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.



  • Individual tumor cells or individual tumor cell clusters (ITCs)



  • 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 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


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


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


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)

Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymph Node Metastases

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