Premenstrual sub-occlusive episodes as initial presentation of metastatic breast cancer: a case report of a previously undescribed entity.

A 53-year-old woman (G2P2A0), regular hookah (waterpipe) smoker and without a significant past medical history, presented to our clinic complaining of severe, diffuse, cramping abdominal pain. Vital signs were within the normal range upon presentation and she appeared well nourished. Her past surgical history includes an uncomplicated C-section done thirty years ago. Upon further questioning, she mentioned obstipation episodes that begins on average 10 days before her menses and resolves by the end of her period. Those episodes started 5 months ago, each one lasted on average 2 days and was followed by watery diarrhea. Additionally, those occurrences were associated with nausea and scant non-bilious vomiting. She denies bowel habits changes beside those events or blood per rectum. She did not report anorexia, involuntary weight loss or night sweats during the preceding months. Her family history is notable for breast cancer in her mother and aunts, all of whom were diagnosed in late adulthood. Her brother was treated for Crohn’s disease and died aged 35 years old from a gastric cancer. On physical exam, her abdominal wall was lax without palpable masses or evidence of fluid accumulation. The pain was diffuse but was mainly localized in the right iliac fossa. There was no rebound tenderness. Digital rectal examination did not reveal masses, indentations, or rectal bleeding. Moreover, no abnormal findings were noted on gynecological examination, as there was no uterine tenderness on palpation or abnormal vaginal discharge. Upon questioning, she mentioned heavy menses but no history of dyspareunia. Clinical breast examination findings at that time were unremarkable as no palpable breast masses or axillary adenopathy were found. On further inquiry, she reported cyclical breast tenderness associated with her menstrual periods. A complete blood count including differential was obtained. She was not anemic and there was no evidence of inflammation with a negative C reactive protein (CRP) and procalcitonin. Biochemistry studies were unremarkable. Calprotectin was 120 mcg/g (borderline) and Fecal Occult Blood Test was negative. A Magnetic Resonance Enterography (MRE) showed a circumferential thickening of the terminal ileum (Fig.  1 ). To further determine the origin of her symptoms, and obtain biopsies that might reveal the clue to the diagnosis, a gastro colonoscopy was done. Gastroscopy showed an erythematous gastric mucosa with multiple erosions compatible with erosive gastritis. Colonoscopy revealed a macroscopically normal large bowel however, the terminal ileum was not adequately visualized because the ileo-cecal valve was stenotic, impeding the passage of the scope into the terminal ileum. Biopsies revealed a well differentiated gastric antral and fundic mucosa with few inflammatory cells in the lamina propria, without evidence of H. pylori. On the other hand, pathologic examination of biopsies taken at the ileo-cecal valve level revealed a focal, nonspecific and mild inflammatory infiltrate without evidence of malignancy(Fig.  2 ). Subsequently, another colonoscopy was done but failed, again, to adequately visualize the terminal ileum. Fig. 1 Magnetic Resonance Enterography showed a 1,2 cm circumferential thickening at the level of the ileo-cecal valve (pointed by the arrow). The remainder of bowel loops were unremarkable and there was no evidence of ascites fluid, intra-abdominal adenopathy or bone lesions Magnetic Resonance Enterography showed a 1,2 cm circumferential thickening at the level of the ileo-cecal valve (pointed by the arrow). The remainder of bowel loops were unremarkable and there was no evidence of ascites fluid, intra-abdominal adenopathy or bone lesions The endoscopically retrieved biopsy showed initially a focal, mild inflammatory infiltrate at the without evidence of malignancy Because the probable etiology was in the terminal ileum according to MRE and twice failure of the colonoscopy to explore this region, the patient was planned for a diagnostic laparoscopy. It revealed a small kinked area at the level of the ileocecal valve, reproducing the appearance of a terminal ileum or ileo-cecal malignant tumor. Accordingly, a decision to treat it by oncologic surgery was taken, and a laparoscopic right hemicolectomy was performed. However, it was converted to an open surgery because the usual anatomic planes were difficult to assess- likely desmoplastic response to malignancy. The patient was discharged few days after surgery and no complications were to be noted. Her recovery period was unremarkable. Surprisingly, on pathological and immunohistochemistry assessment, a diffuse pericolonic and colonic serosa infiltration by a metastatic, poorly differentiated adenocarcinoma compatible with a breast origin was identified(Fig.  3 ). The tumor had lobular features and was predominantly present in serosa and muscularis propria. It also infiltrates diffusely the pericolonic adipose tissue and focally the mesoappendix and appendicular serosa as single cells but maintains E–cadherin positivity. The stroma was fibrotic and moderately inflamed, and the surgical margins were free. There was no perineural or vascular invasion, three to eight mesocolonic lymph nodes were positive and the mitotic index was 10%. Additionally, the tumor cells were positive for CK7, estrogen, progesterone and GAT3 receptors and mammaglobin (Fig.  3 ). However, HER-2 receptors CK20 and CDX2 were absent. Fig. 3 The histological and immunohistochemistry and assessment was consistent with metastatic lobular breast carcinoma. 1,2,3: H&E (hematoxylin and eosin) staining. The tumor was predominantly present in serosa and muscularis propria and had lobular features. The stroma was fibrotic and moderately inflamed. Surgical margins were free, and there was no perineural or vascular invasion. The mitotic index was 10%. The tumor cells-maintained positivity for the following: (4): GATA 3; (5): Mammaglobin; (6): E–cadherin; (7): CK7; (8): Estrogen (90%, strong staining intensity); (9): Progesteron (30%, moderate staining intensity); The tumor cells were found to be negative for the following markers: (10):CDX2; (11):CK20. In view of those findings, a bilateral breast Magnetic Resonance Imaging (MRI) was ordered. It revealed multiple fibroadenomas along with regular nodules and cystic components accompanied by inflammatory changes. The MRI was interpreted as BI-RADS 3, warranting short-term follow-up every 6 months (Fig.  4 ). Axillary fossa lymph nodes were sub-centimetric in size. The patient refused to be biopsied for potentially targetable nodules. Latterly, a positron emission tomography/computed tomography (PET/CT) scan showed a heterogeneous nonspecific radiotracer uptake in both breasts, more focal in the outer quadrants, with a Standardized Uptake Value (SUV) of 1,7- which might be simply reactive in nature. In light of all the clinical, radiological and histological findings, the patient was diagnosed with a T0N0M1 metastatic breast cancer and began treatment with Palbociclib (a CDK4/6 inhibitor) and Letrozole (an aromatase inhibitor). Another PET/CT done 2 months later showed no suspicious radiotracer avid disease within the breast or axillae, but increased radiotracer uptake within the proximal aspect of the transverse colon -which might attest a disease recurrence or can be physiologic. Owing to financial hardship and war in Lebanon and limited access to her prescribed treatment, the patient decided to emigrate and discontinued follow-up care. She presented again after one year of treatment as initially prescribed. At the time of publishing of this article she clinically stable and no clinical symptoms or signs pointing to malignancy are to be noted. In fact, no avid sites of over fixation were found in the last PET/CT, and the time this article is published she is in complete remission. Fig. 4 Magnetic Resonance Imaging of the breasts showed fibrocystic changes at the time of diagnosis classified as BI-RADS 3 The histological and immunohistochemistry and assessment was consistent with metastatic lobular breast carcinoma. 1,2,3: H&E (hematoxylin and eosin) staining. The tumor was predominantly present in serosa and muscularis propria and had lobular features. The stroma was fibrotic and moderately inflamed. Surgical margins were free, and there was no perineural or vascular invasion. The mitotic index was 10%. The tumor cells-maintained positivity for the following: (4): GATA 3; (5): Mammaglobin; (6): E–cadherin; (7): CK7; (8): Estrogen (90%, strong staining intensity); (9): Progesteron (30%, moderate staining intensity); The tumor cells were found to be negative for the following markers: (10):CDX2; (11):CK20. Magnetic Resonance Imaging of the breasts showed fibrocystic changes at the time of diagnosis classified as BI-RADS 3

This article illustrates the challenges that clinicians may be confronted to by unusual metastatic breast cancer clinical presentations and the changes in the clinical reasoning and attitude needed to overcome them. When a hormone-sensitive neoplastic growth invades a physiologic lumen, a cyclical hormone-dependent incomplete luminal blockage would result in periodic, hormonally driven metastatic symptoms depending on the anatomic location involved. By shedding the light on those unusual clinical presentations, case reports are cornerstones for physicians to sharpen an early diagnostic suspicion, establish timely diagnosis, start early on the appropriate therapy and consequently ameliorate patient’s prognosis. Breast cancer, especially when it metastasizes, is a great mimicker that can induce a broad range of both acute and chronic conditions that can potentially lead physicians to look for other benign entities and pathological conditions. For this reason, breast cancer should always be included in the differential diagnosis especially when evaluating a female patient presenting with acute or chronic abdominal pain. Ideally, breast assessment should be included in every woman physical exam. Those initial atypical cases of metastatic breast cancer spread highlight the increased need for the development of more targeted biomarkers in screening campaigns, which could be lifesaving especially when occult metastases precede the detection of the primary tumor. Further research, is needed to unravel the mechanisms of tumor kinetics and metastatic spread, because a deeper understanding of those factors could help to predict the tumor behavior early on, aiming for a tailored approach and treatment for each patient.

This case exemplifies the challenges that clinicians may face in diagnosing and treating breast cancer and its metastatic deposits. To the best of our knowledge, this is the first case in the scientific literature to describe such an initial clinical presentation of breast cancer: premenstrual sub-occlusion episodes. Although rare, but previous cases in which gastrointestinal metastasis are the first presentation of breast cancer have been reported [ 15 – 18 ]. In some cases, an undiagnosed breast cancer revealed abruptly as an intestinal obstruction [ 19 – 21 ] and in other instances, those GI tract metastases became evident after a cancer free-latency, or in a patient already diagnosed with a breast tumor [ 22 – 25 ]. This case is unique for several reasons and, as such, it invites us to rethink the way we approach breast cancer, the way it disseminates, and consequently the multifaceted and potentially confusing clinical pictures it can give rise to. Most importantly, it highlights the need for a change in clinical practice and reasoning and to include breast cancer in the differential diagnosis when evaluating a female patient with a history of abdominal pain with or without intestinal obstruction that may be acute, chronic or presenting with recurrent, unusual symptoms that are associated with the patient’s menstrual cycle. Additionally, it stresses on the fact that breast cancer should not be easily ruled out from the clinician differential diagnosis even if, like this case, primary investigations did not reveal any evidence of malignancy, because it could result in a delay in treatment initiation, lead to a higher treatment failure rate, and ultimately a higher mortality. The major hurdle to diagnosis lied in that the symptoms reported by the patient along with the endoscopic and radiographic findings greatly lacked specificity. Although the gold standard for diagnosis is biopsy but, to further complicate matters, it can also be either inconclusive, reveal nonspecific inflammatory changes like our case, or can even be negative if retrieved endoscopically [ 16 , 26 ]. Indeed, the nonspecific mucosal changes in the stomach and the stenotic ileocecal valve mistakenly led us to make further investigations to rule out primary gastro intestinal disorders. In the concrete, misdiagnosis is common and differential diagnosis is wide, covering a broad spectrum of pathological conditions that differ in their pathophysiology in addition to neoplasms that differ by their biological behavior and progenitor cells. Symptoms rely mainly on the site of the metastatic spread. As a matter of example, besides anorexia and weight loss, metastasis to the esophagus can lead to achalasia and dysphagia, dissemination to the stomach induce nausea, dyspepsia, obstructive symptoms and even perforation [ 16 , 27 ]. Metastasis to the small intestine, colon and rectum can range from abdominal pain, asymptomatic abdominal mass, rectal bleeding, to much serious complications such as stenosis, linis plastica or peritonitis [ 16 , 27 ]. In point of fact, the exact incidence of as well as the most common anatomical location for breast cancer metastatic deposits along the length of GI tract- which can involve any area from the tongue to the anus- is a source of debate and confusion among the scientific literature. There is significant discrepancy between the incidence noted in clinical studies and those reported in autopsy series [ 16 , 28 , 29 ]. It is nevertheless believed that the stomach is the most common GI location of metastatic spread of breast cancer [ 16 ]. The treatment modality should be tailored to the region involved: a stent insertion can help relieve dysphagia in esophageal involvement and in colorectal locations surgery is mainly indicated to solve hemorrhagic or, as was the case in our patient, stenotic complications [ 16 , 30 ]. In this patient the breast cancer origin of this tumor can firmly be confirmed and does not solely rely on its histological and immunohistochemical profile that supports a mammary origin, but, rather by an array of both clinical and radiological findings in addition to the pathological results that excludes all probable differential diagnosis, as this was ascertained by the long term follow up results. If the diagnosis was incorrect, the prescribed treatment for metastatic breast cancer would have no longer be suitable and the patient clinical condition would have deteriorated. As previously mentioned, after one year and few months, no other symptoms suggestive of malignancy were to be noted and the PET/CT showed complete remission. The rigid and thickened circumferential bowel thickening was previously described in case reports where breast cancer metastasized to the GI tract, and the terminal ileum and ileocecal valve has also been previously reported as a site of metastasis of breast cancer [ 31 , 32 ]. The invading malignant cells triggered a fibrotic response which is thought to be the result of the immune response to invading cancer cells, which showed up radiologically as circumferentially thickened bowel loop. Symptoms and signs of those breast cancer metastatic spread can be similar to those of primary gastrointestinal tract diseases or malignancies and the differential diagnosis includes inflammatory bowel disease such as Crohn’s disease, beside primary GI malignancies such as adenocarcinoma, lymphoid tissue-associated neoplasms or neuroendocrine tumors along the length of the GI tract, chronic inflammation by granulomatous diseases, and Ménétrier disease to only name a few [ 16 , 33 ]. Besides the hormone receptor status (ER, PR, HER2), it would be exceptional for a GI malignancy to truly co-express both GATA-3 and mammaglobin. The differential diagnosis also includes gynecological malignancies such as endometrial carcinoma, endometriosis-associated malignancy of the bowel, ovarian tumors (e.g., low-grade serous carcinoma or Krukenberg tumors), Müllerian Adenosarcomas and mesonephric tumors. Although punctual immunophenotyping overlap in expressing mammaglobin or GATA-3 might be observed in tissues originating from the uterus, ovaries or cervix, making them not pathognomonic for mammary gland and breast carcinoma [ 14 , 34 , 35 ], however, given the unremarkable patient gynecological surgical history, and the fact that the multiple PET/CT scans did not show any lesions at the level of the genitals, it makes this possibility unlikely. Given the clinical context and results, a carcinoma of unknown primary origin is also to exclude. Another possibility, at least in theory, is that an ectopic or accessory breast tissue at the level of terminal ileum might have undergone a primary neoplastic process. However, when searching for cases of ectopic breast tissue, they were most commonly found as masses anywhere along the length of on the so called ‘’mammary streak’’ that extends from the groin till axillae, which also makes this hypothesis unlikely as there was no previously reported ectopic breast tissue in the intestines, but rather on the superficial abdominal layers across the ‘’milk line’’. More importantly, if ectopic breast tissue was present in this critical anatomic location, it would have induced those episodes much earlier in life because its intrinsic ability to respond to hormonal fluctuations. By exclusion of other possible malignancies, and considering the immunohistochemistry results associated with the clinical and radiological findings, the leading hypothesis is that an early metastatic spread from an occult or small primary breast lesion making it clinically undetectable, preceded the formal diagnosis of breast cancer. Understanding the mechanisms by which malignant cells disseminate is essential to analyze this clinical presentation. On the contrary of what used to be believed for more than a century, malignant cells anatomic progression is not a meticulous stepwise process. In fact, early metastasis is common, can occur independently of the size of the tumor and even before the diagnosis of the primary neoplasm [ 36 ]. In the case of breast tumors, the metastatic pathways are governed mainly by the tumor histopathology (lobular vs. ductal), the expressed hormonal receptors in addition to the cell-to-cell adhesion molecules status, bedside other parameters [ 37 , 38 ]. The peritumoral tissues and their extracellular matrix play a crucial role in modulating malignant cells growth, their motility, invasiveness, dissemination and ultimately colonization to distant tissues [ 39 ]. Moreover, malignant cells can also temporarily stop their replication. It is currently believed that this tumor cell dormancy is a mechanism to escape an inimical microenvironment. More importantly, those dormant foci of metastatic spread could explain the late recurrence, even years after the primary tumor has been cured. For this reason, clinicians should always be cautious in patients with breast cancer or who have been cured-even years ago- and who present with new or chronic GI symptoms [ 39 ]. The gut microbiota has also gained a growing interest in over the last years: it is currently believed that by shaping an advantageous microenvironment it can participate in initiation, promotion and progression of tumors and, as a matter of fact, dysbiosis of the gut microbiome is currently recognized as a hallmark of cancer [ 40 ]. All those previously mentioned factors emphasize on the countless and diverse parameters that shapes the metastatic potential of mammary neoplasms and consequently the increase need for a personalized approach that consider the specific histopathological, molecular and genomic characteristics of each tumor in every individual in order to predict its way of dissemination. The latter, will be the result of both the predicted organotropism of the malignancy and its site-specific distribution tendency based on anatomical variations such vascular patterns that might preferentially carry those malignant cells to strategically important anatomical locations. On the contrary of previous reported cases in the literature, the obstruction in the GI tract was dynamic rather than a persistently symptomatic one induced by structural changes due to tumoral invasion. The onset of those sub-occlusion episodes before menses strongly suggests a hormonal control of the symptomatology. This temporal relationship is not a coincidence: it is well known that sex hormones have a proliferative effect and are capable of inducing expansion of breast glandular structures by affecting their molecular and cellular activity. Moreover, given that all other differential diagnosis that might induce sub-occlusion such as functional bowel diseases were previously excluded, given the temporal association with menses and the mammary growth ER+/PR + status, it is consequently almost certain that those episodes were induced by the partial tumor fluctuation in size .The retained estrogen sensitivity of the neoplasm associated with the cyclical hormone exposure made it possible for the tumor to respond to changes in hormone levels that occur through the menstrual cycle and its location in this critical anatomical site have driven this observed, unusual cyclic symptom. Being cautious about overgeneralizing, but one could imagine different clinical scenario on the basis of previously reported cases of anatomical location of breast metastases and the potential novel concept our case introduces- that if a body channel was invaded by a breast cancerous growth that retained sensitivity to hormones, it could result in cyclical symptoms that would have different clinical manifestations depending on the anatomical location involved. If for instance the esophagus is involved, it could result in cyclic dysphagia to solids associated with vomiting, if a narrowing of intestinal lumen occurs, it could in periodic, colicky abdominal pain that might be confused with dysmenorrhea, menstrual cramps or other potentially benign GI tract diseases. Metastatic extension of breast cancer within the extrahepatic bile ducts wall -with or without liver involvement-have previously been reported [ 41 , 42 ]. In those cases a hormonedependent fluctuations in obstruction severity could result in cyclical biliary obstruction and episodes of jaundice and right upper abdominal pain, that could in theory be confused with biliary colic, primary extra ductal or pancreatic malignancies .If a mammary growth invades the ureters it could result in renal colic that might or not be associated with hydronephrosis, repeated bouts of pyelonephritis and kidney injury. In fact, such cases where metastatic breast cancer as presented as renal colic and pyelonephritis were already previously reported [ 43 , 44 ].

Breast cancer is the most common cancer in women worldwide and, despite screening and prevention campaigns, it remains associated with significant mortality and financial burden on healthcare systems [ 1 – 3 ]. Breast pathology encompasses a myriad of highly heterogeneous lesions that ranges from reactive changes and harmless benign proliferations to high-risk precursor lesions and invasive malignancies. They differ by their origin, biologic behavior but also by their pattern of metastatic spread. Traditionally, breast cancer has been screened as asymptomatic breast lump detected on physical exam or reported by the patient by self-palpation, that might or not be associated with nipple changes or skin alterations. Breast cancer metastases can virtually target every organ synchronously or even before the formal diagnosis and the unusual and aberrant clinical presentations this phenomenon can give rise to have pushed physicians to document them in the scientific literature across years. In some instances, metastatic breast cancer can show up itself as chronic back pain that can be confused with disc herniation or muscle strain [ 4 ]. In other instances, metastatic breast cancer can diffuse or focal skin changes that might range from diffuse nodular or papulonodular, ulcerated plaques among other possible skin lesions and that can be confused with skin infection or other diseases [ 5 – 8 ]. Metastatic breast cancer has also exceptionally presented as carcinomatous meningitis leading to cranial nerve palsy [ 9 ]. The gastrointestinal tract can also be involved by metastatic breast cancer to cause stenosis, acute obstruction or even appendicitis [ 10 ]. Metastatic breast cancer can also target potentially every bone and can be confused with monoarthritis [ 11 , 12 ]. Moreover, the genitourinary tract can also be affected: where it can lead to ureteral obstruction by direct extension or compression can lead to and pyelonephritis and kidney injury, or target the uterus and induce asymptomatic bleeding [ 13 ]. It is crucial for clinicians to recognize those presentations deviating from classic patterns of breast carcinoma and to cultivate early diagnostic vigilance towards them, because they testify of early occult dissemination of cancer cells which remains one of the leading causes for treatment failure [ 14 ]. In the following sections of this article, we present a comprehensive clinical overview of an unusual initial presentation of metastatic breast cancer.