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A 68-year-old woman presents to the hospital in Connecticut with gastrointestinal (GI) symptoms including nausea, vomiting, pain in the abdomen, and constipation that is not responding to standard treatment. She explains that her symptoms have become progressively worse over the past several months.

She has a history of breast cancer. About 30 years previously, she underwent bilateral mastectomy after being diagnosed with invasive lobular breast cancer that was positive for estrogen receptor (ER) and progesterone receptor (PR), and negative for HER2/neu, and received adjuvant chemo-radiotherapy and hormonal therapy.

The patient explains that about 5 years earlier, the cancer metastasized to the bones, and that since then, she has been treated with anastrozole, letrozole, exemestane, and most recently, fulvestrant and palbociclib.

Physical Examination

Clinicians perform a physical assessment, and note that her abdomen is distended and tender on palpation. Laboratory tests identify chronic anemia (hemoglobin 9.8 g/dL) and mild elevation in liver function tests, for unknown reasons.

An abdominal x-ray reveals proximal large bowel obstruction, but no evidence of pneumoperitoneum. Subsequent gastrografin enema shows a focal, luminal narrowing "apple core" lesion in the sigmoid colon. Clinicians suspect the patient has developed primary colon cancer (figure).

Abdominal computed tomography (CT) scan confirms an obstruction of the large bowel, with a transition point within the distal sigmoid colon. Clinicians note circumferential narrowing and mucosal thickening at the transition point, which they believe is caused by an annular carcinoma. Based on the strong suspicion of a primary GI malignancy, the patient is scheduled for surgery to remove the obstructing mass. However, consideration of her history of breast cancer prompts the clinicians to first perform a colonoscopy with biopsy.

Biopsy reveals diffuse infiltration and proliferation of neoplastic cells in a sheet-like arrangement within the lamina propria and submucosa – findings that suggest a poorly differentiated adenocarcinoma.

Immunohistochemistry (IHC) staining of the biopsy sample is strongly positive for cytokeratin 7 (CK7) and positive for both ER and PR; the sample tests negative for HER2/neu, CK20, caudal-type homeobox 2 (CDX2), and cancer antigen 19-9. Clinicians decide that based on these results, the tumor is not primary colon cancer, but rather a late metastasis of lobular breast cancer.

The patient's ongoing treatment with palbociclib and fulvestrant is later changed to everolimus and exemestane. However, when side effects develop and the cancer proves to be aggressive, she is switched to oral capecitabine.

After beginning treatment with capecitabine, the patient develops pain in the upper abdomen. Clinicians perform an endoscopy of the upper GI tract that reveals a dominant lesion in the gastric body highly suspicious for stomach cancer. Histology is consistent with signet ring carcinoma, a rare variant of lobular carcinoma.

IHC testing shows that the tumor cells are strongly positive for GATA-binding protein 3 (GATA-3), ER, and PR, and negative for HER2/neu and CDX2. Clinicians therefore conclude that the stomach tumor is a breast cancer metastasis with signet ring phenotype.

Case Follow-up

The patient receives palliative paclitaxel and gemcitabine chemotherapy. However, she subsequently develops septic shock with multiorgan failure, and dies shortly thereafter -- 34 years after the initial diagnosis of lobular breast cancer.

Discussion

Clinicians reporting this of a woman with late GI metastases decades after her initial diagnosis of breast cancer point out that clinical, radiographic, and histologic findings for these tumors can mimic primary GI cancers. Noting that about half of breast cancers recur or metastasize – sometimes decades after the initial diagnosis and treatment – the case authors urge a thorough investigation of new GI symptoms in patients with a prior history of breast cancer.

Improvements in screening and treatment have increased overall survival -- and therefore also the number of patients with advanced, disseminated metastatic disease. The site of breast cancer metastasis varies depending on histological subtypes. Breast cancer frequently metastasizes to the bones, lungs, central nervous system, and liver, whereas metastasis in the GI tract is rare, occurring in only about 3.4% to 4.5% of patients.

Invasive/infiltrating lobular breast cancer – which represents 8-14% of all breast cancers – tends to metastasize more frequently than other subtypes of breast cancer, most commonly to the lungs, liver, lymph nodes, and brain. However, atypical sites might be more common than expected, the case authors noted.

Because metastasis in these patients shares clinical and imaging characteristics with primary GI tumors and non-Hodgkin's lymphoma, differentiating the precise type of malignancy can pose a challenge. Obtaining a detailed IHC profile is central to establishing a diagnosis and thus appropriate treatment.

in up to 4.5% of cases, compared with 0.2% of invasive ductal carcinomas. The stomach is the most commonly affected site -- an analysis by of lobular breast carcinoma patients with GI metastases showed that 80% of patients had presented with GI symptoms, 92% of which had stomach involvement.

The symptoms of breast cancer metastasis to the GI tract are often nonspecific, such as abdominal pain, diarrhea, weight loss, bowel obstruction, anemia, and bleeding. This makes it challenging to differentiate breast cancer metastasis to the GI tract from primary GI malignancies or other primary GI diseases such as inflammatory bowel disease.

Radiographic imaging is not particularly helpful, since cancer involvement of the small intestine can be easily mistaken for Crohn's disease, the case authors noted. These factors have led to delay in appropriate referrals to consultants, use of invasive diagnostic modalities, and to delayed treatment.

Differentiating Metastases from Primary Cancers

As breast cancer progresses, GI metastases may appear on imaging as nodular or circumferential thickening with narrowing; this is secondary to tumor cell infiltration in the colonic wall, which can subsequently lead to distinct strictures. In contrast, primary GI malignancies frequently present as exophytic masses.

Similarly, metastases to the stomach may result in diffuse infiltration of the stomach wall, resulting in linitis plastica in about 50% of cases. Such metastases can also present as a single mucosal lesion resembling primary gastric cancer. On endoscopy, mucosal involvement may appear as flat, elevated, polypoid-appearing lesions or as erosive ulcers with visualization of enlarged mucosal folds. This can be easily mistaken for primary GI malignancies.

When a biopsy identifies intracellular mucin, it is important to remember that it may resemble signet cell appearance, which mimics primary gastric malignancies. The clinicians reporting this case note that signet cell morphology may present in metastatic lesions of invasive, primary lobular breast cancer, as in this patient, as well as in signet cell stomach cancer. Gastric cancer can be diagnosed in patients whose biopsy sample shows more than 20% signet cells.

In cases where metastases involve only the submucosa, the authors recommend taking multiple deep biopsies, noting that biopsies obtained via endoscopy or colonoscopy might result in false-negative results.

Importance of IHC Staining

As outlined above, difficulties inherent in the diagnostic process make use of vital to the process of making the correct diagnosis.

Although breast cancer cells are typically ER and PR positive, 20% may be negative for ER. Of gastric malignancies, data suggests that 32% are ER-positive and 12% are PR positive.

In addition, current diagnostic tests use other markers including gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin (MGB). GCDFP-15 has a specificity of 98-99%, and a sensitivity of 50-74%, the case authors note. In contrast, MGB has a specificity of 92% for detecting breast cancer, and a greater sensitivity than GCDFP-15.

Other markers that help differentiate breast cancers from GI cancers include the following:

• GATA-3: Positive in 100% of lobular breast cancers and 96% of ductal breast cancers, versus in only 5% of gastric cancers

• Immune markers: Most breast cancer adenocarcinoma cells are positive for Mucin (MUC)1 and negative for MUC2, whereas most GI cancer adenocarcinoma cells are negative for MUC1 and positive for MUC2

• Similarly, most breast cancers are positive for CK7 and negative for CK20, whereas the opposite is the case for most GI cancers (i.e., negative for CK7 and positive for CK20)

The authors emphasized the importance of establishing the correct diagnosis as early as possible, since primary GI malignancy and breast cancer metastasis require different treatments – surgical resection vs systemic chemotherapy and/or hormonal therapy – and have a different prognosis.

And while there is no consensus around care for GI metastases from breast cancer, surgical treatment has not been shown to improve survival, the authors noted, adding, however, that surgery may still be used palliatively to help control symptoms.

This patient's presentation with bowel obstruction suggestive of primary colon cancer might have led to primary surgical resection; fortunately, this plan was aborted when IHC results established the correct diagnosis of metastatic breast cancer. Similarly, IHC confirmed the patient's subsequent breast cancer metastasis to the stomach several months later, following her presentation with nonspecific epigastric pain, and identification of a gastric lesion with signet cell morphology that raised suspicion of primary gastric cancer.

The clinician authors concluded that breast cancer metastases can be clinically and morphologically very heterogeneous, and that breast cancer patients should have close follow-up throughout their lifetime, as recurrence and metastatic lesions can present ambiguously even decades later.

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