Lymph Node Metastases

Lymph Node Metastases
Radioactive tracer or blue dye can be used to identify the sentinel node, which is the node (or often 2 nodes) that first receives lymphatic drainage from the breast. Metastases are most frequent at the pole of the node stained by the dye. In order to find all macrometastases (> 2 mm), each node must be thinly sectioned (at 2-3 mm) and all slices embedded in paraffin for slide preparation. Macrometastases will be seen in > 98% of cases on 1 representative H&E section. Smaller metastases (micrometastases or ITCs) may or may not be seen if additional deeper levels through the block are prepared. To identify all tumor cells, the entire node, or ˜ 500 slides, needs to be examined.
TERMINOLOGY
Abbreviations
  • Individual tumor cells or individual tumor cell clusters (ITCs)
ETIOLOGY/PATHOGENESIS
Histogenesis
  • Majority of breast cancers metastasize via lymphatics and likely also metastasize via blood vessels
    • A subgroup of cancers metastasize only via blood vessels and do not involve lymph nodes
      • Spindle cell carcinomas, high-grade phyllodes tumors, and sarcomas typically metastasize without involving regional nodes
  • Major outflow of lymph from the breast is to 1 or 2 sentinel lymph nodes in the axilla
    • Negative sentinel node is predictive of absence of metastases in remainder of axillary nodes in ˜ 90% of patients
    • Nonsentinel node metastases occur in up to 10% of patients with a negative sentinel node
      • Some cases are due to sentinel node being replaced by tumor, not allowing uptake of radioactive tracer or dye
      • Some cases may be due to aberrant drainage patterns in a few patients
      • Some cases are due to failure of mapping technique
    • Rare cancers metastasize via lymphatics draining to other nodal basins, such as internal mammary nodes
    • Intramammary nodes may be involved by carcinoma but are rarely, if ever, the sentinel node
CLINICAL IMPLICATIONS
Clinical Significance of Lymph Node Metastases
  • Macrometastases (≥ 0.2 cm) are prognostically significant for overall and disease-free survival
    • 0.2 cm was originally chosen as size that could be measured with a ruler and did not require special measuring devices
    • 0.2 cm is also size that can be reliably detected by thinly slicing nodes and examining all slices with 1 H&E section
  • Prognosis is diminished with each additional lymph node metastasis
    • Difference in survival between 0 positive nodes and 1 positive node is similar to difference for each additional node; there is no sharp drop-off in survival
    • Total number of involved lymph nodes should be counted and reported
      • Nodes with ITCs are not included in total node count
      • Axillary nodes and intramammary nodes are counted together
    • Number of uninvolved nodes and ratio of positive/negative nodes also has prognostic significance
      • Very important to always identify as many separate nodes as possible
      • When 1 sentinel node is involved, number of additional negative nodes may be used to determine need for additional node dissection
  • Extranodal invasion is an adverse prognostic factor
    • Not extensively studied due to rarity of this finding
    • Extensive extranodal invasion correlates with clinical finding of matted axillary nodes
      • It may be necessary to estimate number of nodes present when extensive
    • May be used in decisions on benefit of axillary radiation
  • Smaller metastases (micrometastases and ITCs) have a very small effect on prognosis
    • Survival is diminished by < 3% at 5-10 years as compared with node-negative women
    • No practical technique can detect all small metastases; hundreds of slides per lymph node would need to be examined
    • Clinical impact is too small to uniformly recommend studies to detect a subset of these metastases
      • No currently used clinically feasible protocols detect all ITCs that may be present in nodes
      • Effect on prognosis is so small that treatment recommendations should be based on their presence with caution
    • Cancers associated with small metastases often have other adverse prognostic factors that would be indications for systemic treatment
  • Rare cancers drain to internal mammary nodes
    • These nodes lie below ribs and sternum and are difficult to approach surgically
    • If radiologic findings are inconclusive as to whether these nodes are involved, fine needle aspiration (FNA) to establish positivity may be attempted
  • Lymph node metastases after neoadjuvant treatment are an adverse prognostic finding
    • Indication of an incomplete response to therapy
    • Small residual metastases are as prognostically important as larger metastases
      • Although ITCs are classified as pN0(i+), this finding is not considered a pathologic complete response (pCR)
    • Response in nodal metastases has more prognostic significance than the response of cancer in the breast
    • Degree of response of metastases to treatment should be reported (e.g., presence and extent of fibrosis)
    • Some metastases can resolve completely after treatment without leaving a fibrous scar
      • Alternatively, some nodes not involved by metastasis can have small areas of fibrosis
      • Therefore, if nodes are free of carcinoma after treatment, it cannot be determined with certainty whether or not they were involved prior to treatment
      • pCR in nodes cannot be determined with certainty unless a metastasis has been documented before treatment by either fine needle aspiration or core needle biopsy
    • Sentinel node biopsy after neoadjuvant treatment is less accurate than in absence of treatment
      • Response to treatment is not uniform across all nodes
      • Metastasis in sentinel node may completely respond to treatment, but this does not ensure that all metastases to nonsentinel nodes will also have undergone a complete response
    • Documenting metastatic disease to lymph nodes is necessary to accurately classify patients for neoadjuvant trials and to derive the most information about treatment response
      • Palpable nodes may be sampled by FNA or core needle biopsy
      • Nonpalpable but enlarged nodes can be identified by ultrasound and sampled by needle biopsy
      • If no enlarged nodes are identified, sentinel node biopsy can be used to document a negative node; no additional nodal sampling is then necessary after treatment
MACROSCOPIC FINDINGS
General Features
  • Gross appearance
    • Large metastases efface surface of lymph node and appear as firm white nodule(s)
      • Gross size of metastasis should be noted
      • Sampling may be limited to 1 section most likely to show extranodal invasion
    • Metastases < 1 cm may not be grossly evident
    • Number of nodes examined and number of positive nodes must be determined as accurately as possible
      • Each node should be separately identified
      • Nodes should be inked with different colors if slices from more than 1 node will be placed in same cassette
      • Size &/or shape of node is not reliable to identify different nodes when submitted together
    • If extensive extranodal invasion is present, it may be difficult to determine number of positive nodes
      • Attempt must be made to identify as many separate nodes as possible
Specimen Handling
  • Sentinel lymph nodes
  • Should be identified as “sentinel” by surgeon
    • May be identified by blue dye, radioactive tracer, or both
      • Success rate for finding sentinel node is highest when both methods are used
    • Majority of sentinel nodes will be both blue and hot (i.e., radioactive)
      • ˜ 5% of sentinel nodes are blue but not hot; these are likely true sentinel nodes
      • ˜ 10-40% of nodes may be hot but not blue; these nodes rarely contain metastases and are likely due to tracer being taken up by nonsentinel lymph nodes
    • Number of sentinel nodes identified may determine need for completion axillary dissection
      • Therefore, each node must be separately identified and evaluated
  • Small metastases are at pole of lymph node identified by dye in > 80% of cases
    • Metastasis can be missed if a node is bisected and only 1/2 of node examined
      • 20-40% of macrometastases can be missed if only 1/2 of node examined
    • Examination of entire node histologically is recommended in order to find all macrometastases
    • Ancillary studies (additional levels, IHC) will detect additional micrometastases and ITCs
      • Smaller metastases have very minimal impact on survival
      • Additional studies beyond H&E evaluation are not currently required for AJCC staging
      • Ancillary studies are not currently recommended by the College of American Pathologists or the Association of Directors of Surgical Pathology
  • Nonsentinel lymph nodes
    • Each node should be sliced thinly
    • All nodal tissue should be examined microscopically
    • Ancillary studies are not required and are not recommended
  • Methods of finding nodes
    • “Squash” method
      • Fatty tissue is compressed and flattened by firmly pressing with finger or thumb
      • Lymph nodes are firm nodules that cannot be compressed by firmly pressing on tissue
      • This method can find nodes as small as 1-2 mm in size
    • Clearing methods
      • Special solutions cause adipose tissue to become transparent
      • Additional very small nodes may be found
      • Solutions generally contain toxic chemicals and are time-consuming to use
      • Clinical significance of very small nodes found after using clearing methods and careful gross examination is unclear
    • Bouin solution
      • Adipose tissue is dyed yellow, and nodes appear white when sectioned
      • Bouin adversely affects immunoreactivity for hormone receptors
      • Bouin fixative should not be used on any tissue for which hormone receptor studies might be required
      • Bouin also degrades DNA and should not be used for tissue that may be used for FISH or other DNA/RNA studies
      • After node is identified, it should be dissected out of tissue to avoid counting multiple slices as multiple nodes
    • If lymph nodes are not found, or very few are found, examination of remaining tissue should be considered
      • Nodes with extensive fatty replacement may be difficult to see grossly
      • Small nodes may be found near vessels
REPORTING CRITERIA
AJCC/UICC N Classification
  • N classification is based solely on axillary lymph nodes in majority of breast cancers
    • In rare cases in which other nodal groups are involved at presentation (e.g., internal mammary nodes, infraclavicular or level III nodes), additional N categories apply
    • Intramammary nodes are included in total count with axillary nodes
    • At least 1 metastasis must be a macrometastasis for classification as pN1a or higher
    • Nodes with ITCs are not included in total count of positive nodes
  • pN0: No metastases are detected in nodes
  • pN0(i+): Isolated tumor cells are present
    • Largest cohesive cluster measures ≤ 0.02 cm
    • No more than 200 cells should be present on any single complete cross section of node
    • pN0 (i-) is undefined term, as no technique completely eliminates possibility of ITCs
  • pN0(mol+): Molecular test (generally RT-PCR) is positive, but no metastases are seen on H&E
    • Size of metastasis cannot be determined with certainty
    • Macrometastases can be missed depending on amount of tissue apportioned for assay
    • False-positive results occur with RT-PCR in 5% or more of patients
  • pN1mi: A micrometastasis is present
    • Defined as > 0.02 cm or more than 200 cells but ≤ 0.2 cm
  • PN1a: Metastases in 1-3 axillary lymph nodes
  • PN2a: Metastases in 4-10 axillary lymph nodes
  • PN3a: Metastases in > 10 axillary lymph nodes
  • (sn) Modifier
    • Modifier “(sn)” was introduced in the AJCC 6th edition to indicate cases in which nodal classification was based only on sentinel nodes
    • In these cases, only 1 or 2 nodes may be examined, and actual nodal classification could be different if all axillary nodes were examined
      • In some cases, however, several sentinel nodes are removed such that the number is similar to a low axillary dissection
    • In the 7th edition, modifier (sn) allowed only if ≤ 5 sentinel and nonsentinel nodes are removed
ANCILLARY STUDIES
Use of Ancillary Studies
  • Ancillary studies for lymph node evaluation are not required or recommended by AJCC, CAP, or ADASP
  • Lymph nodes can be classified for staging using a representative H&E slide
  • In selected cases, additional levels or IHC studies can be helpful to identify and classify cells that are not clearly metastatic carcinoma by histologic appearance
Multiple H&E Levels
  • Recommended that nodes be thinly sliced at 0.2-0.3 cm and that all slices be examined microscopically
  • This method will detect > 95% of macrometastases (> 0.2 cm)
    • Additional levels deeper through paraffin block detect micrometastases and ITCs
    • Routine “levels” are generally only 10-20 microns apart
    • Levels used to detect additional metastases must be equally spaced in block of tissue and typically must be hundreds of microns apart
      • Need for widely spaced levels must be specifically communicated to histotechnologist
  • Number of levels and spacing of levels determine size of metastases that can be detected
    • 1 level: ≥ 0.2 cm metastases
    • 3 equally spaced levels: ≥ 0.1 cm metastases
    • 6 equally spaced levels: ≥ 0.05 cm metastases
Immunohistochemistry (IHC)
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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymph Node Metastases

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