Case Report and Literature Review: Unusual Presentation of Genitourinary & Gastrointestinal Metastases from Invasive Lobular Carcinoma of the Breast

Unlike invasive ductal carcinoma, lobular carcinoma exhibits a distinct metastatic pattern. It is likely to spread to gynecological organs, peritoneum, retroperitoneum, brain and gastrointestinal tract in comparison to ductal carcinoma, which spreads to liver, lung, and brain tissues. The diagnosis becomes more unlikely on the rare occasion when it represents the first manifestation of breast cancer. It is important to differentiate the metastasis from primary carcinoma of genital or GI tract as the management substantially differs. In this report; we present a 47 years-old female patient who presented with gynecological organs & gastrointestinal tract involvement as initial presentation and literature review done for these unusual sites of metastasis. rectal mass. heterogeneous


Introduction
Invasive lobular carcinoma (ILC) is the second most common type of invasive carcinoma of the breast after invasive ductal carcinoma (IDC). Although ILC accounts for 5% to 15% of newly diagnosed breast cancers, its incidence is increasing while invasive ductal carcinoma has not changed in the last two decades [1] . Sixty percent of patients with invasive lobular carcinoma will already have metastatic disease at time of diagnosis while 30-80% of patients will develop metastatic disease following surgery and/or systemic therapy or radiotherapy [2] . The pattern of metastatic spread differs significantly between ILC and ductal carcinoma where lobular carcinoma tends to exhibit unusual sites of metastasis. It is likely to spread to gynecological organs, peritoneum, retroperitoneum, brain and gastrointestinal tract (GI) in comparison to ductal carcinoma, which spreads to the liver, lung, and brain tissues [1] .
We present a case report of a 47-year-old woman who was referred to our breast surgical clinic with a concurrent cervical, endometrium and rectal cancer that on further evaluation was diagnosed as metastatic invasive lobular carcinoma of the breast.

Case report
A 47-year-old pre-menopausal Omani female un-known to have any medial problem presented to the department of gynecology with abnormal uterine bleeding of two months duration. She was asymptomatic for anemia and she didn't receive any blood transfusion.
On physical examination, she was found to be pale but her vital signs were normal. Pelvic examination revealed hard hypertrophied cervix which was flushed into the vagina. In addition there was a vulvar mass. There was no history of rectal bleeding or gastrointestinal symptoms. Laboratory values revealed low hemoglobin of 8.5 g/dL, with normal platelet and white blood cell counts. Chemistry panel was normal. Pelvic ultrasound revealed a 30 mm dilated endometrial cavity by blood clots. Pap smear was done and it showed poor cellularity. She had an endometrial biopsy that revealed scanty atypical cells suggestive of neoplastic epithelial lesion.
Subsequently Magnetic resonance imaging (MRI) of pelvis was performed. It showed focal eccentric nodular wall thickening involving the rectum close to the rectosigmoid junction with stranding in mesorectum and post contrast enhancement, suggestive of neoplastic rectal mass. Diffuse heterogeneous bone marrow signals with multiple small T2W hypointense lesions highly suspicious for metastases. No endometrial cervical mass however there is loss of zonal anatomy of the cervix with diffuse T2 hypointensity that is continuous with the uterine junctional zone. Minimal free fluid in the Pouch of Douglas along with multifocal T2 hypointense and enhancing nodular thickening along the surface of left ovary, peritoneal reflections and on the dome of the urinary bladder with a differential diagnosis of either endometriosis or peritoneal carcinomatosis ( Figure 1).

Figure 1: MRI pelvis T2 sagittal view showing diffuse T2 hypo intensity of the cervical stroma with loss of zonal anatomy (thick arrow)
. Diffuse thickening of the junctional zone. There is a circumferential mass seen in the rectum (arrow). Mild ascites with T2 hypo intense nodular thickening of the peritoneal reflection, dome of the urinary bladder (star). Heterogeneous signal of the bone marrow. Gartner duct cyst is seen * On subsequent per rectal examination, the rectal mass was felt. Then she underwent repeated hysteroscopy with endometrial sampling and cervical punch biopsy. She had diagnostic colonoscopy done by gastroenterologist demonstrating fungating, friable, circumferential, non-negotiable mass started distally at 4 cm from the anal verge. Multiple biopsies were taken and the pathology report from all biopsy site including rectum, endometrium, vulva and cervix revealed poorly differentiated neoplasm consistent with metastatic breast lobular carcinoma, ER: positive, PR: positive. (Figure 2, 3)  Following this, she was evaluated by breast surgeon and upon further questioning; she reported to have one-year history of bilateral breast hardness with changing in shape and size. She had never brought it to anyone's attention. Reproductive history consisted of menarche at age of 13 years.
She had two children with first live birth at age of 34 years. No history of taken combined oral contraceptive bills & no family history of breast or ovarian cancer. She has never had screening mammogram. Breast examination was performed and revealed ( Figure 4, 5) asymmetrical breast with left side smaller in size and distorted compared to right breast. The left breast was occupied by totally by big hard fixed immobile mass with skin nodules. The right breast also was occupied by big hard fixed mass but it was mobile and associated with skin thickening but no skin nodules. She had bilateral fixed axillary lymph nodes and left supraclavicular lymph node.    Further investigations with staging CT chest, abdomen and pelvis showed in addition to the known rectal and uterine cervical mass, subcutaneous soft tissue deposit, right and possibly left orbital metastatic involvement. Multiple bilateral cervical lymph nodes. Moderate bilateral pleural effusions. Mass lesion is seen infiltrating the left kidney and the tail of pancreas. Nodular appearance of adrenal glands. Mild to moderate bilateral hydronephrosis. There are extensive patchy mixed lytic and sclerotic bone lesions. Bone scan showed widespread, diffuse and extensive metastatic deposits involving almost the entire axial skeleton including the proximal upper and lower limbs sparing the skull. (Figure 9, 10, 11). MRI brain performed showed significant infiltration of the bilateral orbital muscles noted along with suggestion of heterogenous lesion noted along right lateral globe along with compression of the intracranial part of bilateral optic nerves. Bony infiltration of the bones of vault of skull and skull base. No definite brain metastasis.

Discussion
Invasive lobular carcinoma accounts for 5% to 15% of newly diagnosed breast cancers. Unlike IDC, ILC exhibits a distinct metastatic pattern. It preferentially occurs in the bones, gynecological organs, peritoneum, retroperitoneum, and GI tract in comparison to ductal carcinoma, which spreads to liver, lung, and brain tissues [1] . Our patient presented with metastasis to bones, genitourinary system and GI system. This pattern of metastasis is supported by the prospective study, which compared the pattern of metastasis between ILC vs. IDC. ILC had more frequent metastases to the bone (56.8 vs. 37.7%, p = 0.001), ovarian (5.7 vs. 2.1%, p = 0.042), and gastrointestinal (GI) tract (5.7 vs. 0.3%, p < 0.001) and less to organs such as lung (5.7 vs. 24.2%, p < 0.001) and liver (4.6 vs. 11.4%, p = 0.049) [3] . In another study which followed the patient diagnosed with breast cancer for 24 years, it was found that ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (P < .01). Same study showed that patients with ILC were older compared to IDC, more frequently with ER-positive, and less vascular invasion [4] . Compared to our case, the patient was young, ER positive, and had no vascular invasion. The knowledge regarding the unusual metastatic pattern of lobular carcinoma is essential to differentiate it from second primary and then plan appropriate treatment. Metastasis in the female genital tract from an extragenital primary tumor is uncommon. Mazur et al in 1984 analyzed 325 cases of metastasis to female genital tract [5] . The majority of the extragenital primaries metastasizing to gynecological organs were adenocarcinoma from gastrointestinal tract. They originated less frequently from the breast and other organs. In literature review, lobular histotype seems to metastasize to the genital tract more frequently than ductal tumors [6] . The incidence of ILC metastasizing to the genital tract is 36%-52% in autopsy series and 2% -5% in clinical series. Kumar et al published a review in 1988 with 63 cases of metastatic cancers to uterine corpus from extragenital neoplasms [7] . The most common primary metastasizing to uterus in this series was breast cancer (47.3%). Interestingly, the myometrium was found to be more involved than the endometrium although most of the endometrial curettage showed metastatic tumor cells. Le Bouedec et al in 1993 described 12 patients with metastatic breast cancer to the uterus out of which ten had ILC [8] . Abnormal vaginal bleeding may be a sign of neoplastic uterine involvement although this is also infrequent [9] . This may include abnormal duration of periods, bleeding between periods, and postmenopausal bleeding [10] .
Breast cancer metastasizing to cervix is very rare. Of 325 metastatic female genital neoplasms, Mazur et al found only 3.7% involved the cervix, and none of these represented primary breast carcinomas [5] . Pérez-Montiel D et al reports the most common tumor metastasizing to cervix are gastrointestinal tract and ovarian cancers [11] . Only a few cases have been reported so far. Considering the rarity the actual incidence of cervix metastasis is unknown. In the literature most of the cases of breast cancer with genital tract metastasis occurred in advanced breast cancer while on tamoxifen treatment or during follow-up. There are only a few cases where genital tract involvement as initial presentation was reported [12] . This highlights the rarity of presentation in our case. The patient underwent full investigations for vaginal bleeding and the breast cancer was diagnosed later.
The Breast cancer is the second most common cancer to metastasize to the GI tract, following malignant melanoma. Although GI metastasis from invasive breast cancer is rare (< 1% in clinical practice), the incidence might be underestimated and is likely to increase [13,14] . Autopsy series report a rate of GI tract metastasis up to 15% [14] . It rarely metastasizes to the colon or rectum, more commonly metastasizing to the stomach or small bowel. GI metastasis is usually associated with extensive systemic spread [14] .
In the big series presented by Borst et al. invasive lobular carcinoma was more likely to give metastases to GI tract than invasive ductal carcinoma, with the incidence of 4.5% and 0.2%, respectively [15] . Sites of metastasis can vary from the oropharynx to the anus. Anorectal involvement is very rare [16,17] . Rectal metastasis from ILC usually occurs 5-7 years after diagnosis of the primary tumor, but there have been cases reported with synchronously rectal metastasis, as well as metastasis up to 20-30 years after diagnosis of primary ILC [18,19] . There were very few reports about coexistence of breast cancer metastases and adenocarcinoma in GI tract. In fact, only Jafferbhoy et al. described the case of synchronous GIST, colon and breast adenocarcinoma with double colonic polyp metastases [9] . It was mentioned in literature that colonic involvement in metastasis ILC can be as high as 12 % [20] . A fifteen years' study analyzed pathological diagnosis of breast cancer metastatic to the gastrointestinal tract or peritoneum has found that Infiltrating lobular carcinoma represented 34 (64%) of the 53 gastrointestinal metastases, with 45 % involving the colon and the rectum, followed by the stomach with 28% [21] However, a larger study was conducted before of Three hundred and thirty-seven autopsies on patients who died of carcinoma of the breast published in 1968 by Asch et al. 52 cases of these 337 were GI metastasis. The distribution of these metastases was as follows: esophagus (25%), stomach (25%), small intestine (28%), colon (19%), and rectum (4%) [22] . Other literatures which have been published showed also that stomach is the most common site of gastrointestinal involvement by metastatic breast cancer, specifically lobular form, with an incidence of up to 15% on autopsy. Mostly it's hematogenous metastases [23] , but involvement via peritoneal and lymphatic spread also occurs [24] . Metastasis of ILC to colon can occur even after treatment, as it was reported a case of ILC metastasized to sigmoid colon after 3 months of treatment [25] .
The time interval between primary breast cancer and gastrointestinal involvement may range from synchronous presentation to as long as 30 years but reverse is also true, with the GI manifestation preceding a diagnosis of breast cancer [26][27] . Matsuda et al and Schwarz et al reported a median interval of GI metastatic progression of 6 years with a range of 0.25 to 12.5 years [12] . Also, GI metastatic disease confers poorer prognosis, possibly due to hematogenous spread with cancer seeding in other organ systems compared to usual lymphocytic spread of breast cancer. The clinical manifestations that metastatic breast cancer to the GI tract can have are variable. Symptoms may range from non-specific complaints to acute GI symptoms & may be considered treatmentrelated or as inflammatory GI disease. They can also mimic a primary cancer of the GI tract, which is more common than isolated GI metastasis of primary BC [18][19][20][21] . The diagnosis becomes more unlikely on the rare occasion when it represents the first manifestation of breast cancer [28] . In our case the patient was asymptotic and rectal lesion was detected only in MRI pelvis.
The combination of its rarity, the often unusually long interval and the non-specific clinical presentation makes the diagnosis of GI metastasis from primary breast carcinoma a challenge. Endoscopy is important in making a correct diagnosis [14][15][16][17] . The metastatic lesion may simulate inflammatory bowel disease macroscopically, so taking biopsies is important. It is important to differentiate the metastasis from primary carcinoma of genital or GI tract as the management is dramatically different. The histological diagnosis of the secondary deposit is crucial for the correct diagnosis. The histological recognition of lobular carcinoma at the metastatic sites may be difficult. Nevertheless, in our case the metastatic sites maintained their characteristics to the primary. Microscopically, metastases from ILC consist of spindleshaped cells usually that show a single-file growth pattern with no dominant mass The lack of dysplasia or atypia of the rectal epithelium and the glands surrounding the malignant cells is often helpful in distinguishing between a primary and a metastatic lesion, but immunohistochemistry will allow for the most accurate diagnosis. Markers that help confirm the diagnosis are gross cystic disease fluid protein-15 (GCDFP-15), estrogen (ER) and progesterone (PR) receptors. The GCDFP-15 and the ER and/or PR are positive in metastatic lesions of the breast, in contrast to most colorectal or gastric carcinomas, which are usually negative. Studies have found ILC more likely to be ER+/PR+ than ductal carcinomas. HER-2 protein overexpression or gene amplification have been reported in <1% to 6.2% of all ILC cases. Few ILC cases (1.5%) exhibit a triple negative phenotype [29] . Our patient was positive for ER and PR and negative for HER-2 protein.
In the retrospective analysis by Sanuki-Fujimoto N et al prognosis of patients with unusual metastases was similar to that of patients with metastasis only at usual sites [30] . Systemic treatment with chemotherapy, endocrine therapy or a combination of both is usually started in patients with breast cancer that metastasize to the GI tract. Surgery should be limited to cases with complications such as stenosis or obstruction, or for obtaining a diagnosis [18][19][20][21] . Remissions are observed in 32-53% of patients [18] . Survival after diagnosis of GI metastases from a breast primary is poor with few patients surviving beyond two years, although survival up to nine years has been reported [31][32]

Conclusion
This case highlights the importance of understanding that ILC has a unique pattern of metastasis compared to most other types of breast cancer. A high index of clinical suspicion should be maintained for unusual patterns of metastases. Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or GI symptoms. Accurate diagnosis is essential as the treatments for primary genital tract or GI carcinoma and metastatic lobular carcinoma are different.

Conflicts of Interest
The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.