Originally published as JCO Early Release 10.1200/JCO.2005.04.7076 on April 10 2006

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Axillary Sentinel Lymph Nodes Can Be Falsely Positive Due to Iatrogenic Displacement and Transport of Benign Epithelial Cells in Patients With Breast Carcinoma

Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer

From the Lillian and Henry Stratton/Hans Popper Department of Pathology, Mount Sinai School of Medicine, New York, NY

Address reprint requests to: Ira J. Bleiweiss, MD, Department of Pathology, Mount Sinai School of Medicine, Box 1194, 1 Gustave L. Levy Pl, New York, NY 10029; e-mail: i.bleiweiss{at}mountsinai.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Immunohistochemical (IHC) staining for cytokeratins (CK) is common practice in evaluating sentinel lymph nodes (SLNs) in patients with breast carcinoma. IHC positivity typically indicates metastasis. SLN procedures are increasingly common in patients with pure intraductal carcinoma (DCIS). Iatrogenic epithelial cell displacement and benign transport of breast epithelial cells into axillary lymph nodes are recently described phenomena. We report 25 cases in which these factors probably resulted in benign epithelial cells in axillary SLNs (ie, false positivity).

METHODS: We reviewed 25 cases of CK-positive SLNs in which the epithelial cells had histologic and IHC characteristics different from their respective patients’ underlying breast carcinomas.

RESULTS: In all cases, the cytologic features of the epithelial cells in the SLNs were benign, and 22 matched those of corresponding intraductal papillomas that were involved by or were separate from the DCIS in the original cores or surgical biopsies. Fifteen cases were pure DCIS; most invasive tumors were smaller than 1.0 cm. In six carcinomas (DCIS) showing strong Her-2/neu staining, the corresponding epithelial cells in the SLNs were negative. In 13 tumors that were strongly and uniformly positive for estrogen receptor (ER), the cytokeratin-positive cells in the SLNs were negative for ER. Nineteen cases showed benign epithelial cell displacement at the biopsy site.

CONCLUSION: Epithelial cells in SLNs may result from transport of displaced cells, usually originating in intraductal papillomas. Positive immunohistochemical results in SLNs should be interpreted with extreme caution to avoid automatically concluding that such cells represent metastasis. Sentinel lymph nodes in breast carcinoma can be falsely positive.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Since its inception approximately 10 years ago,^1,2 the practice of sentinel lymph node (SLN) identification has become routine in surgical staging of invasive carcinoma of the breast. More recently, the technique’s application has been extended to patients with intraductal carcinoma (DCIS),^3-5 particularly to those with large areas of high nuclear-grade DCIS, especially when mastectomy is being performed.^6,7 The concern in such cases is that the finding of epithelial cells in the lymph node implies the presence of not only an occult invasive carcinoma, but an aggressive one, capable of metastasis despite a size below the level of clinical and radiologic detection. We recently observed 25 cases that challenge this assumption and therefore have important implications for the staging and treatment of breast carcinoma and for interpretation of clinical trials.

The sentinel lymph nodes of the patients we describe herein were found to contain epithelial cells with benign cytologic features and morphologic and immunophenotypic characteristics different from the cells of the patients’ respective underlying tumors. It is likely that these sentinel lymph nodes became falsely positive secondary to the combination of needle-induced iatrogenic epithelial cell displacement and benign transport of epithelial cells, both recently described phenomena.^8-16 The vast majority of such cases occur in the context of carcinoma involving an intraductal papilloma.^15,16

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
We reviewed 25 cases of CK-positive SLNs in which the epithelial cells in the SLNs had both histologic and immunohistochemical (IHC) characteristics different from those of their respective patients’ underlying breast carcinomas. The cases were prospectively received in our routine and consultation surgical pathology practice. The number of slides reviewed in each case ranged from 28 to 118 (mean, 62 slides). In the 13 cases received as consultations from other institutions, we made certain that we were able to review all of the slides which had been prepared, in some cases requesting additional slides and/or sections for immunohistochemical tests. Of the 12 cases that were seen in our routine hospital practice, five patients underwent breast conservation with the entire lumpectomy specimen being embedded and examined histologically, while the seven mastectomy specimens were sampled extensively with at least the core biopsy site being entirely examined histologically, the goal being assessment of entire areas of carcinoma for clinically and radiologically occult invasive disease.

The patients were all women, ranging in age from 39 to 81 years (mean, 56 years). All of the patients had lesions present on breast imaging studies as densities, calcifications, architectural distortion, or combinations thereof. Two patients with radiologic densities also had nipple discharge. The initial diagnostic procedure was stereotactic core biopsy (five patients), sonography-guided nonmammotome core biopsy (seven; one accompanied by fine-needle aspiration), surgical biopsy with wire localization (12 patients), or fine-needle aspiration (one patient). Axillary dissection consisted of SLN(s) only (16 patients) or SLN plus a few non-SLN's (seven patients). Two patients had follow-up completion axillary dissection. The timeframe between initial procedure and SLN identification ranged between 11 and 254 days (mean, 59 days).

Sentinel lymph nodes removed in our institution were bisected, embedded entirely, and sectioned via our routine protocol of five additional levels stained with hematoxylin and eosin followed by two IHC stains for keratins (CAM 5.2 and AE1/AE3). The methods of pathologic handling of SLNs at other institutions were variable in terms of number of additional levels and IHC stains performed. In 12 of the 13 consultation cases, the original pathologist interpreted the SLN as positive for metastasis. The remaining case was initially diagnosed as uncertain for metastasis.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Primary Tumor Pathology
The nuclear grade of the DCIS in each case was categorized as low (one patient), intermediate (eight patients), or high (16 patients). In general, estrogen receptor was positive and Her-2/neu was negative in the DCIS of low to intermediate grade, and the reverse was true only in a subset of the high-grade DCIS (Fig 1). Fifteen of the patients had DCIS with no invasive carcinoma detected despite the extensive histologic examination described above. Nine patients had T1 invasive duct carcinomas (five T1a or microinvasive, two T1b, and two T1c). The remaining patient had a T2 invasive duct carcinoma separate from an area of DCIS. Two of the patients had multiple invasive tumors: one patient had three separate invasive well-differentiated duct carcinomas, and one had invasive lobular carcinoma and invasive well-differentiated duct carcinoma. Nine of the invasive tumors were ER-positive and Her-2/neu–negative. One case of microinvasion could not be tested. Displaced benign epithelial cells (Figs 2 and 3) were identified in granulation tissue of the biopsy site (17 cases, three of which also had displaced cells in lymphatic channels), in lymphatic channels only (one patient), and in adjacent ducts (one patient). Twenty-two of the cases’ biopsy sites had intraductal papilloma, some sclerosing, and some with involvement by DCIS. Some of the papillomata contained apocrine metaplasia (Table 1) .

View larger version (124K): [in this window] [in a new window]   Fig 1. Photomicrograph of intraductal carcinoma. The cells have large, pleomorphic nuclei with prominent nucleoli. Note that the nuclei are 5 to 6 times the size of those of the lymphocytes on the right.

View larger version (118K): [in this window] [in a new window]   Fig 2. A displaced cohesive cluster of benign epithelial cells amid granulation tissue of a core biopsy site. The cells have prominent eosinophilic cytoplasm (apocrine features).

View larger version (106K): [in this window] [in a new window]   Fig 3. Benign epithelial cells in lymphatic channels. (A) Papillary apocrine cells in the same case as Figure 2. (B) Uniform epithelial cells with bland nuclei in a growth pattern identical to florid duct hyperplasia with a small hyalinized area (top center) as seen in intraductal papilloma.

View larger version (101K): [in this window] [in a new window]   Fig 4. Benign epithelial cells in a cohesive cluster in a peripheral sinus of a sentinel lymph node (same case as Fig 1). (A) The growth pattern is that of florid duct hyperplasia, and the relatively uniform nuclei are only slightly larger than those of the adjacent lymphocytes. (B) Immunohistochemistry is positive for cytokeratin after a previously negative stain for Her-2/neu. The intraductal carcinoma (DCIS) in this case was positive for Her-2/neu.

View larger version (97K): [in this window] [in a new window]   Fig 5. Serial immunohistochemical stain for cytokeratin (CAM 5.2) and estrogen receptor protein reveals epithelial cells in a sentinel lymph node which were not apparent on routine stains. The nonstaining nuclei in the center of each cell are uniform and indicate estrogen receptor (ER) negativity while the patient’s DCIS was ER positive.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
SLN identification has rapidly become routine in the surgical staging of invasive carcinoma of the breast. Numerous reports have both confirmed the validity of the procedure^17,18 and established its utility in decreasing standard axillary dissections because SLN negativity predicts absence of disease in the remainder of the axilla.¹⁹ The procedure has also allowed pathologists to subject the SLN to additional examination in order to identify small foci of metastatic disease at least in the lymph node most likely to contain it.^20-22 This, in part, has led to revision of the American Joint Committee on Cancer (AJCC) staging system.^23,24 The methods of examination and clinical implications of such micrometastatic or individual tumor cell metastasis are beyond the scope of this publication.

In recent years, SLN identification is increasingly being performed in patients with DCIS. The rationale for this is clearly apparent in selected cases, namely those patients with radiologically large areas (typically > 2.5 cm) of high nuclear-grade DCIS in whom mastectomy is being performed after core or surgical biopsy. These patients are more likely to harbor clinically and radiographically occult invasive carcinoma,²⁵ and thus performing SLN would abrogate the need for an additional surgical procedure after the discovery of invasion. Furthermore, accurate SLN might not be possible postmastectomy, certainly once reconstruction has been completed, and such patients would need to submit to standard axillary dissection. Our experience indicates, however, that the pathologic results of this procedure must be interpreted with great caution.

To understand the mechanism for falsely positive SLNs, it is necessary to review and merge a few related important concepts:

(1) Benign epithelial cells can be found in axillary lymph nodes. Pathologists have long been aware of the occasional, albeit rare, presence of benign glandular breast tissue in axillary lymph nodes,^26-29 as in one of the cases above. More recently, Carter et al¹² described the presence of benign breast epithelial cells in peripheral sinuses of axillary lymph nodes (almost all not derived from SLN procedures), a phenomenon termed benign transport.

(2) Needling procedures can cause epithelial cells to be displaced out of their normal intraductal milieu. Youngson noted this phenomenon in 1994⁸ in the context of core biopsies, fine-needle aspiration, wire localization, and even lidocaine injection. The vast majority of cases, however, occur after image-guided core biopsy, probably the most common current scenario for breast cancer diagnosis. Benign and/or malignant cells³⁰ can be displaced and histologically evident in the granulation tissue of the biopsy site, in lymphatic channels, or in both.

(3) We recently reported that displacement is almost exclusively seen in papillary lesions (benign or malignant) of the breast.¹⁶ Papillary lesions are extremely friable, being built of epithelial cells lining delicate fibrovascular stalks. Manipulation of such areas causes the lesions to fragment such that resultant core biopsy specimens normally include such loose tissue fragments and cells in blood. Fragmentation should therefore also be evident at the biopsy site.

(4) A traumatized area heals in part by its contents being drained to regional lymph nodes. The SLN by definition is the first lymph node in the drainage pathway and, in fact, is identified as such by taking advantage of this phenomenon. SLNs do not choose what they are to drain. Whatever is present in the biopsy site can potentially be passively transported to the SLN. We have found calcifications, mucin, benign nevus cells, silicone and polyurethane fragments from breast implants, and foreign body reactions in SLNs but not in other lymph nodes of the same patients.

(5) Intraductal papilloma of the breast is a common entity, and malignancy involving it is not infrequent. A variable but substantial upstage rate has been reported for excisions of lesions core biopsy-diagnosed as simple intraductal papilloma.^31,32 Molecular evidence also indicates the premalignant potential of these lesions.^33-35 Thus, whether the papilloma is the initial radiologic target and or if it is secondarily involved by a large area of DCIS, the coexistence of papilloma and DCIS is not surprising.

All of the above factors combine to create the situation whereby an initial needling procedure can cause epithelial cells to be displaced into a healing biopsy site from which they are physiologically transported to the sentinel lymph node. The potential for such cells to be overinterpreted as evidence of metastatic carcinoma simply because they are epithelial is very real. Certainly micrometastasis from tiny occult invasive carcinomas exists, albeit rarely. The question then becomes how to separate out what is real from what is not, and, if it is real, is it clinically relevant? In our view, the first step is to compare the cytologic and IHC characteristics of the cells in the lymph node with those of the tumor, keeping in mind that there is typically excellent correlation between the nuclear grade and IHC features of a given DCIS and its respective invasive duct carcinoma (eg, high-grade ER/PR-negative, Her-2–positive DCIS begets invasive duct carcinoma with the same characteristics).³⁶ True metastasis from occult invasion should also therefore have these features, whereas cells originating from a benign population may not. Indeed, although few in number, studies have shown excellent concordance between primary carcinomas and their respective lymph node metastases in terms of ER³⁷ and Her-2³⁸ status.

Interpretation becomes more complicated, however. Tumor cells can also be displaced iatrogenically and presumably transported; thus, the simple finding of malignant cells in the SLN does not necessarily equate with metastasis. In this scenario the cells’ characteristics will match those of the carcinoma, making the distinction between transport and true metastasis virtually impossible, even in cases with known invasive carcinoma. Some authors¹³ have brought forth the concept of established metastasis, ie, evidence of tumor cells establishing themselves in the lymph node by invasion of the parenchyma (beyond the sinuses) and proliferating (mitoses); however, even such lesions must presumably originate from cells in the sinuses, and therefore the lack of such a pattern cannot completely exclude the possibility of metastasis. Given the small volume of tumor cells involved, mitotic activity would be rare even in true metastasis. One must realize, however, that in some cases (eg, low nuclear grade ER+/PR+ tumors) even the distinction between benign and malignant cells in the SLN may be impossible. One could argue that, even in our cases, scattered low nuclear grade epithelial cells in SLN sinuses could represent metastasis from an occult invasive lobular carcinoma; however, such cells should be ER+, not negative as in our results. We have seen no real evidence and can think of no hypothetical reasons that intrinsically invasive cells can be iatrogenically displaced and transported, and thus, when one encounters epithelial cells in the SLN that are identical in all respects to those of the invasive tumor, they should probably be considered metastatic, especially in the absence of histologic displacement at the biopsy site.

In addition, can iatrogenically transported DCIS cells survive and mutate in the systemic circulation to establish metastasis? Although currently the lack of a molecular difference between in situ and invasive components of a tumor would imply this possibility, the lack of clinical relevance of positive lymph nodes in DCIS³⁹ would argue against this. Clearly something must be different about cells with metastatic capacity on a molecular level, and a test for this difference would be the only method of sorting out these possibilities. We would further argue that until a metastasis-specific assay is developed any currently available molecular test (eg, polymerase chain reaction for cytokeratins) is contraindicated on SLNs, since by their nature such tests lack morphologic correlation of the cells that caused the positive test. For example, benign glandular inclusions, albeit rare, may be present in axillary lymph nodes, and would cause a false-positive PCR reaction.

Given the previously mentioned results, how should the pathologist handle SLNs? Certainly this is still a contentious matter. Some might interpret these findings as a reason not to do IHC on SLNs at all. We, however, feel that cautious interpretation of such tests is more important, not the lack thereof. While the majority of these cases are evident as a result of IHC staining, epithelial cells in SLNs can be found on routine histology. In fact, only by utilizing both methods can one hope to separate the wheat from the chaff and eventually understand the clinical relevance of true metastasis consisting of isolated tumor cells.

The presented findings also have important implications for staging of invasive breast carcinoma and for interpretation of prior trials. One must allow for the possibility that some cases containing minimal tumor cells in sentinel (or nonsentinel in older literature) lymph nodes may not represent metastatic carcinoma at all, but displaced and transported benign and/or malignant cells. This may, in part, explain the current lack of literature consensus about the predictive value of micrometastasis or individual tumor cell metastases in terms of both disease-free survival and death from disease.

In the end, the presence of epithelial cells in SLNs must be evaluated carefully on a case by case basis with comparative histology and immunohistochemistry until a reliable metastasis specific marker can be developed. The failure to do so could cause improper staging and prompt unnecessary chemotherapy and/or completion axillary dissection. In our view, until a patient has a histologically proven invasive tumor, sentinel lymph node dissection should not be a routine procedure, particularly in cases of intraductal carcinoma involving an intraductal papilloma.

Author’s Note
After this article was accepted for publication, we encountered another case of estrogen-receptor (ER)–positive ductal carcinoma in situ and intraductal papilloma, in which ER-negative, benign-appearing, epithelial cells in a sentinel lymph node were accompanied by myoepithelial cells, as was demonstrated by nuclear staining for P-63 protein. This provides additional evidence of the benign nature of these cells and their origin from intraductal papilloma.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer Provision of study materials or patients: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer Collection and assembly of data: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer Data analysis and interpretation: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer Manuscript writing: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer Final approval of manuscript: Ira J. Bleiweiss, Chandandeep S. Nagi, Shabnam Jaffer

 

	ACKNOWLEDGMENTS

 
The authors wish to thank Marc Citron, MD, for his valuable comments.

	NOTES

 
Presented in part at the 27th Annual San Antonio Breast Cancer Symposium, December 2004, and at the United States/Canadian Academy of Pathologists Annual Meeting, Vancouver, BC, March 2004. The study was approved by the institutional review board of the authors’ institution.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted October 23, 2005; accepted January 6, 2006.

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