Colon metastases as first clinical manifestation of lobular breast carcinoma with no subsequent evidence of breast disease

Abstract

A 73-year-old woman was brought to the oestrogen receptor for altered mental status. She was found to be hypotensive and hypoglycaemic and admitted to the intensive care unit. She had a history of chronic watery diarrhoea which had recently increased over the last 2 weeks and was associated with vague abdominal pain. A CT showed bowel wall thickening concerning for colitis. Due to the increasing diarrhoea, a colonoscopy was done after all stool studies came back negative. Polyps in the ascending, transverse and sigmoid colon were found to be tubular adenomas but random colonic mucosa biopsies were revealed to be histologically consistent with metastatic lobular breast carcinoma. Further workup revealed no primary breast disease.

Background

Invasive lobular breast carcinoma accounts for about 13%–15% of all breast carcinomas and it is the sixth most frequently diagnosed cancer in women in the USA with about 39 000 new cases being diagnosed each year.¹ While breast cancer rarely metastasizes to the gastrointestinal (GI) tract, lobular histology is more likely to do so, often years after the first diagnosis of breast disease. Diagnosis can often be difficult as the initial presentation can be very vague. Differentiation between primary GI malignancies and metastatic breast carcinoma is essential as the management of both is extremely different.

Here, we discuss a unique presentation of lobular breast carcinoma in a patient with non-specific GI symptoms who was found to have colon metastases but no discernible primary breast disease on workup.

Case presentation

A 73-year-old woman with a history of chronic watery diarrhoea was brought to the emergency department with altered mental status. She was complaining of 1 day duration of left lower abdominal pain associated with worsening in her chronic watery diarrhoea. She had been previously worked up as an outpatient for the diarrhoea as well and all studies were benign. She had been recommended a Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols (FODMAP) diet and underwent a colonoscopy 3 years prior which showed two polyps in the ascending colon which were tubular adenomas histologically. Random biopsies for microscopic colitis were negative. A CT colonography followed that revealed a small 5 mm pedunculated polyp in the hepatic flexure. Her stool changes were thought to be likely secondary to her diabetes at the time. She had been recently admitted for a urinary tract infection and had been eating and drinking poorly since her discharge. She was also a former smoker.

At the time of her presentation, she was hypotensive. She was confused but able to answer simple questions. Her abdomen was soft with mild diffuse tenderness. Her laboratories were significant for hypoglycaemic and elevated creatinine and lactic acidosis.

Other history was significant for diabetes mellitus complicated by neuropathy, coronary artery disease, hypertension, obstructive sleep apnoea, depression and anxiety. Her medications at the time of admission were metformin, glipizide, gabapentin, aspirin, atorvastatin, carvedilol, amlodipine, lisinopril, furosemide, fluoxetine, topiramate, trazodone, prazosin, omeprazole and vitamin supplements.

Family history revealed a diagnosis of breast cancer in her mother in her late 40s/early 50s and a cousin with bilateral breast cancer who was also diagnosed in her 50s. Her brother was diagnosed with colon cancer at the age of 61 years.

Investigations

She was started on broad spectrum antibiotics while the source of her presumed sepsis was being investigated with the GI tract being a major focus due to her chronic diarrhoea that had recently worsened. During that hospital admission, gastroenterology service was consulted. Amylase, lipase, gastric pathogen panel, lactoferrin and Clostridium difficile testing were all negative. CT abdomen/pelvis was concerning for possible colitis. A colonoscopy was performed and showed a polyp in the ascending colon, two semisessile polyps in the transverse colon and a hyperplastic polyp in the sigmoid colon which were all biopsied along with an area of mildly congested mucosa in the rectosigmoid colon alongside other random biopsies in the remaining colon (figures 1 and 2).

Figure 1.

Ascending colon tubular adenoma.

Figure 2.

Transverse colon tubular adenoma.

Pathology results of the randomly sampled colonic mucosa indicated carcinoma that tested positive for pancytokeratin, oestrogen receptor (ER) (58.34%), GATA3 (trans-acting T-cell-specific transcription factor) and negative for e-cadherin, CDX2 and SOX10. Progestin receptor and human epidermal growth factor receptor 2 were both negative. This indicated metastatic lobular carcinoma of the breast. The slides were also sent to Mayo Clinic for confirmation. Morphological and immunohistochemical features were one again reported as consistent with metastatic lobular carcinoma of the breast. CA 27.29 (Cancer Antigen) was subsequently done which was positive at 188 (figures 3–5).

Figure 3.

Malignant ovoid cells expanding the lamina propria of the colon (red arrow).

Figure 4.

The malignant cells in the lamina propria of the colon are negative for E-cadherin immunostain consistent with lobular carcinoma of the breast (red arrow).

Figure 5.

The malignant cells in the lamina propria of the colon are positive for oestrogen receptor (red arrow).

The patient had a mammogram done 2 years prior which was unremarkable. She underwent repeat mammographic and sonographic studies that revealed heterogeneously dense breast tissue without a primary breast lesion. CT brain was negative for any lesions and Positron Emission Tomography (PET) scan showed increased metabolic activity throughout the colon which was reported as likely being secondary to metformin and could be obscuring other colonic lesions. The decision was made to not image the breasts further with MRI as it was unlikely to alter the course of treatment. The other polyps pathology results were of benign tubular adenoma histology.

Treatment

The patient was started on letrozole and palbociclib at the time of diagnosis.

Outcome

Follow-up consisted of CA 27.29 levels and regular imaging studies to monitor for any increase in disease burden. Her CA 27.29 levels initially oscillated around her baseline of 188 but then lowered to a nadir of 136. Her disease course was complicated with multiple hospital admissions due to urinary tract infections which prompted urological workup that included CT urogram and cystoscopy. Slight erythematous area in the posterior aspect of the bladder was detected, but urinary cytology was negative and the abnormality seen was likely related to a recent urinary tract infection. The patient also experienced one hospitalisation for C. difficile colitis following antibiotic course for a urinary tract infection. Palbociclib treatment was held multiple times due to her acute illness. Patient passed away from urosepsis 2 years after diagnosis.

Discussion

Breast carcinoma metastases to the GI tract are extremely rare with reported rates varying from <1% to as much as 35% on autopsy series.² It is well known that lobular carcinoma metastasizes to the GI tract far more frequently than ductal with the stomach and peritoneum being most commonly involved followed by colorectum, small intestine, and rarely, the oesophagus.^3–6 The reason for the predilection of lobular carcinoma to the GI tract is not well known but is thought to be related to the loss of E-cadherin that manifests as the absence of cell-cell adhesion.

Intervals between a history of breast cancer and GI manifestations have been reported to be varied from 0.25 to 28 years and this also includes patients who had remained disease free.^{7 8} Thus, this history should always be kept in mind in these patients who subsequently present with GI symptoms.

Very rarely, GI manifestations, usually gastric, have been known to be the first presentation of breast cancer.⁶ However, in these cases, the patient either had a remote history of breast cancer and GI manifestations were the first episode of a recurrence, or breast lesions were found soon in the course of the disease after the GI lesions were found, even on examination. It has also been suggested that for all women in the USA in whom the diagnosis of diffuse type gastric cancer is being considered, the presence of metastatic lobular carcinoma should be examined given the low incidence of diffuse gastric carcinoma.⁶

Symptoms can be vague and patients present with general GI complaints like nausea, vomiting, change in stool habits, weight changes, distension, early satiety and pain. Patients have also been known to present with obstruction, melena, faecal occult blood and may even remain asymptomatic.⁵ These non-specific GI symptoms prompt, reasonably so, GI workup with the primary thought of ruling out GI malignancies as second GI primaries are more likely in women with breast cancer. Imaging and endoscopic findings are usually not enough to differentiate the two. Strictures, circumferential thickening and linitis plastica-type lesions, can be seen in both scenarios on imaging and can be misdiagnosed as inflammatory GI lesions or primary GI malignancies. Endoscopically, they can easily mimic poorly differentiated gastric carcinoma, primary colon cancer, inflammatory bowel disease or present as solitary polyps. Often, endoscopic biopsies may also be negative as the disease may be submucosal and focal and thus deeper biopsies may be needed, and often, repeated endoscopic procedures with random biopsies may be necessitated. Invasive lobular carcinoma metastases are far more likely to be negative on biopsy than ductal carcinoma (64% vs 90%).⁹ It is also important to compare these biopsies with the original biopsies in patient who have a history of breast cancer, no matter how remote.

Immunohistochemical staining and pathological assessment prove to be vital in establishing a diagnosis in these cases. Commonly, the presence of ER and absence of HER2/neu is seen with invasive lobular carcinoma, consistent with a luminal molecular subtype, as was the case in our patient as well.¹⁰ GATA3 has been shown to be positive in >90% of primary and metastatic lobular and ductal breast carcinomas. Cancers of the GI tract can also rarely be GATA3 positive (37% for pancreatic ductal carcinomas and <10% in case of adenocarcinomas of the colon and stomach).¹¹ Negative E-cadherin expression is also very characteristic of invasive lobular carcinoma.¹² The absence of CDX2 in our case also went against a primary GI malignancy as CDX2 expression is seen in 97% of colorectal cancers, 61% of gastric cancers and 16% of pancreatic cancers.¹³ The absence of surrounding atypia or dysplasia of the stomach or colon can also be a hint towards a metastatic lesion than a GI primary.

Progesterone receptor (PR) expression, although negative in our patient, also does corroborate a breast primary and also has prognostic value with higher expression associated with relapse and death. Colon carcinoma itself can also be positive for ER/PR.¹⁴ CK7+/CK20- phenotype, BRST-2 and gross cystic disease fluid protein 15 all indicate mammary origin.^{15 16}

We did find one report similar to ours in which a patient was diagnosed with lobular carcinoma metastases to the colon with no primary discovered in the breast but this patient had a remote history of benign breast disease.¹⁷ Similarly, there is no evidence of a primary breast lesion in our patient yet and the only risk factor is positive family history. While breast MRI is certainly indicated per the American College of Radiology in case of metastatic cancer when the breast is suspected to be the primary, we opted to forego an MRI in this case after a mammogram and ultrasound did not show evidence of disease.¹⁸ Since there was already pathological confirmation of lobular carcinoma metastases to the GI tract, the course of treatment—systemic therapy—would not have been affected by evidence of primary breast disease. Generally, patients with breast metastases to the GI tract are treated with systemic therapy, either hormonal or chemotherapy, sometimes with surgery as an adjunct. Usually, however, surgical intervention is only considered for palliation in the event of obstructive symptoms or mass effect and has no significant impact on survival. However, this can be considered on a case-by-case basis as there have been instances of benefit of surgery in patients with gastric metastases from hormone positive breast cancer.^{2 19} Response to systemic therapy of patients with breast cancer and GI metastases ranges from 30% to 50% with an overall survival averages around 2–3 years but survival up to 9 years has also been reported.^{2 6}

These unique factors—low incidence; variable, often large interval between primary breast disease and metastatic lesions; non-specific symptoms; overlapping endoscopic and radiological features; false negative biopsies and GI manifestations as the first presentation of breast disease—make it imperative to have a high index of suspicion for this entity and underline the importance of a thorough medical and family history to allow risk stratification in order to avoid unnecessary surgical intervention and a delay in treatment.

Learning points.

• Gastrointestinal (GI) manifestations can be the first presentation of metastatic breast cancer.

• There can be a very large interval between a history of breast cancer and the development of GI metastases. Thus, there should always be a low index of suspicion in a patient with new onset GI symptoms and a history of breast cancer, no matter how remote.

• It is imperative to differentiate primary GI malignancies from metastatic breast lesions as the management is vastly different. It can often get difficult due to vague symptoms at onset and, often, the absence of any breast complaints. Endoscopic evaluations may also not always be successful due to focal submucosal involvement and the absence of overt lesions.

• Compared with invasive ductal carcinomas, invasive lobular carcinomas have lower fluorodeoxyglucose (FDG) uptake. The sensitivity of PET scanning is also lower in this case.

• When further imaging is unlikely to change clinical management, it is reasonable to forego it.