Metastatic breast cancer manifested as refractory anemia and gastric polyps.

ABSTRACT

Gastric metastasis from breast cancer is uncommon and typically occurs in patients with disseminated disease. The vast majority of patients with gastric lesions have a known preexisting diagnosis of breast cancer. In contrast, we describe a case in which a minimal breast cancer was found to be the primary tumor during the workup of a patient first diagnosed with carcinoma of unknown primary and subsequently presumed to have metastatic gastric cancer. Our case illustrates that a diagnosis of breast cancer metastatic to the stomach may require a high index of suspicion, as well as a meticulous breast workup. It also emphasizes that even tiny breast cancers have a small but real risk of metastatic spread. Determination of the correct primary source in these cases may not be only an academic exercise, since the treatment and prognosis of metastatic breast cancer (especially receptor positive) and metastatic gastric cancer are different.

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BREAST CANCER most commonly metastasizes to the regional nodal basins, lungs, bone, liver, and brain. (1) Gastrointestinal (GI) tract metastases are uncommon, occurring in 4% to 18% of patients with advanced disseminated disease. (2, 3) One series in particular has reviewed that subset of breast cancer patients with gastric metastases. (4) All patients in that series, as in other previous reports, (5-10) had a known diagnosis of breast cancer when the gastric lesion was discovered. We describe a case in which minimal breast cancer was retrospectively found to be the primary tumor during the workup of a patient who was first diagnosed with carcinoma of unknown primary and was later presumed to have metastatic gastric cancer.

CASE REPORT

A 53-year-old white woman with a history of diabetes, dyspepsia, and previous cigarette and alcohol use, was evaluated in the hematology clinic at Oregon Health Sciences University (OHSU) for refractory anemia of 2 years' duration. The anemia was originally thought to be due to erythropoietin deficiency, but after 6 months of successful replacement therapy, it became refractory to this treatment. Bone marrow biopsy showed metastatic signet-ring cell adenocarcinoma. Esophagogastroduodenoscopy (EGD) revealed multiple polypoid lesions, diffusely distributed within the gastric mucosa (Fig 1). There were no dominant masses, and no thickened gastric folds of gastric cancer were seen. Biopsy showed signet-ring cell adenocarcinoma with the same histologic pattern of tumor cells seen on the bone marrow examination. An extensive staging workup was then done, including posteroanterior and lateral chest radiographs and computed tomography of the chest, abdomen, and pelvis, which were unremarkable. A diagnosis of gastric cancer with metatastases to the bone marrow was made.

The patient was presented at the OHSU GI tumor board to discuss treatment options. During that presentation, the pathologist (C.C.) noted that although the tumor was of signet-ring cell type, it had a keratin profile consistent with an upper GI, breast, ovarian, or lung primary. On immunohistochemical staining, the cancer was found to be ER+/PR+, Her-2/neu negative, PAS mucin CK7+, GCDFP 15+, and CK 20-, TTF-, and CA-125--. These results, combined with the endoscopist's impression that the tumor had an appearance more consistent with metastatic disease than with a primary gastric cancer, led to the discussion of occult breast cancer as a possible primary lesion. Accordingly, the patient was next referred to our multidisciplinary breast clinic.

The patient's metastatic workup had included a clinical breast examination (CBE), as well as a screening mammogram. While the CBE raised the question of a mass in the upper outer quadrant of the right breast, the mammogram revealed two clustered groups of pleiomorphic calcifications in the left breast (Fig 2).

During the breast clinic consultation, the patient had no breast-related complaints. She was premenopausal, gravida 7, para 1, abortus 6. Her age at menarche was 13, and her menstrual cycles were reported as regular. She denied any family history of breast, ovarian, or other cancers. Review of systems was positive for night sweats and peripheral neuropathy due to longstanding diabetes mellitus.

Physical examination revealed a thin woman with normal vital signs and in no acute distress. The breast examination demonstrated symmetric, small breasts. The nipples and overlying skin were normal bilaterally. Palpation revealed bilateral thickened fibrocystic tissue in the upper outer quadrant of each breast. Careful palpation of these areas revealed no dominant or suggestive masses. There was no cervical, supraclavicular, or axillary adenopathy on either side. Ultrasound examination of each upper outer quadrant confirmed the presence of bilateral fibrocystic tissue without any areas of suspicion.

However, a "second reading" of the mammogram reported two distinct sites of suggestive calcification in the left breast. The first area was located deep and centrally and was interpreted as BI-RADS (Breast Imaging Reporting and Data System) III; a second more superficial area was more suggestive (BI-RADS IV). Neither of these areas were palpable on CBE, and they were therefore biopsied by stereotactic core biopsy. While the first area showed only benign fibrocystic tissue, the second was found to be moderately differentiated invasive cluctal carcinoma with a lobular growth pattern and signet-ring cell features (Fig 3). The tumor was ER+/PR+, Her-2/neu negative, and the remaining histologic and immunostaining profile also matched those of both the gastric and bone marrow biopsies (Fig 3). Thus, the patient was given a diagnosis of breast cancer metastatic to the stomach and bone marrow.

Although cytotoxic chemotherapy was recommended, the patient opted for hormonal therapy and was given arimidex. She remains transfusion dependent. No treatment for the primary breast tumor was deemed necessary at this time.

DISCUSSION

Although breast cancer metastatic to the stomach is a well-known phenomenon, this case has several unusual features. First, while such lesions typically appear in patients with a well-established primary breast cancer (2-10) and up to 30 years after the diagnosis (9)), our patient's primary breast lesion was found only after the discovery of the gastric lesion, resulting in the initial consideration of the diagnosis of gastric cancer. Review of the literature reveals only two cases in which the GI metastasis was found first, and in neither of these cases was the GI lesion in the stomach. (11,12)

Indeed, the diagnosis of breast cancer could easily have been missed in this patient, since the original mammogram report was thought to be a "red herring." The correct diagnosis in this case can in part be attributed to the multidisciplinary nature of our tumor boards. In accordance with the guidelines of the Commission on Cancer, our tumor boards use a "working format" that discusses cases prospectively, as early as the workup phase, to guide diagnosis and treatment. (13)

Second, although the described breast primaries in cases with gastric metastases are typically large and clinically obvious, in our case the primary was actually occult (Fig 2). In a series of seven cases reported by Schwarz et al, (4) the primary tumor was stage I in only one case, and that lesion was palpable on CBE (R. Schwarz, MD, oral communication, June 1999). in contrast, the lesion we found was radiographically less than 5 mm (Fig 2) and was therefore clinically T1aN0, so-called minimal breast cancer. Thus, our case illustrates that a diagnosis of breast cancer metastatic to the stomach may require a high index of suspicion, as well as a standard, rigorous breast workup (beyond CBE alone), and it also emphasizes that even tiny breast cancers have a small but real risk of metastatic spread. (1)

Despite these unique features, our case also illustrates some well-described features of breast cancer metastatic to the stomach. As in other reports, our patient's gastric mucosal involvement showed a diffuse (rather than solitary) pattern (Fig 1) (2,4,11) and lobular features on histology (Fig 3). (4) The predilection for infiltrating lobular (as opposed to ductal) breast tumors to spread to unusual serosal and endocrine sites is well described but poorly understood. (4,14)

We agree with Schwarz et al (4) that because of the relative rarity of gastric cancer compared with breast cancer, the diagnosis of breast cancer metastatic to the stomach should be considered when a malignant gastric lesion suggesting a metastatic focus is found, in a female patient. The morphology of the metastatic gastric lesions on endoscopy and the immunostaining features (such as ER, PR, and GCDFP positivity (15) and the keratin pattern (16)) help to elicit the correct diagnosis. Determination of the correct primary source in these cases is not just an academic exercise, since the treatment and prognosis of metastatic breast cancer (especially receptor positive disease) and metastatic gastric cancer are different.

The treatment of widely metastatic breast cancer involves mainly cytotoxic chemotherapy or endocrine manipulation. (17) Endocrine manipulation may entail surgical or radiation-induced castration, antiestrogens such as tamoxifen, progestins, aminoglutethimide and aromatase inhibitors, and luteinizing hormone--releasing hormone analogs. In most series, response rates to endocrine therapy for women with ER-positive, PR-positive tumors range from 65% to 75%. (17) Oophorectomy is generally recommended as the first-line endocrine treatment for premenopausal women older than 35 and without significant visceral or marrow involvement, with goserelin or tamoxifen as alternative agents. (17,18) Although this patient had an ER-positive, PR-positive tumor, endocrine therapy would not be the first choice because of its slow onset of action, the presence of visceral organ involvement, and significant hematopoietic depression.

Conventional chemotherapeutic regimens for patients with clinically disseminated breast cancer include doxorubicin-based or taxane therapy. (17,18) Although the presence of significant hematopoietic depression due to the myelophthisic sydrome produced by bone marrow infiltration with tumor may preclude the use of full-dose conventional chemotherapy, we believe that aggressive eradication of tumor from the marrow may actually improve hematopoiesis. Furthermore, we have found that weekly taxane therapy has shown less myelosuppression than the standard 3-week dosage regimen. (19,20) Additonally, myelostimulating factors such as G-CSF can be supplemented to augment marrow recovery after anthracycline or taxane chemotherapy. (20) Thus, we favor treatment of systemic breast cancer in this setting with doxorubicin-based or weekly scheduled taxane therapy.

CONCLUSION

In contrast to previously reported cases of breast cancer metastatic to the stomach, in which the primary lesions were previously known and often clinically obvious, we describe a case in which minimal breast cancer was found in retrospect to be the primary tumor during the workup of a patient with presumed metastatic gastric cancer. A high index of suspicion, a multidisciplinary approach to the patient's workup, attention to the morphology of the gastric lesions on endoscopy, and the immunostaining features of the tumor were all instrumental in eliciting the correct diagnosis, which in turn led to a significant change in both the treatment recommendation and expected prognosis.

References

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(3.) Catino A, Lorusso V, Gargano G, et al: Metastatic involvement of the stomach secondary to breast carcinoma, a case report. Eur J Gynaecol 1992; 13:85-88

(4.) Schwarz RE, Klimstra DS, Turnbull ADM: Metastatic breast cancer masquerading as gastrointestinal primary. Am J Gastroenterol 1998; 93:111-114

(5.) Davis H Jr, Murray RK, Korbitz BC: Breast carcinoma metastatic to the stomach, report of a case in a male and review of an autopsy series. Am J Dig Dis 1968; 13:868-873

(6.) Klein MS, Sherlock P: Gastric and colonic metastases from breast cancer. Am J Dig Dis 1972; 17:881-886

(7.) Hattori T, Mine H, Abe Y, et al: Metastatic involvement of the stomach from breast cancer. Jpn J Surg 1973; 3:98-105

(8.) Appel MF: Gastric metastases from breast carcinoma. Am Surg 1974; 40:253-255

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(10.) Wile AG, Espinoza FP, Cohen AJ, et al: Metastatic breast cancer mimicking stomach cancer. Surg Rounds 1996; 19:436-439

(11.) Clavien PA, Laffer U, Torhost J, et al: Gastro-intestinal metastasis as first manifestation of a breast cancer. Eur J Surg Oncol 1990; 12:121-126

(12.) Hansen RM, Lewis JD, Janajan NA, et al: Occult carcinoma of the breast masquerading as primary adenocarcinoma of the small intestine, a case report. J Clin Gastroenterol 1988; 10:213-217

(13.) Vetto JT, Richert-Boe K, Desler MS. et al: Tumor board formats: "fascinating case" vs. "working conference." J Cancer Educ 1996; 11:84-88

(14.) Bumpers HL, Hassett J Jr, Penetrante RB, et al: Endocrine organ metastases in subjects with lobular carcinoma of the breast. Arch Surg 1993; 128:1344-1347

(15.) Monteagudo C, Merino MJ, LaPorte N, et al: Value of gross cystic disease fluid protein-15 in distinguishing metastatic breast carcinomas among poorly differentiated neoplasms involving the ovary. Hum Pathol 1991; 22:368-372

(16.) Wang N, Zee S, Zarbo R, et al: Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem 1995; 3:99-107

(17.) DeVita VT Jr, Hellman S, Rosenburg SA: Cancer: Principles and Practice of Oncology. Philadelphia, JB Lippincott Co, 4th Ed, 1993, pp 1315-1323

(18.) Cameron JL: Current Surgical Therapy. St. Louis, CV Mosby Co, 6th Ed, 1998, pp 659-662

(19.) Luck HJ, Scholz U, Kuhnle H, et al: UFT/oral calcium folinate plus weekly paclitaxel for metastatic breast cancer. Oncology 1999; 13:74-76

(20.) Frasci C, Comella P, D'Aiuto G, et al: Weekly paclitaxel-cisplatin administration with G-CSF support in advanced breast cancer. a phase II study. Breast Cancer Res Treat 1998; 49:13-26

RELATED ARTICLE: KEY POINTS

* Gastric metastasis from breast cancer is uncommon.

* The vast majority of patients with gastric metastases have advanced breast cancer.

* Tumors of unknown primary site require meticulous clinical and pathologic evaluation.

From the Departments of surgery (Section of Surgical Oncology), Medicine (Divisions of Hematology/Medical Oncology and Gastroenterology), and Pathology, Oregon Health Sciences University, Portland.

Reprint requests to John T. Vetto, MD, Oregon Health Sciences University, Section of Surgical Oncology, L223A 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098.