FGT from primary extragenital tumors reported in one study, the ovary (75.8%) and vagina (13.4%) were the most frequent locations, followed by the endometrium (4.7%) and cervix (3.4%) [72]. The majority of FGT metastases from breast cancer occurred in advanced cases during hormonal treatment or follow-up [53].
In the literature, the incidence of ILC metastasis to the FGT ranges from 2% to 5% in clinical series [5,73] and from 36% to 52% in autopsy series [74,75]. This difference is probably due to the fact that autopsy may discover clinically occult micrometastases. Adnexal involvement was reported in 21% of patients in a series [76].
The ovaries frequently receive metastases from primary malignant tumors both of genital and extragenital sites [77,78]. This can be explained by the fact that they provide an excellent environment for malignant cell implantation due to their rich vasculature and extensive lymphatic network, as well as due to a favorable pH and oxygen pressure in the ovarian stroma [31].
In a number of studies, the most common primary site varies between the gastrointestinal tract and the breast [79]. Ovarian metastasis from breast carcinoma constitutes 3–38% of all ovarian neoplasms, with a variable incidence depending on diagnostic methods, geographic distributions, and other variables [80,81,82]. Studies have shown that breast cancer patients have an incidence of ovarian metastases in 13–47% of cases, either in autopsy or surgical material [83,84,85].
ILC ovarian metastasis usually manifests as bilateral solid and cystic masses, the so-called Krukenberg tumor(s). Micrometastatic disease may remain undetected both on clinical examination and imaging studies [86].
Metastases in the ovaries may occasionally mimic clinical and histological characteristics of primary ovarian carcinomas [79]. The distinction of metastatic versus primary ovarian carcinoma is of paramount importance since their management differs [77,87,88,89]. To date, there are no clear guidelines concerning the management of carcinomas metastatic to the ovary. However, surgical resection may increase patient survival [79].
Some clinicopathologic factors of primary breast carcinoma have been identified to be related to increased risk for ovarian metastasis. ILC has an increased metastatic potential to the ovaries [5,74,75,90,91,92]. Also, young age and premenopausal status are factors related to increased risk [81,93,94,95,96]. Other factors related to the development of ovarian metastases are other co-existent metastatic sites [85], large primary tumor size [85,97], inflammatory breast cancer [85], positive lymph nodes [85,97], higher stage (III-IV)[97,98,99], and bilaterality [81].
The incidental finding of an ovarian mass in an asymptomatic patient may be the first sign of ovarian metastasis [77,98,99,100,101,102]. Usually, they are bilateral, small, and solid [81,82,87,103,104,105,106,107,108]. Other symptoms, including gastrointestinal symptoms, ascites, pelvic pain, and vaginal bleeding, can be observed in some patients [77,94]. However, none of these clinical manifestations is related to either breast metastasis or primary ovarian carcinoma [78,82,107]. In our review, only 3/20 (15%) [30,48,51] cases were asymptomatic.
Imaging examinations are also widely used for diagnosis, staging, and monitoring of curative effects.
The pathologic examination of a specimen includes gross, microscopic, and immunohistochemical testing. These are considered the ‘gold standard’ in the diagnosis of metastatic breast cancer to the ovaries [109].
On gross examination, bilateral involvement, small size, and a solid mass are clues related to metastatic breast carcinoma [81,82,87,98,103,105,106,108,109]. Metastases in the ovaries are usually located in the ovarian medulla and/or cortex [94]. On the other hand, primary tumors are typically located in the ovarian surface epithelium and superficial cortex [102].
Microscopically, ovarian metastases sometimes mimic histological features of primary ovarian carcinomas [103,110,111], which makes their distinction difficult. The characteristic pattern of ILC with small, discohesive cells forming single-cell files will usually allow to make the diagnosis on hematoxylin and eosin stains. In difficult cases, immunohistochemical analysis typically resolves any diagnostic problem. Immunostaining for GATA-3, GCDFP-15, and Mammaglobin is diagnostic for metastatic ILC, whereas PAX-8, WT-1 p53, and p16 are positive in primary ovarian carcinoma.
Concerning treatment options, most breast cancer patients have other non-FGT metastases at the time of ovarian metastasis. The treatment should be for systemic disease. The regimen should be tailored to the clinicopathological aspects of the metastatic site, the burden of disease and the eventual visceral crisis, the symptoms, and the performance status of the patient. Drug toxicity profile and patient preferences are of utmost importance [85,103].
The prognosis of patients with breast carcinoma ovarian metastases is poor since the median progression-free survival ranges from 9 to 30 months, the median overall survival is 16 to 38 months, and the 5-year survival rate is 6 to 26% [79].
Clinicopathologic factors that affect survival are age [103], time interval to ovarian metastasis [82], unilaterality [109], adenocarcinoma [112], and menstrual status [89].
Uterine metastases from extragenital cancers are much less common than ovarian metastases ones [52]. Metastases confined to the uterus, without ovarian involvement, are very rare and can occur through hematogenous spread [52]. The myometrium is the most commonly involved location within the corpus uteri that metastatic ILC involves, followed by the endometrium. The first manifestation of metastatic disease may be abnormal uterine bleeding [86].
ILC is, in most cases, ER-positive. Premenopausal patients regularly receive Tamoxifen as part of the adjuvant treatment, which, increases the risk for endometrioid carcinoma of the endometrium [86].
Differentiating metastatic ILC from a primary endometrial carcinoma can be difficult but is of huge importance since the treatment is different for these carcinomas.
Metastasis from breast carcinoma to the cervix uteri is very rare, with an estimated frequency of 0.8–1.7% [113]. This is possibly due to its small size, its reduced blood flow and distal circulation, and the presence of abundant fibrous tissue [114]. The true incidence of cervical metastasis from ILC remains unknown. Other distant metastases were found at the time of diagnosis of cervical metastasis in 67%–89% of the cases [115].
In our review, we found 22 cases of ILC metastatic to the cervix.
Differential diagnosis between a cervical primary and ILC cervical metastasis may occasionally prove difficult. Dedifferentiation of cervical adenocarcinoma and squamous cell carcinoma with acantholytic changes may result in the simulation of the morphology of ILC [116,117]. Again, the finding of the characteristic morphology of ILC, i.e., discohesive cells and the formation of single cell files within the cervical stroma, especially when the cervical epithelium is spared, should raise the suspicion of metastatic disease. Appropriate immunohistostaining with GATA3, mammaglobin, and GCDFP-15 will give the diagnostic solution in ambiguous cases.
Vaginal metastasis is second in frequency after ovarian involvement in the FGT. Treatment consists of surgical debulking chemotherapy and/or radiotherapy. For patients with vaginal metastasis from breast carcinoma, a very important prognostic feature is the finding of metastases in other sites [118]. A lot of times, when vaginal metastases occur, there are already metastases in other organs. Whenever this happens, the prognosis is poor [119].
Breast cancer metastasis to the vulva is very rare. In these cases, the differential diagnosis is done with primary breast carcinoma of the vulva [120]. The most important distinguishing feature is the previous history of breast cancer. Additionally, the histological similarity between the primary breast and the metastatic lesion, as well as the absence of an in situ element, will guide the pathologist in diagnosing a metastatic lesion [120].

5. Conclusions

In summary, we reviewed cases and case series of ILC metastasis to the FGT, describing the clinical, pathological, therapeutical, and follow-up data. We also discussed the current literature focusing on the differential diagnosis, treatment, and prognosis of ILC metastasis to the FGT.

Author Contributions

Conceptualization, N.I.K. and I.B.; methodology, G.B, R.C and M.Zi.; software, K.S., M.G.S. and A.Pou; validation, M.G.S, T.N. N.A. and A.Psy.; formal analysis, G.B., R.C. and M.Zi and ; investigation, I.S.P, D.G.; resources, K.S., T.N. and J.S.; data curation, A.P. , S.S. and M.Z.; writing—original draft preparation, N.I.K., A.Pou and J.S.; writing—review and editing, all authors; visualization, I.S.P and D.G..; supervision, N.A. A.Psy. and I.G.P.; project administration, S.S. I.B. and A.K.; funding acquisition, A.P., I.G.P. and M.Z.. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding. This study was partially supported by the Italian Ministry of Health - Ricerca Corrente Annual Program 2026.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 2. Kaplan Meier curves for overall survival in relation to ER status of the secondary tumor.
Figure 2. Kaplan Meier curves for overall survival in relation to ER status of the secondary tumor.
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Table 1. Descriptive characteristics of the reported cases in the studied case reports. ANED: Alive, no evidence of disease, AWD: Alive with the disease, DOD: died of disease, SD: Standard deviation.
Table 1. Descriptive characteristics of the reported cases in the studied case reports. ANED: Alive, no evidence of disease, AWD: Alive with the disease, DOD: died of disease, SD: Standard deviation.
Characteristic Measure
Number of cases 61
Age
Mean±SD 57.4±12.2
Median [Min, Max] 56.0 [32.0, 86.0]
Tumor Size (cm)
Mean±SD 3.65±2.11
Median [Min, Max] 3.65 [0.900, 10.0]
Missing 39 (63.9%)
Primary tumor ER status
Negative 2 (3.3%)
Positive 34 (55.7%)
Missing 25 (41.0%)
Primary tumor PR status
Negative 2 (3.3%)
Positive 34 (55.7%)
Missing 25 (41.0%)
HER-2/Cc-erbB-2 status
Negative 21 (34.4%)
Positive 3 (4.9%)
Missing 37 (60.7%)
Secondary tumor ER status
Negative 3 (4.9%)
Positive 31 (50.8%)
Missing 27 (44.3%)
Secondary tumor PR status
Negative 6 (9.8%)
Positive 24 (39.3%)
Missing 31 (50.8%)
HER-2 status
Negative 9 (14.8%)
Positive 3 (4.9%)
Missing 49 (80.3%)
Stage pT component
pT1 1 (1.6%)
pT1b 1 (1.6%)
pT1c 6 (9.8%)
pT2 15 (24.6%)
pT3 6 (9.8%)
pT4 1 (1.6%)
Missing 31 (50.8%)
Stage pN component
N0 8 (13.1%)
N1 10 (16.4%)
N2 5 (8.2%)
N3 9 (14.7%)
Missing 29 (47.5%)
Stage pM component
M0 22 (36.1%)
M1 6 (9.8%)
Missing 33 (54.1%)
Radiotherapy
No 24 (39.3%)
Yes 27 (44.3%)
Missing 10 (16.4%)
Interval to Met (in months)
Mean±SD 65.6±70.0
Median [Min, Max] 48.0 [2.00, 360]
Missing 20 (32.8%)
Last, follow up (in months)
Mean±SD 71.1±67.6
Median [Min, Max] 54.0 [1.00, 308]
Missing 30 (49.2%)
Last, follow up status
ANED 19 (31.1%)
AWD 9 (14.8%)
DOD 10 (16.4%)
Missing 23 (37.7%)
Tumor grade
Grade II 10 (16.4%)
Grade III 2 (3.3%)
Missing 49 (80.3%)
Table 2. Demographic and clinicopathological features of the reported cases.
Table 2. Demographic and clinicopathological features of the reported cases.
Authors Year Age Clinical Presentation Tumor Size (cm) Stage Site of metastasis FGT[16–69 Other metastatic sites
Aranda et al. 1993 76 Asymptomatic NM pTx, N0 Endometrial polyps -
Sugiyama et al. 1995 51 Hypermenorrhea 4 pT2, N1, M1 Uterine leiomyoma -
Menzin et al. 1998 53 Vulvar tumor 2,5 pT2, N0, M1 Vulva Vertebrae and pelvic bones.
Arnould et al. 2002 59 Abdominal and pelvic pain - - Ovarian granulosa cell tumor -
Alvarez et al. 2003 69 Metrorrhagia - pT2, N1, M0 Endometrial polyps and uterus Skull and spine.
Ogino et al. 2003 49 Abnormal genital bleeding 3.5 pT2, N0, M0 Cervix Pancreas, stomach
Rau et al. 2003 55 Abdominal pain 5 pT4, N1, M0 Cervix -
Blecharz et al. 2004 46 Enlarged uterus 1 pT1c, N2 Uterine leiomyoma Bone
Famoriyo et al. 2004 78 Postmenstrual bleeding - NM Uterus and cervix -
Sheen-Chen et al. 2004 32 Vulvar tumor 3 pT2, N0, M0 Vulva -
Al-brachim et al. 2005 53 Vaginal bleeding NM pTxN1 Endometrial polyps -
Lee et al. 2005 76 Asymptomatic NM NM Uterine leiomyoma, myometrium, endometrial polyps, cervical stroma and
soft tissue adjacent to the uterus and the cervix		 -
Scopa et al. 2005 50 Vaginal bleeding 6 pT3N3 Endometrium, endocervix, ovaries, and fallopian tubes. -
Scopa et al. 2005 81 Vaginal bleeding 1,6 pT1c, N3 Endometrium -
Chen et al. 2006 47 Poor appetite and abdominal fullness pT3, N0, M0 Ovary -
Erkanli et al. 2006 63 Asymptomatic NM pT2, N3, M0 Endometrium, cervix, and ovaries. -
Perisic et al. 2007 65 Asymptomatic NM pT2, N1, M0 Cervix -
Manci et al. 2008 41 Asymptomatic 1 pT1c, N0, M0 Cervix -
Manipadan et al. 2008 70 Vaginal bleeding NM NM Endometrial polyps -
Bogliolo et al. 2009 78 Asymptomatic 0,9 pT1b, N2, M1 Cervix -
Ustaalioglu et al. 2009 56 Vaginal bleeding NM pT2, N2, M0 Endometrium, myometrium, cervix, left uterine tube and left ovary. -
Engelstaedter et al. 2011 64 Asymptomatic 4 pT3, N3, M1 uterus, adnexa Liver
Hooker et al. 2011 83 Postmenopausal uterine bleeding NM NM Endometrial polyps, vulva Pleura, peritoneum, stomach
Isci et al. 2011 48 Increased abdominal girth urinary incontinence NM NM Both the ovaries, tubes, abdominal washing fluid, myometrium, and the huge leiomyoma Liver, bone
Horikawa et al. 2012 52 abdominal discomfort, polyuria. 5 pT2, N3, M1 Cervix, endometrium -
Komeda et al. 2012 59 Asymptomatic 3,8 pT3, N2, M0 Uterus multiple metastases
Vicioso et al. 2013 67 Metrorrhagia 3,2 pT2, N2, M0 Uterus Left femur, calvarial skull, axial skeleton, and rib cage.
Alligood-Percoco et al. 2015 36 Abdominal bloating NM NM Ovaries / vulva Peritoneum, lymph nodes
Bezpalko et al. 2015 47 Vaginal bleeding 1,8 pT1c, Nx, M1 Endometrium gallbladder, bone marrow, lymph nodes, and peritoneum.
Lokadasan et al. 2015 49 Menorrhagia NM NM Endometrium, myometrium, fibroid, cervix, bilateral ovaries. -
Lokadasan et al. 2015 49 Abdominal distention, pain NM pT3, N3, M0 Cervix, bilateral adnexa Omentum
Toyoshima et al. 2015 62 Abdominal compression. NM pT2, N1, M0 Uterine leiomyomata, myometrium -
Waks et al. 2015 53 Postcoital bleeding NM pT2, N1, M0 Cervix, corpus uteri Pelvic and para-aortic lymph nodes
Lai et al. 2016 54 Asymptomatic NM pT3, N3, M0 Endometrium Stomach
Makris et al. 2016 45 Asymptomatic NM pT2, N1, M0 Ovary -
Martinez et al. 2016 40 Vaginal bleeding NM NM Endometrium Orbit, bone
Martinez et al. 2016 48 Asymptomatic NM NM Endometrium, myometrium -
Akhtar et al. 2017 62 Asymptomatic 2,9 NM Endometrium, cervix -
Bennett et al. 2017 53 Asymptomatic NM Bilateral ovaries -
Bennett et al. 2017 64 Vaginal fullness and discomfort NM Bilateral ovaries, uterus, fallopian tubes -
Bennett et al. 2017 54 Adnexal mass NM - -
Bennett et al. 2017 41 Adnexal mass NM Bilateral ovaries, fallopian tube -
Bennett et al. 2017 48 NM NM Left ovary, uterine serosa -
Razia et al. 2017 58 Abnormal uterine bleeding NM NM Endometrial polyps, uterine leiomyoma, cervix -
Seo et al. 2017 46 Vaginal bleeding 4 pT1, N0, M0 Uterine corpus, endocervix, left ovary -
Aytekin et al. 2018 38 Vaginal bleeding NM pT2, N3, M0 Uterus, bilateral ovaries, vaginal cuff, cervix -
Briki et al. 2018 50 Postmenopausal uterine bleeding NM pT2, N1, M0 Endometrium -
Franko-Marquez et al. 2019 86 Abnormal uterine bleeding. NM NM Endometrium -
Kachi et al. 2019 58 Altered bowel habits, abdominal pain, bloating. NM NM Bilateral ovaries large bowel, appendix
Fontinele et al. 2019 57 Abnormal uterine bleeding 10 ypT0, N0, M0 Cervix -
Abdallah et al. 2020 59 Lower abdominal pain 5 NM Endometrium, myometrium, leiomyoma, cervix Scapula
Arif et al. 2020 55 Vaginal bleeding, lower abdominal pain. NM NM Endometrial polyp -
Gomez et al. 2020 69 Post menopausal bleeding NM NM Endometrium -
Yuan et al. 2020 64 Asymptomatic NM NM Endometrium, cervix Bones
Akizawa et al. 2021 49 Abdominal distention 5 NM Ovary Bones
Awazu et al. 2021 66 Abnormal genital bleeding NM NM Endometrium Bones
Lim et al. 2021 57 Vaginal bleeding 5,6 NM Uterus, cervix, bilateral ovaries, fallopian tubes -
Kong et al. 2022 64 Right shoulder pain 1,5 pT1c, N3 M0 Uterus, cervix, bilateral ovaries, fallopian tubes Bones
Li et al. 2022 61 stomach discomfort NM pT1c, N1, M0 Bilateral ovaries, peritoneum Stomach
Benlghazi et al. 2024 56 abnormal uterine bleeding NM NM Endometrial polyps -
Faur et al. 2024 82 abdominal distension and pain NM NM Ovarian fibroma -
Abbreviations: FGT: female genital tract; HBSO: hysterectomy and bilateral salpingo-oophorectomy; Met: metastasis; Mo: months; N: No; Neoadj.: neoadjuvant; NM: not mentioned; OM: omentectomy; RT: radiotherapy; Y: Yes.
Table 3. ER, PR, and Her-2 status and histological grade of the reported cases.
Table 3. ER, PR, and Her-2 status and histological grade of the reported cases.
Authors Primary tumor Metastatic tumor Tumor grade
ER status PR status HER-2 status ER status PR status HER-2 status
Aranda et al. NM NM NM NM NM NM NM
Sugiyama et al. NM NM NM NM NM NM NM
Menzin et al. + + NM + + NM NM
Arnould et al. NM NM NM + + NM NM
Alvarez et al. + + NM + + NM NM
Ogino et al. - + NM - + NM NM
Rau et al. NM NM NM NM NM NM NM
Blecharz et al. + + NM + - NM NM
Famoriyo et al. NM NM NM NM NM NM NM
Sheen-Chen et al. NM NM NM NM NM NM NM
Al-brachim et al. NM NM NM + + NM NM
Lee et al. NM NM NM + + NM Grade II
Scopa et al. - + NM - + + NM
Scopa et al. NM NM NM + + NM NM
Chen et al. + + - + + - Grade III
Erkanli et al. + + - NM NM NM -
Perisic et al. + + NM NM NM NM Grade II
Manci et al. + + - + + + NM
Manipadan et al. Not done Not done Not done NM NM NM NM
Bogliolo et al. + + - NM NM NM Grade II
Ustaalioglu et al. + + - + + - NM
Engelstaedter et al. + + Grade II
Hooker et al. + + - + - NM NM
Isci et al. + - - NM NM NM NM
Horikawa et al. + + - + NM NM NM
Komeda et al. + + - - - NM NM
Vicioso et al. + + - + - Grade II
Alligood-Percoco et al. + + NM + NM NM NM
Bezpalko et al. + + - NM NM NM Grade II
Lokadasan et al. + + - NM NM NM NM
Lokadasan et al. + + NM + + NM Grade II
Toyoshima et al. + + + + - NM NM
Waks et al. + + + + - NM
Lai et al. + + - + + - Grade II
Makris et al. + + NM + + NM NM
Martinez et al. NM NM NM NM NM NM
Martinez et al. NM NM NM NM NM NM NM
Akhtar et al. + + - + + NM NM
Bennett et al. NM NM NM NM NM NM NM
Bennett et al. NM NM NM NM NM NM NM
Bennett et al. NM NM NM NM NM NM NM
Bennett et al. NM NM NM NM NM NM NM
Bennett et al. NM NM NM NM NM NM NM
Razia et al. NM NM NM + + + NM
Seo et al. + + NM + + NM NM
Aytekin et al. + + - NM NM NM NM
Briki et al. + + - NM NM NM NM
Franko-Marquez et al. + + + + NM NM NM
Kachi et al. NM NM NM + + NM NM
Silva Fontinele et al. + + - + + - Grade II
Abdallah et al. + + - + + NM NM
Arif et al. NM NM NM NM NM NM NM
Gomez et al. NM NM NM NM NM NM Grade II
Yuan et al. NM NM NM + + - NM
Akizawa et al. + + - + NM NM NM
Awazu et al. NM NM NM + + - NM
Lim et al. + + + NM NM NM NM
Kong et al. + - - + + - NM
Li et al. NM NM NM NM NM NM NM
Benlghazi et al. + + - + - - Grade III
Faur et al. NM NM NM NM NM NM NM
Abbreviations: ER: estrogen receptors; NM: not mentioned; PR: progesterone receptors.
Table 4. Treatment and follow-up features of the reported cases.
Table 4. Treatment and follow-up features of the reported cases.
Authors Surgery CHT RT Hormonal therapy Interval to Met (Mo) Second-Line
Therapy 		Outcome
Aranda et al. NM NM NM NM 36 HBSO NM
Sugiyama et al. MRM 5-FU, mitomycin
C, and pirarubicin		 N Tamoxifen Concomitant - 48 ANED
Menzin et al. Quadrantectomy, ALND, and partial vulvectomy. NM N Tamoxifen Concomitant - 18 AWD
Arnould et al. NM CHT Y Tamoxifen 48 Bilateral oophorectomy, letrozole 60 ANED
Alvarez et al. MRM 6 x CMF Y Tamoxifen 48 Biopsy NM
Ogino et al. MRM No N Tamoxifen 128 Pancreatoduodenectomy, HBSO, ADM-TXL CHT and anastrozole. 136 DOD
Rau et al. MRM 6x CHT Y Tamoxifen 48 Patient refused Lost to follow-up
Blecharz et al. MRM, HBSO 6 x ADR, CTX, 5-FU. N Tamoxifen Concomitant Aromatase inhibitors and biphosphonates and palliative radiotherapy of the thoracic and lumbar vertebrae. 59 AWD
Famoriyo et al. NM NM NM Tamoxifen NM NM NM
Sheen-Chen et al. MRM 6 x CMF N Tamoxifen 40 Wide excision of the tumor, cyclophosphamide, epirubicin, and 5-FU. 40 AWD
Al-brachim et al. MRM No N Tamoxifen 48 NM NM
Lee et al. MRM CHT Y Tamoxifen 18 HBSO
Scopa et al. MRM 4 x epirubicin Y Tamoxifen and LH-RH agonist 36 HBSO 54 DOD
Scopa et al. MRM 4 x cyclophosphamide and adriamycin. N Tamoxifen and LH-RH agonist 24 HBSO 30 DOD
Chen et al. MRM 6 x CHT Y Tamoxifen 56 HBSO, partial OM, and pelvic lymph
node sampling		 NM
Erkanli et al. MRM Patient refused CHT Patient refused RT - 8 HBSO, omentectomy, and pelvic lymphadenectomy. Cyclophosphamide, epirubicin, and 5-FU 8 AWD
Perisic et al. MRM 6 x CMF Y Tamoxifen 52 The patient refused CHT 72 DOD
Manci et al. quadrentectomy No Y Tamoxifen 130 HBSO, pelvic lymphadenectomy, CHT, Femara. 150 ANED
Manipadan et al. Biopsy 6 x docetaxel and zoledronic acid N No 2 Polypectomy NM
Bogliolo et al. Quadrantectomy, SLNB, endometrial and cervical biopsy. 6 x 5-FU, epirubicin, cyclophosphamide, and docetaxel Y Letrozole Concomitant - 30 AWD
Ustaalioglu et al. MRM 4 x doxorubicine, cyclophosphamide / 4 x docetaxel Y Anastrozole 36 HBSO, exemestane 45 ANED
Engelstaedter et al. HBSO, OM, lumpectomy, ALND. Navelbine. N Tamoxifen Concomitant - 65 ANED
Hooker et al. No No N Letrozole, Tamoxifen, Fulvestrant 60 Polypectomy 72 ANED
Isci et al. No CHT N Letrozole and ibandronate. 15 HBSO, CHT 27 ANED
Horikawa et al. HBSO, MRM No N Anastrozole, S-1 Concomitant - 84 ANED
Komeda et al. MRM 4 x doxorubicin, cyclophosphamide/ 6 x paclitaxel N Letrozole 15 The patient refused HBSO, doxorubicin, and cyclophosphamide. 28 DOD
Vicioso et al. Quadrantectomy, ALND. 6 x taxotere, adriamycin, and cyclophosphamide. N Tamoxifen 72 HBSO, letrozole, RT. 163 AWD
Alligood-Percoco et al. MRM 4 x doxorubicin, 8 x CMF. Y Tamoxifen 116 / 240 HBSO, appendectomy, debulking, Taxotere, and Xeloda / Arimidex 240 AWD
Bezpalko et al. Biopsy CHT N Hormonal therapy Concomitant - 1 DOD
Lokadasan et al. Biopsy 5-FU, epirubicin, cyclophosphamide N Hormonal therapy Concomitant - NM
Lokadasan et al. MRM 3 x 5-FU, adriamycin, cyclophosphamide / 3 x docetaxel Y Tamoxifen 48 Carboplatin, gemcitabine. NM
Toyoshima et al. Breast conserving surgery 6 x 5-FU, epirubicin, cyclophosphamide. Y Anastrozole 84 HBSO, exemestane ANED
Waks et al. Breast conserving surgery, ALND methotrexate, cyclophosphamide, 5-FU Y Tamoxifen 180 Biopsy, CHT NM
Lai et al. MRM CHT Y Tamoxifen / anastrozole / exemestane 84 endometrial biopsy, CHT AWD
Makris et al. Lumpectomy, ALND 6 x docetaxel, doxorubicin, cyclophosphamide Y No 24 HBSO, omentectomy, peritoneal biopsies, 6 x carboplatin, paclitaxel 18 ANED
Martinez et al. MRM, endometrial biopsy CHT N Tamoxifen Concomitant -
Martinez et al. MRM CHT Y Tamoxifen 18 HBSO NM
Akhtar et al. Biopsy Patient refused CHT N N Concomitant - Lost to follow-up
Bennett et al. NM NM NM NM NM ΝΜ 49 DOD
Bennett et al. NM NM NM NM NM ΝΜ 84 AWD
Bennett et al. NM NM NM NM NM ΝΜ 9 DOD
Bennett et al. NM NM NM NM NM ΝΜ NM
Bennett et al. NM NM NM NM NM ΝΜ NM
Razia et al. Surgery doxifluridine, cyclophosphamide, docetaxel Y Goserelin acetate, Tamoxifen, toremifene citrate 108 HBSO, a partial colectomy, an aromatase inhibitor ANED
Seo et al. Breast conserving surgery, ALND 2 x neoadj. Cyclophosphamide, adriamycin 4 x adj.
cyclophosphamide, adriamycin		 Y Goserelin, TamoxifenTamoxifenTamoxifen 24 HBSO ANED
Aytekin et al. MRM 4 x adriamycin, cyclophosphamide / 12 x paclitaxel Y tamoxifen and luteinizing hormone-releasing hormone analog 10 HBSO, CHT 16 DOD
Briki et al. MRM CHT Y Tamoxifen 24 HBSO NM
Franko-Marquez et al. MRM CHT N NM 360 Biopsy, CHT NM
Kachi et al. MRM 9 x CHT Y Tamoxifen 60 Anterior resection, BO, appendectomy NM
Silva Fontinele et al. MRM Neoadj. 4x doxorubicin, cyclophosphamide/ 12 x paclitaxel Y Tamoxifen 39 HBSO, anastrozole 66 ANED
Abdallah et al. HBSO 6 x cycolphosphamide, epirubicin 5-FU N Hormonal therapy Concomitant - NM
Arif et al. NM NM N Tamoxifen 84 HBSO 96 ANED
Gomez et al. MRM NM NM Tamoxifen 60 Biopsy NM
Yuan et al. MRM CHT Y Hormonal therapy 132 Biopsy ANED
Akizawa et al. HBSO, OM Palbociclib, denosumab N Letrozole Concomitant - ANED
Awazu et al. Surgery CHT NM aromatase inhibitors/tamoxifen 276 HBSO, partial OM, a biopsy of the peritoneum, fulvestrant, toremifene citrate, and tegafur 308 ANED
Lim et al. MRM 4 x cyclophosphamide, adriamycin, 5-FU/ 4 x taxotere Y Tamoxifen 30 HBSO, fulvestrant, ribociclib NM
Kong et al. MRM 4 x epirubicin, cyclophosphamide / 4 x paclitaxel patient refused RT Letrozole 29 Radiotherapy, zoledronate / HBSO, 6 x paclitaxel, capecitabine, radiotherapy, zoledronate / 2 x gemcitabine, cisplatin 49 DOD
Li et al. MRM 6 x docetaxel, doxorubicin, cyclophosphamide Y Anastrozole 36 hyperthermic perfusion chemotherapy (paclitaxel) ANED
Benlghazi et al. MRM 3 x Epirubicine, cyclophosphamide, 5FU / 3 x Docetaxel Y Tamoxifen 60 HBSO, hormonal treatment 78 ANED
Faur et al. NM NM NM NM NM NM NM
Abbreviations: Adj.: Adjuvant; Adriamycin-Cyclophosphamide (AC), ADR: Adriamycin; ADM-TXL: doxorubicin (ADM), paclitaxel (TXL); ANED: Alive no evidence of disease; AWD: Alive with disease; BO: Bilateral oophorectomy; Cyclophosphamide-adriamycin-5-Fluorouracil (CAF); Cyclophosphamide- Methotrexate- 5 Fluorouracil (CMF); CHT: chemotherapy (not specified); CTX: Cyclophosphamide; Docetaxel-doxorubicin- cyclophosphamide (TAC); DOD: Died of disease; Epirubicin-Cyclophosphamide (EC); Epirubicin-cyclophosphamide-5FU (FEC); FGT: female genital tract; 5-FU: 5 Fluorouracil; HBSO: hysterectomy and bilateral salpingo-oophorectomy; Met: metastasis; Mo: months; N: No; Neoadj.: neoadjuvant; NM: not mentioned; OM: omentectomy; RT: radiotherapy; Y: Yes.
Table 5. Role of the study variables in patient overall survival. HR: Hazard Ratio, CI: Confidence interval, N: Number of valid cases.
Table 5. Role of the study variables in patient overall survival. HR: Hazard Ratio, CI: Confidence interval, N: Number of valid cases.
Characteristic HR and 95% CI p-value N
Primary tumor ER status 0.41 (0.08-2.18) 0.283 22
Primary tumor PR status 0.27 (0.03-2.6) 0.223 22
Secondary tumor ER status 0.13 (0.02-0.8) 0.01 18
Secondary tumor PR status 2.04 (0.23-18.39) 0.518 16
HER-2 status 1.73 (0.11-27.89) 0.695 7
Stage pN 4.91 (0.2-118.15) 0.31 20
Stage pM 0.64 (0.07-5.76) 0.686 18
Other metastasis 0.82 (0.22-3.03) 0.76 31
RT 0.72 (0.17-3.02) 0.65 27
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