Lymph node metastasis from ductal carcinoma in situ with microinvasion
Widespread use of mammography has increased the detection of ductal carcinoma in situ with microinvasion (DCISM) in pathology specimens. Currently there is disagreement regarding the incidence of axillary metastasis from DCISM. The controversy centers on whether complete lymphadenectomy is indicated for axillary staging, given its morbidity and the reportedly minimal rate of axillary involvement in these patients. Intraoperative lymphatic mapping and sentinel lymphadenectomy (SLND) may obviate complete axillary lymph node dissection in selected breast carcinoma patients. In intraoperative lymphatic mapping, isosulfan blue dye is used to demonstrate the course of lymphatic flow from the breast tumor to the first draining or sentinel lymph node. This blue-stained lymph node is selectively excised for pathologic examination; its tumor status is used to predict the tumor status of the other axillary lymph nodes. The authors examined whether SLND would be suitable for staging DCISM.
From February 1992 to January 1997, 14 patients with DCISM underwent intraoperative lymphatic mapping and SLND at the John Wayne Cancer Institute in Santa Monica, California. Clinical and pathologic data were prospectively collected.
Primary DCISM tumors ranged in size from 0.9 to 6.5 cm. Nine patients presented with mammographic abnormalities, two patients presented with Paget's disease and a palpable lesion, and three patients presented with palpable lesions. Two patients (14.3%) had tumor-involved sentinel lymph nodes. One of these patients had two sentinel lymph nodes, both of which contained single cancer cells identified by immunohistochemistry. The other patient had 1 sentinel lymph node, in which a 0.3-cm metastasis was revealed by light microscopy. Completion axillary dissection was performed on both patients and revealed no further tumor positive lymph node metastases.
SLND can detect lymph node micrometastases (tumor deposits <2 mm) in patients with DCISM. The clinical relevance of these micrometastases is unknown, but their existence shows that DCISM can involve the lymph nodes. Cancer 1999;85:2439–43. © 1999 American Cancer Society.
Before the widespread use of mammography, ductal carcinoma in situ (DCIS) presented as a palpable mass, Paget's disease, or a bloody nipple discharge. The nonmetastatic nature of DCIS was unappreciated in part because lesions discovered before mammography were larger and often associated with frank or occult invasion. In 1971, Haagensen1 made a diagnosis of DCIS if less than half of the lesion had histologically invasive elements. This definition has since changed to exclude tumors with any invasive characteristics, no matter how small.
Without breach of the basement membrane, lymph node metastasis is impossible. Examination of axillary lymph nodes is therefore not necessary to stage DCIS, and the extremely low rate of axillary metastasis (less than 1%) combined with the success of breast-conserving therapy has allowed surgeons to abandon axillary dissection for DCIS in those patients who are amenable to lumpectomy.2, 3 However, once the basement membrane has been violated, by even one cell, the diagnosis changes to DCIS with microinvasion (DCISM) and the possibility of lymph node metastasis is introduced. Is this risk high enough to warrant surgical staging of the axilla? Some believe that axillary lymph node dissection (ALND) is not necessary for DCISM, because it is generally not associated with lymph node metastasis and has a favorable natural history.4, 5 Other groups report rates of lymph node metastasis ranging from 2.7% to 20% and advocate complete ALND.6–9
However, complete ALND carries a morbidity that may not justify its use for patients with DCISM. In patients with invasive breast carcinoma, intraoperative lymphatic mapping and sentinel lymph node dissection (SLND) reduces the morbidity of axillary staging by minimizing lymphatic disruption.10 It also increases the sensitivity of staging because it involves focused pathologic examination of the sentinel lymph node by immunohistochemical as well as conventional staining techniques. We therefore examined SLND for axillary staging of DCISM.
PATIENTS AND METHODS
We reviewed the records of all patients with a diagnosis of DCISM who underwent SLND and a definitive breast operation at our institution between February 1992 and January 1997. From this group we selected for study all patients whose primary breast tumors fulfilled the criteria of Silver and Tavassoli:5 1 tumor focus not greater than 2 mm, or up to 3 foci each not greater than 1 mm. All 14 patients who met these criteria had been prospectively treated and followed. The following clinical data were compiled for each patient: method of tumor detection, method of diagnosis, type of surgery performed, date of surgery, and postoperative clinical course.
Intraoperative lymphatic mapping with SLND was performed as follows: Patients were placed under general anesthesia, and the breast, axilla, and arm were prepped in a sterile field. A 25-gauge needle was used to inject 3–5 cc of 1% isosulfan blue dye (Lymphazurin, Hirsch Industries, Richmond, VA) into the parenchyma surrounding a palpable tumor or into the wall of a biopsy cavity. If the primary tumor was nonpalpable, the blue dye was injected through the needles used for mammographic localization. After 3–5 minutes of massage to increase lymphatic flow, a transverse incision was made 1 cm beneath the hair-bearing portion of the axilla. A blue-stained lymphatic tract was identified in the axilla and followed by blunt dissection to the first “sentinel” lymph node(s) that stained blue. All lymph nodes that stained blue were removed and sent for pathologic evaluation. The planned operation was then completed.
Pathologic examination of the breast tissue employed standard techniques. For smaller tumors, the entire tumor was embedded and sectioned; for larger tumors, multiple representative sections were examined. All slides were reviewed and DCIS was graded on a three-level system based primarily on nuclear grade and secondarily on necrosis.11 Features recorded included pathologic size, histologic pattern, nuclear grade, and presence of necrosis. DCISM was diagnosed on the basis of clear or suspected microinvasion of carcinoma cells into stromal tissue outside defined mammary ducts and lobules. In some cases, immunohistochemical staining for smooth muscle actin and cytokeratin filaments was used to identify evidence of microinvasion. Microinvasive foci were measured with an ocular micrometer and counted as one or more than one (multiple).
Each sentinel lymph node was bisected or macroscopically sectioned at 2–3 mm intervals. Following intraoperative frozen section examination at one level, the tissue was embedded and permanent sections were prepared at two levels for hematoxylin and eosin (H & E) and cytokeratin immunohistochemical (IHC) staining as previously described.10
Nine patients had nonpalpable mammographic abnormalities, two had Paget's disease associated with a palpable mass, and three had a palpable mass. Ten patients underwent SLND after excisional biopsy of the primary revealed microinvasion. Two patients opted for SLND prior to a diagnosis of microinvasion, because a second operation would be waived if microinvasion was found at segmental mastectomy. The two patients with Paget's disease underwent SLND as part of a modified radical mastectomy. In both cases, DCISM had been diagnosed by excisional biopsy of the palpable lesion. Three patients underwent complete ALND, in two cases for positive sentinel lymph nodes. In the remaining patient, ALND was undertaken because at that time it was still routinely performed after SLND independent of the tumor status of the sentinel lymph node. The clinical findings are summarized in Table 1.
Table 1. Detection and Surgical Treatment of DCISM in the Study Population
|1||Mammogram||SM for DCIS on core biopsy||SM+ SLND|
|2||Mammogram||Excisional biopsy||SM+ SLND|
|3||Mammogram||Excisional biopsy||SM+ SLND|
|4||Paget's disease+ palpable mass||MRM for DCIS on nipple biopsy||MRM+ SLND|
|5||Mammogram||SM for DCIS on core biopsy||SM+ SLND|
|6||Mammogram||Excisional biopsy||SM+ SLND|
|7||Mammogram||SM for DCIS on core biopsy||SM+ SLND|
|8||Paget's disease+ palpable mass||MRM for DCIS on nipple biopsy||MRM+ SLND|
|9||Mammogram||SM for DCIS on core biopsy||SM+ SLND|
|10||Palpable mass||SM+ SLND for DCIS on core biopsy||SM+ SLND|
|11||Mammogram||Excisional biopsy||SM+ SLND|
|12||Mammogram||SM+ SLND for DCIS on core biopsy||SM+ SLND|
|13||Palpable mass||Excisional biopsy||SM+ SLND|
|14||Palpable mass||Excisional biopsy||SM+ ALND|
The tumors ranged in size from 0.9 to 6.5 cm, with a mean of 3.2 cm (Table 2). Eleven patients had a Grade 3 tumor, 2 had a Grade 2 tumor, and 1 had a Grade 1 tumor. Five tumors had solid and comedo growth patterns, three had solid patterns, two had solid and clinging growth patterns, one had cribiform and comedo patterns, one had a pure cribiform pattern, one had a pure comedo pattern, and one had papillary and comedo patterns. Twelve tumors demonstrated necrosis and all appeared to be unicentric.
Table 2. Pathologic Findings
|1||5.5 cm||3||<0.1 cm||0/4|
|2||2.5 cm||3||<0.1 cm||0/2|
|3||1.8 cm||3||<0.1 cm||0/2|
|4||2.0 cm||2||0.2 cm||0/1|
|5||1.5 cm||3||<0.1 cm||0/2|
|6||2.0 cm||3||<0.1 cm||0/2|
|7||6.5 cm||3||<0.1 cm||0/2|
|8||4.5 cm||3||<0.1 cm||1/1|
|9||0.9 cm||2||<0.1 cm||0/1|
|10||6.0 cm||3||<0.1 cm||0/1|
|11||3.5 cm||1||<0.1 cm||0/3|
|12||5.0 cm||3||0.2 cm||0/1|
|13||3.0 cm||3||0.1 cm||0/1|
|14||4.5 cm||3||0.2 cm||2/2|
Seven of the tumors had only one focus of microinvasion, and seven had multiple foci. Seven specimens revealed definite microinvasion; the other seven were labeled suspicious for microinvasion by the pathologist. Eleven tumors had areas of microinvasion that were less than 0.1 cm and therefore met the American Joint Committee on Cancer's recently revised definition of DCISM as microinvasion <0.1 cm, whether it involves single or multiple foci.12 These 11 tumors included one with lymph node involvement (see below). The three remaining tumors each had a suspicious area of 0.2 cm and therefore did not fit the more stringent definition of the American Joint Committee on Cancer. No tumor had evidence of lymphatic vascular invasion.
One to four sentinel lymph nodes from each patient were examined (mean, 1.9). The total number of sentinel lymph nodes examined was 27. Two patients had lymph node metastases (Table 2). One of them (Patient 8) presented with Paget's disease and a palpable mass. Her tumor was Grade 3, with a 4.5-cm noninvasive component and a solid and clinging histologic pattern. Multiple foci suspicious for microinvasion were <1 mm. The sentinel lymph node was positive for a 0.3-cm metastasis by light microscopy. Completion ALND revealed 17 benign lymph nodes. She currently is alive with disease, having developed a malignant pleural effusion 29 months after breast surgery. The second patient (Patient 14) presented with a palpable mass. Her tumor was Grade 3, with a 4.5-cm noninvasive component. The microinvasive carcinoma measured 2 mm. Two sentinel lymph nodes had rare IHC positive individual cells. Completion ALND revealed 18 benign lymph nodes. At 31 months of follow-up, this patient was without clinical evidence of disease.
Although microinvasion is a property of invasive disease, the potential for lymphatic spread from a microinvasive tumor is not clear. Some authors have advocated no axillary dissection for DCISM based on the absence of lymph node spread.4, 5 Wong et al.4 studied 41 patients with DCISM defined not by size but by a microfocus of tumor cells in the basement membrane. Twenty-three patients had a palpable mass and 17 had mammographic abnormalities; 1 had Paget's disease. No lymph node metastases were found, and there were no local recurrences or deaths during a median follow-up of 37 months. Silver and Tavassoli5 examined 38 cases of DCISM; 18 were detected by mammography, 19 were palpable lesions, and 1 was Paget's disease. DCISM was defined as 1 tumor focus <2 mm, or no more than 3 foci <1 mm each. Thirty-one had a comedo pattern. Again, no lymph node metastases were found. Other authors advocate no axillary dissection for DCISM based on a lack of difference in disease free or overall survival between DCIS and DCISM.13
However, Rosner et al.6 reported lymph node disease in 2.7% of patients with DCISM, defined by areas of invasion up to 10% of the surface area of the histologic sections examined. This broader definition may have included patients omitted from other studies. Kinne et al.3 reported a 10% chance of lymph node disease for 42 patients with DCISM defined by unspecified criteria. At a median follow-up of 11.5 years, 94% were without clinical evidence of disease. Shuch et al.7 analyzed findings of 30 patients with DCISM defined by stromal invasion without reference to size. Six patients (20%) had lymph node involvement and 4 eventually died of their disease; however, 63% of the population presented with a palpable primary tumor.
Our study population was too small for meaningful analysis of the incidence of axillary metastasis in DCISM, but it did confirm the feasibility of SLND as a staging alternative to conventional ALND for this neoplasm. Because SLND removes only 1–3 lymph nodes, compared with the average of 19 removed during ALND, it causes less lymphatic disruption and therefore greatly reduces seroma formation.14 Moreover, the intercostal brachial nerve is not sacrificed in SLND, which essentially eliminates the postoperative complaint of inner arm numbness associated with ALND. We previously demonstrated that SLND offered improved staging of primary invasive breast carcinoma.10 In that study, 134 patients treated with ALND alone were compared with 162 patients who underwent SLND followed by ALND. The respective rates of lymph node involvement were 29.1% and 42.0%, and the corresponding incidence rates of lymph node micrometastases (<2 mm) were 10.3% and 38.2%.
The sensitivity of sentinel lymph node assessment based on serial sections and IHC should determine whether microinvasion increases the risk of lymph node micrometastasis in patients with DCIS. Microinvasion associated with small DCIS tumors might be a marker of aggressiveness. Although the clinical relevance of micrometastasis is debatable, adjuvant treatment for these patients would be prudent, because some studies have found a survival disadvantage to be associated with micrometastasis.15, 16
SLND is a way to determine axillary tumor status without the morbidity of a complete ALND. When applied to disease processes such as DCISM, it will not only yield information that is valuable to clinical decision-making but also contribute to the understanding of the incidence of tumor spread in the earliest stages of invasive disease.