Axillary nodal metastasis of occult breast primary cancer

Introduction
Occult carcinoma of the breast presenting as an axillary mass has been recognized since the turn of the 20th century. In most cases the carcinoma is identified in the breast after clinical and/or pathological examination. Xeromammography supplemented by various lesion localization techniques greatly increases the pick up rate of clinically undetectable breast tumors. The recognition of certain breast parenchymal patterns associated with a high hazard of concomitant carcinoma will undoubtedly improve our diagnostic accuracy. There still remains a small number of cases in which no primary cancer is found in the ipsilateral breast despite pathologically established axillary nodal metastases consistent with a breast primary.
Traditionally, occult breast cancer is treated with total mastectomy and axillary dissection, but accumulating data suggest that primary breast irradiation following axillary dissection may provide an equivalent survival with the advantage of breast conservation. Occult breast cancer patients are eligible for adjuvant chemotherapy and radiation as stage II/ III node-positive patients would be treated. Overall, the prognosis for occult breast cancer is equivalent to or slightly better than staged counterparts with detectable primary breast tumors.
In 1907, Halsted (1) first described two patients with 'extensive carcinomatous involvement of the axilla' due to occult breast cancer: 'In the course of a few months, thereafter, the mammary disease manifested itself in both patients'. Occult breast cancer is uncommon, accounting for fewer than 1% of all breast cancer patients (2- 4). This paper describes a case of occult breast cancer which was diagnosed by right axillary lymph node metastasis, together with a review of the literature.

Case report
A 42-year-old woman visited our clinic complaining of a 35 × 29 mm tumor in the right axilla. Clinically, no mass was palpable in the right breast and no nipple discharge was seen. Calcifications were found in the breast by mammography and ultrasonography of the right axilla demonstrated a pathologic mass (fig. 1). The patient underwent a fine needle aspiration cytology,that was positive for malignancy (fig. 2). Excisional biopsy of the tumor was performed. Histological examination showed a metastatic ductal carcinoma in the lymph node (fig. 3).

The patient underwent a work-up including ultrasono-graphy, computed tomography, esophago-gastrography, barium enema and scintigraphy for examination of the neck, chest, abdomen, pelvis and bone, which were all negative. Serum levels of CEA, CA15-3, CA19-9, CA125 and AFP were within normal ranges. Estrogen receptor (ER) analysis of the axillary lymph node using enzyme immunoassay method was positive, but progesterone receptor (PR) analysis was negative (43.8 and 4.2 fmol/mg protein, respectively). There were no mutations of c-erbB2 and p53 gene in the PCR analysis of the lymph node. Immunostaining of ER was positive, but CEA, c-erbB2, p53 and thyroglobulin were negative in the lymph node. Since occult breast cancer was the most likely diagnosis, modified radical mastectomy was performed. The removed specimen was serially sectioned in a 5 mm stepwise fashion and 96 sections were examined. Microscopy of the specimen failed to find the primary breast cancer lesion. There was no other metastasis in 28 resected axillary and infraclavicular lymph nodes and accessory breast gland was not revealed. Because only one node was involved and there was no evidence of systemic spread, the patient received cobalt radiotherapy to the axillary and supraclavicular area. One year postoperatively she is alive and well and without tumor recurrence.

Discussion
A carcinoma found in the axillary lymph node may be caused by primary carcinoma of heterotopic glandular tissue or metastatic neoplasm. Carcinomas arising in the heterotopic glandular tissue should accompany the pre-existing non-neoplastic glandular component and the ectopic tissue may be present in more than one lymph node (5). In the present case, there were no heterotopic glandular tissues in the axillary lymph nodes.
Aside from breast cancer, many other adenocarcinomas have been shown to metastasize to axillary lymph nodes (6). The most common of these include lung, thyroid, stomach, colo-rectum and pancreas. Once a diagnosis of metastatic adenocarcinoma on an axillary lymph node has been made in a female patient, there is a tendency to subject the patient to an exhaustive investigation. However, most of these additio-nal tests failed to identify another primary site of carcinoma. Kemeny et al. (7) reported that further diagnostic work-up was unnecessary. A thorough history, physical examination, screening blood work and chest roentogenogram are sufficient for locating other potential primary sites of carcinoma.
ER/PR analysis should be performed for two reasons (8, 9). Positive findings are suggestive of breast cancer and these occur in approximately 50% of females. Negative ER/PR do not exclude the diagnosis of breast cancer, however, and it is important to remember that other malignancies (e.g. colon, ovary, endometrium, kidney and melanoma) may demonstrate detectable ER/PR activity (10, 11). The second reason for obtaining ER/PR studies on the initial biopsy is that a primary tumor may never be identified or, if found, may be so small as to render ER/PR assay impracticable (9, 12). Tumor marker studies such as CEA and CA15-3 can also contribute to a more reliable diagnosis. Immunohistochemical stains for lactalbumin, CEA, ER and PR are recommended for the diagnosis of breast cancer (9, 11). CEA and ER are not specific for breast cancer, but their positivity unequivocally supports the diagnosis of metastatic breast cancer. In the present case, tumor markers were all negative, but analysis and stain of ER were strongly positive.
There have been reports of some cases where the primary breast tumor could not be identified even in radical mastectomy specimens as in our case. A primary breast cancer will be not found in the specimen in about one third of the cases in the literature (3, 4, 7, 12). Occult breast cancer demonstrated an 8-20% incidence of in situ cancer as the primary lesion (3) and this is in contrast to the reported 1% incidence of axillary metastases in series of non-palpable in situ carcinoma of the breast (13). Kyokane et al. (4) reported that the primary tumors of non-palpable breast cancer presenting as an axillary mass were smaller than 5 mm in 19 of 62 cases, and 9 of 72 cases were intraductal carcinoma with or without minimal invasion. Little has been reported on spontaneous regression of the tumor of breast cancer. In the present case, the primary tumor was probably smaller than 5 mm. Ozzello and Sanpitak (14) speculated that either the thorough sampling process failed to locate the primary invasive cancer or, as seen with electron microscopy, invasion through the basement membrane may occur before detection by light microscopy. However, it is not clear that basement membrane invasion that is only detected by electron microscopy has any clinical significance.
The treatment of occult breast cancer remains controversial. Traditionally, the treatment of choice for these patients was radical or modified radical mastectomy (1, 2, 12). Most groups have shown long-term survival with mastectomy to be at least comparable with that for node-positive palpable breast cancer, even when no primary is found in the mastectomy specimen. Recent studies have suggested that there was no statistically significant difference in outcome between mastec-tomy and breast conservative treatment such as limited resection and/or radiation and/or chemotherapy (3, 7, 15). In recent years, radiation treatment has been an alternative to mastectomy (16). The high incidence of early lesions and the current trend toward breast conservation argue in favor of this approach 9 (17).
The role of adjuvant systemic therapy in occult breast cancer has never been investigated in a prospective randomized fashion. There are two retrospective studies (3,15). However, there were only a small number of patients, which makes it difficult to detect a statistically significant improvement in survival with adjuvant chemotherapy. The most reasonable recommendation is still that these patients be treated like other node-positive breast cancer patients, with adjuvant chemotherapy or hormonal therapy. Furthermore, since patients with negative ER generally have a poor survival, this prognostic factor may be useful in determining the need for adjuvant chemotherapy.
The overall 10 year survival for patients with occult breast cancer is 50-71% (3, 7, 15). Survival has not been shown to be dependent on whether the primary cancer in the mastectomy specimen is found (3, 12). Both the nodal and ER status have been shown to be the major prognostic variables (3,12). In the absence of good prospective randomized data, it is reasonable to treat these patients similarly to other patients with node-positive and palpable breast cancer, with adjuvant chemo-endocrine therapy.
The increasing worldwide tendency for conservative breast surgery places great emphasis on the need to assess precisely the full extent of cancer in the breast. Indeed, inadequate surgical management of breast cancer is common, as shown by the number of excision biopsies with positive resection margins. Although radiation therapy and chemotherapy play important roles in managing undetected malignant foci, the fact that these foci are not surgically removed may lead to an increased local recurrence. This increase is of particular interest for multicentric cancers, when the distant focus is probably outside the field of boost radiotherapy. Similarly, it is of dramatic importance for synchronous bilateral cancers. Starting from the viewpoint that conservative therapy for breast cancer requires the ability to screen the entire breast for additional sites of malignancy with a high sensitivity (a difficult task in dense breasts), F. Sardanelli et al (18) compared MRI to mammography in breasts of various densities. Their results indicate that MRI is significantly more sensitive than mammography for the detection of multiple malignant foci in scattered fibroglandular or heterogeneously and extremely dense breasts, but is not significantly more sensitive in fatty breasts. Mammo-graphy misses more invasive and larger cancer foci than MRI. However, false-positives are a problem for both techniques. The relatively low specificity of MRI makes the availability of MRI-guided breast biopsy mandatory. even if the cost is in the range of $1,300 to $2,000" should be considered. Despite the fact that MRI is the best technique available for the detection of multifocal, multicentric breast cancers, improved performance may still be achievable. In terms of sensitivity, a gain could be achieved using a higher in-plane and through-plane spatial resolution. In terms of specificity, improved performance may be achieved by integrating the best morphologic and dynamic data, by means of proton MR spectroscopy, and by the use of short-term antiestrogen (tamoxifen) medication before MRI. We are aware that the real clinical significance of malignant foci detected solely on MRI is still a matter for debate. If combined with radiation therapy, breast-conserving surgery gives survival rates that are not significantly different from those obtained with mastectomy. Randomized studies comparing the outcome of patients undergoing pretreatment MRI with a control group not undergoing pretreatment MRI are needed to define the effects of a more precise evaluation of the extent of disease on relapse rate, quality of life, and survival rate.
Color Doppler sonography has been proposed as an alternative imaging technique for occult breast lesions. This technique can detect "tumor flow signal" seen with malignancies and can provide an accurate method of preoperative localization. Wei-Jei Lee et al. (19) were able to identify two occult breast cancers using color Doppler sonography that were subsequently biopsied by sonogram-guided wire localization, and they revealed a carcinoma in both cases. Both women successfully had breast conservation with a wide local excision and axillary node dissection.
Other investigational imaging modalities include positron emission tomography (PET) scan and thermography. PET is an imaging technique that allows evaluation of the metabolic activity of a tumor by injecting a radiolabeled analog of glucose. Avril et al. (20) demonstrated that PET could be used to evaluate for large axillary metastases in breast cancer patients, with a 95% sensitivity and a 65% specificity. PET scanning has been successfully used to identify hypermetabolic foci in mammographically occult breast cancer patients, and it may be a useful diagnostic tool in the management of patients with occult breast cancer.
Total mastectomy with axillary dissection has traditionally been the recommended treatment for occult breast cancer since the time of Halsted (1). Over the years, many groups have reported on alternative treatments, avoiding mastectomy or axillary dissection. However, failure to treat the breast has led to an unacceptable tumor recurrence rate in many reports (21).
There has been considerable support for primary breast irradiation for local control following complete axillary dissection as a method of breast conservation. One early convincing report is from Vilcoq et al. (16) at the Institute Curie. They described 11 patients with subclinical breast cancers who were treated primarily by radical radiotherapy to the breast, axilla, and supraclavicular nodes. Eight of these patients had excision of the axillary mass prior to radiation, and two had a delayed axillary dissection for persistent disease after radiotherapy. The radiation dose was 5000 to 6500 rads given over a 5- to 6-week course. Three local recurrences in the breast were discovered, two of which were salvaged by mastectomy. Ten of 11 patients were disease-free at 5 years, comparable with the results of mastectomy. The results of this study strongly support the use of radiation therapy as an alternative to mastectomy in occult breast cancer.

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