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

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.

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.

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.