Sectioning
Sectioning
There is wide agreement on the general principles that govern acceptable histologic examination of SN from melanoma patients, but limited consensus on optimum sectioning and staining protocols. Multiple sections should be cut from each half of the SN and stained with hematoxylin and eosin (H&E) and immunohistochemically, using antibodies directed to melanoma-associated epitopes. The number of sections to be stained conventionally and by immunohistochemistry and the interval between sections for evaluation remain subject to debate.
- (
6
6SDUH
µPJDS
- (
6
,QODUJHRUURXQGO\PSKQRGHVWKH µPJDSPD\EHLQFUHDVHG
XSWRDPD[LPXPRIµP
In initial studies of nodal micrometastases, we observed that early melanoma metastases are usually located in a relatively narrow band of tissue adjacent to the longest nodal meridian.1 Thus carefully sampling the tissues adjacent to the nodal meridian should detect the subgroup of melanoma patients with early nodal metastases. In this study, additional sampling of more peripheral areas of the node did not increase the proportion of melanoma-positive lymph nodes. This is in contrast to other tumors, such as breast cancer, where the tumor cells spread more widely across the nodal surface, and thus more extensive sampling progressively increases the proportion of tumor-positive lymph nodes. On the basis of these findings in lymph nodes from melanoma patients, we have consistently recommended examination of 10 full-face serial sections cut from both faces of the node and stained by H&E (sections 1, 3, 5, and 10), S100 (section 2), HMB-45 (section 4), MART-1 (section 6), and SOX-10 (section 7).1 Sections 7–9 are retained as spares. If tumor cells are not found in the initial 20 sections cut from both halves of an SN of a patient with a primary melanoma thicker than 1.2 mm (and thus significantly at risk for nodal metastases), additional sections may be prepared and examined, although the yield from this additional evaluation is, in our experience, low. This approach detects melanoma in 16–20% of SNB specimens, a figure that varies according to the thickness of the primary melanomas included in the study group and that is closely similar to the rate of development of clinically detectable metastatic melanoma in the ipsilateral regional lymph nodes of patients observed for up to 10 years after wide excision of a primary melanoma.2 It is arguable that this relatively simple focused sampling protocol detects most or all of the clinically significant melanoma deposits in SN.3
metastases in some patients where sections closer to the nodal meridian were tumor free.4–8 The clinical significance of these additional melanoma cells detected by extended sampling remains unknown, and elucidation of their biology will require that patients be followed for up to 10 years.
Recent studies, however, have reported that more extended sampling to allow evaluation of sections cut from deeper areas of SN identifies melanoma
Cook and coworkers have reported that examination of six pairs of sections cut at 50-µm intervals and stained respectively with H&E and S100 detects melanoma in up to 33.8% of SNs.5 Spare sections are cut at each level and retained to permit additional immunohistochemistry in the event of ambiguous results from initial sections. These studies were undertaken because the authors had encountered practical difficulty in accurately cutting the SN through the true meridional plane and wished to reconcile reported differences in the rate of detection of tumor-positive SN by histopathology and molecular techniques (RT-PCR) (see below). A modification of this protocol has recently been adopted by the European Organisation for Research and Treatment of Cancer (EORTC) and is currently a requirement for evaluation of the SN of melanoma patients entering EORTC clinical trials (Fig. 28.9).
1393 The role of immunohistochemistry in detecting tumor in sentinel nodes
In choosing a protocol for sampling SNs, pathologists, in consultation with their surgical colleagues, should balance the need for accuracy with cost and workload considerations.9
The role of immunohistochemistry in detecting tumor in sentinel nodes
It may be extremely difficult to identify single melanoma cells or small clusters of melanoma cells (micrometastases) in H&E-stained sections. Without the assistance of immunohistochemistry, even experienced pathologists may overlook small amounts of tumor in up to 12% of SN specimens (Fig. 28.10). For this reason, and to minimize delays in reporting, immunohistochemical studies are best ordered at the time of initial processing. It is important to be selective in choosing the antibodies to be used in this evaluation.1 Antibodies to S100 protein detect nuclear and cytoplasmic epitopes in virtually all melanomas, including desmoplastic melanomas (100% sensitive for melanoma), but are relatively non-specific, staining dendritic leukocytes in the nodal paracortex (Figs 28.11 and 28.12), some sinus histiocytes, fat cells within and outside lymph nodes, Schwann cells of node-associated nerves, and capsular/trabecular nevus cells (Figs 28.13–28.15). Some pathologists dislike antibodies to S100 because of this non-specificity, but with experience it is usually relatively easy to separate clusters of dendritic cells (DC) that tend to lie toward the periphery of paracortical nodules from melanoma cells, which are usually larger and nondendritic and are characteristically located in the subcapsular zone and deeper parenchymal tissues (Figs 28.16 and 28.17). Dendritic cells may be encountered in the subcapsular and other nodal sinuses, in which case they are regarded as immature DC (originally Langerhans cells) migrating from the skin to the nodal paracortex. Melanoma cells can be dendritic, but this morphology is usually observed in the radial growth phase of lentiginous melanomas and is exceedingly rare in vertical growth phase or metastatic melanoma. Paradoxically, nodal dendritic leukocytes in some SNs may be poorly dendritic or nondendritic. This is considered to indicate down-regulation of the paracortical dendritic cells as part of the tumor-induced immune suppression that affects SNs.2 Nondendritic cells are recognized by their location in the nodal paracortex and characteristic immunophenotype: S100 positive, MART-1, SOX-10, and HMB-45 negative.
A
B
The epitopes detected by MART-1 and HMB-45 are located in the cytoplasm of melanoma and other melanocyte-derived cells. Such epitopes are more specific for cells of melanocytic lineage than S100, but are not expressed by the cells of up to 25% of melanomas, particularly metastatic melanomas.1 Antityrosinase antibodies are also relatively specific, but of comparably limited sensitivity. There are reports of the use of combinations of antibodies (antibody cocktails), but these seem to be no more sensitive than S100 and do not allow the critical separation of melanoma cells from nevus cells on the basis of immunophenotype (see below).
Pathologist error accounts for some, but not all, cases of false-negative SNB, where – despite a reportedly negative SN – the patient later develops metastatic melanoma in the ipsilateral nodal basin (3–5% in most published series). Such cases may also reflect incorrect identification of the SN by nuclear medicine or at surgery, or a quirk of biology in which, at the time of SNB, the eventually metastatic tumor cells have departed the primary site, but have not yet arrived at the nodal basin. It is highly important to minimize the frequency of false-negative SN as patients in this category have an unfavorable prognosis, comparable to that of patients who develop nodal metastases during a period of observation after wide excision of a primary melanoma.3
False-positive assessment of an SN is relatively uncommon, but may lead to patients being subjected to immediate CLND, an operation that is associated with considerably more morbidity than SNB alone and that confers no benefit on patients without nodally metastatic melanoma.3 False positivity is usually due to misinterpretation of benign cells in the lymph node as melanoma cells. Misidentification often involves macrophages (Figs 28.18 and 28.19), particularly melanin-containing macrophages and macrophages that have phagocytosed melanosomal fragments that express the epitopes of MART-1/Melan-A or HMB-45 released from disrupted melanoma cells, dendritic leukocytes, and capsular and trabecular nodal nevus cells. Confusion
C
between melanin-containing macrophages and immunopositive melanoma cells may be reduced by using a colored chromogen, such as aminoethylcarbazole or alkaline phosphatase (followed by ‘fast red’), in place of brown diaminobenzidine that may be misinterpreted as melanin (Fig. 28.20). However, since colored chromogens are less frequently used, pathologists may
1394 Sentinel lymph node biopsies
find such preparations more difficult to interpret. Other potential sources of false-positivity are S100-positive Schwann cells of intranodal and perinodal nerves (Fig. 28.21), ganglion cells, and mast cells. Distinction of these potential confounding cells is usually achieved by scrutiny of their cytology, their location in or adjacent to the lymph node, and immunophenotype. SNs, particularly inguinal SNs removed from older patients, may show extracellular HMB-45 reactivity associated with calcified foci in the collagen of the nodal trabeculae.
We have encountered an unusual potential cause of a false-positive interpretation of an SN in patients where a small piece of melanoma is
included on the slide as a positive control. In rare instances, cells from the positive control tissue may detach and float over to settle on top of the nodal section under evaluation. The keys to identifying these ‘internal floaters’ are to recognize that the tumor cells are not in the plane of the section and then to confirm that the ‘floater’ tumor cells are morphologically and immunophenotypically identical to the cells of the positive control tissue.
Microscopic evaluation of sentinel nodes for metastatic melanoma
It is useful to examine the immunohistochemically stained sections first since MART-1/Melan-A, HMB-45, SOX-10, and S100 protein stains can detect truly small numbers of melanoma cells that are difficult to identify in H&E preparations. The entire slide is scanned at low power, and the
A
B
1395 Separation of nevus cells and metastatic melanoma in sentinel nodes
C
D
(C) A capsular nevus stained for MART-1/Melan-A demonstrating epitope confined to the cytoplasm. (D) A capsular nevus stained for HMB-45. The great majority of nevus cells do not express HMB-45, although occasional cells may show a trace of epitope in the cytoplasm.
Fig. 28.9 Guidelines (left panel, UCLA sampling; right panel, EORTC sampling): the left column depicts long-standing recommendations from UCLA that the two halves of the sentinel node are intensively sampled using H&E and immunohistochemistry on sequential full-face sections. This approach intensively samples the parameridional tissues, uses three separate immunomarkers of varying sensitivity and specificity, but does not evaluate the more peripheral parts of the node. This technique detects melanoma in 16% to 20% of sentinel nodes, a frequency identical to the ipsilateral failure rate of patients treated by wide excision alone. The right column depicts the node sampling technique adopted by the EORTC Melanoma Group. This uses H&E staining and S100 protein (spare sections may be used for additional immunomarkers). It samples more peripheral portions of the two halves of the sentinel node and is reported to detect melanoma in up to 33.8% of sentinel nodes. The clinical significance of the additional positive nodes detected in this way will become clear from extended follow-up studies that are in progress. This approach calls for some additional technical effort and a significant increment in pathologist work.
Fig. 28.10 Single melanoma cells immunohistochemistry: detected by their expression of (A) S100 protein; (B) MART-1/Melan-A; and (C) HMB-45. In the illustration of the HMB-45-stained section, there is a granular macrophage below and to the right of the central melanoma cells.
Fig. 28.11 Lymph node stained for S100 protein: the illustration shows a paracortical nodule with an abundant population of polydendritic dendritic cells (DCs) that tend to cluster in a ring around the periphery of the paracortical tissue. This classic distribution of DCs is best seen at moderate magnification. DC may also be encountered in the lymph node sinuses and less abundantly in B-cell areas. In addition to their distribution, the presence of multiple complex dendritic processes, relatively small size, and lack of a prominent S100 positive nucleus allows separation of these cells from melanoma cells. Additionally, DC do not express MART-1/Melan-A or HMB-45. In some SN, DC may lose their dendrites, and this may present more of a diagnostic challenge.
Fig. 28.12 Poorly dendritic and nondendritic DC in a sentinel node: reduced expression of dendrites by DC is viewed as evidence that they are down-regulated by tumor-induced immune suppression. Nondendritic DC are recognized by their scattered distribution in nodal paracortex and sinuses and their characteristic immunophenotype: S100 positive, MART-1 and HMB-45 negative.
Fig. 28.13 Capsular nevus: (A) shows a nevus that is clearly confined to a slightly expanded nodal capsule (H&E). Nevus cells are smaller than most melanoma cells, have limited cytoplasm, usually show only traces of cytoplasmic melanin, and may resemble large lymphocytes. Their nuclei are bland and lack large nucleoli or mitoses. (B) A capsular nevus stained for S100 demonstrating epitope in nuclei and cytoplasm.
Fig. 28.14 Trabecular nevus cells: (A) shows a column of nevus cells located in a nodal trabeculum and flanked by a peritrabecular sinus and lymphoid parenchyma; (B) shows the same trabecular nevus stained for S100 and again flanked by a peritrabecular sinus and lymphoid parenchyma. The S100 positive cells in the peritrabecular sinus and parenchyma are dendritic cells.
Fig. 28.15 Diagram demonstrating the relationship of capsular and trabecular nevus cells to the lymph node: note that the nevus cells can also be present in fine arborizations of the nodal trabecular frame work (which may only become visible with special stains for collagen and reticulin). In the absence of special staining, it may be incorrectly assumed that such cells are free within the nodal parenchyma and they may be incorrectly interpreted as melanoma metastases.
Fig. 28.16 Subcapsular sinus melanoma metastases: (A) this shows a ribbon of melanoma cells sandwiched between the nodal capsule and the nodal parenchyma (H&E). (B) There is a small collection of S100-positive melanoma cells immediately deep to the capsule. Note that deeper in the node there are S100 positive dendritic cells that lack the prominent nuclear staining by S100 that is seen in the melanoma cells. Most of these are poorly dendritic, but some have well-developed dendritic processes.
Fig. 28.17 Parenchymal melanoma metastases: these panels show a metastasis of melanoma located deep in the nodal parenchyma. (A) While visible in an H&E-stained section, the fact that (B) the amelanotic lesion expresses S100 protein, (C) MART-1/Melan-A, and (D) HMB-45 confirms that it is a melanoma.
Fig. 28.18 Care must be taken to avoid the overinterpretation of nodal macrophages as melanoma cells. In panel (A), relatively large epithelioid macrophages are scattered among lymphocytes in a subcapsular position. These cells were negative for S100, MART-1/Melan-A, and HMB-45. Panel (B) shows a collection of relatively large macrophages containing abundant coarsely granular melanin (melanophages). These cells were negative for S100, MART-1/Melan-A, and HMB-45. Panel (C) shows a small granuloma-like collection of epithelioid macrophages. These cells were negative for S100.
Fig. 28.19 Nodal macrophages: a further problem with nodal macrophages is that they may ingest fragments of melanosomes that express melanoma-associated epitopes from disrupted melanocytic cells and react positively in immunohistochemical studies: (A) shows a MART-1/Melan-A-stained section with metastatic melanoma at the left and toward the right scattered macrophages that contain MART-1/Melan-A positive granules; (B) shows a collection of macrophages that contain coarse HMB-45 positive granules.
Fig. 28.20 Melanoma: this small collection of melanoma cells stains positively for HMB-45 and is highlighted by the red chromogen aminoethylcarbazole. Note the granuloma-like collections of melanin-containing macrophages that surround these cells. Traces of AEC-highlighted, HMB-45 positive material are present in some of the macrophages.
Fig. 28.21 Perinodal nerve: the Schwann cells are stained with an antibody to S100. While the neural nature of such structures is usually (as in this case) readily apparent, there may occasionally be a problem in distinguishing neural structures from melanoma cells in a lymphatic or free in the tissue. This type of problem is most likely to occur when the nerves are intranodal or if the tissue section is thick or from poorly fixed material. Nerves stain negatively with antibodies to MART-1/ Melan-A and HMB-45.
A
B
different nodal compartments are assessed, starting with the subcapsular sinus, the commonest location of early metastases (Fig. 28.22). Tumor cells may occupy substantial areas of the node or be few, and singly dispersed or organized as microcolonies in subcapsular sinuses, lymphoid parenchyma, and deeper sinuses. The afferent lymphatics should be specifically evaluated for the presence of tumor. Tumor in afferent lymphatics, including intracapsular lymphatics, has the same clinical implications as intranodal tumor and is equivalent to a positive SN (Fig. 28.23). High-power (× 400) fields are examined to confirm the cytology and nature of single or clustered melanocyte-derived cells. Extracapsular extension (Fig. 28.24) is infrequent, especially when the tumor burden is small, but should be recorded if present.
The great majority of nodal nevus cell collections derive from cutaneous nevi in the catchment area of the lymph node, the nevus cells apparently reaching the node via afferent lymphatics. Careful scrutiny will often show that benign nevi abut and deform adjacent dermal lymphatics. In rare instances, nodal nevi may be the result of aberrant migration of neural crest-derived melanocyte precursors (melanoblasts) during embryogenesis or even of melanocyte stem cells.3 Accurate discrimination of nodally located benign nevi from melanoma cells is very important. This requires careful consideration of the location of the melanocyte-derived cells in the nodal architecture and detailed assessment of their cytology and immunophenotype. Melanoma cells are mostly larger than nevus cells (although the occasional nevoid melanoma may present a considerable diagnostic challenge) and are commonly located in the subcapsular sinus and deeper lymphoid tissues of the node. Unlike nevus cells, melanoma cells are seldom present in the nodal capsule other than within afferent lymphatics. Cytological features that may be used to distinguish melanoma from nevus cells include large cell size, high nuclear to cytoplasmic ratio, prominent nucleoli, and mitotic figures (especially atypical mitoses). Both melanoma and nevus cells
Separation of nevus cells and metastatic melanoma in sentinel nodes
Benign nevus cells can be identified in the connective tissue architecture of up to 24% of lymph nodes, predominantly in the capsule and trabeculae.1,2
1396 Sentinel lymph node biopsies
may contain finely dispersed small melanin granules (single melanized melanosomes that are just visible under the microscope) that indicate melanin synthesis within the cell (Fig. 28.25). The amount of melanin in melanoma cells is widely variable, but in most instances (with the notable exception of the cells of heavily melanized cellular blue nevi) is greater than that encountered in the cells of melanocytic nevi. Coarse melanin granules (aggregates of melanosomes that are readily visible under the microscope) are characteristic of melanin-containing macrophages (melanophages), but may be seen, admixed with smaller melanin granules, in some melanoma cells. Melanoma cells are almost always S100 protein-positive (staining of nuclei and cytoplasm), SOX-10 (nuclear staining), most (up to 85%) stain positively for MART-1/Melan-A and HMB-45, and Ki67 reactive nuclei are present at relatively high frequency.
A Nevocytes in lymph node capsule
Conventional nodal nevus cells are smaller than most melanoma cells, have limited cytoplasm, usually show only traces of cytoplasmic melanin, and may resemble large lymphocytes. Their nuclei are bland and lack prominent nucleoli or mitoses. They stain positively for S100 protein, SOX-10, MART-1/Melan-A, and P164, but weakly or negatively for Ki67 and HMB-45.5 Up to 25% of melanoma patients have capsular or trabecular nevus cells in one or more regional node(s). Location of nevi in connective tissue is usually obvious, although it may be necessary to use a connective tissue stain to rule out extension into the subcapsular parenchyma. Extension of nevi into perivascular stroma or ultrafine reticulations of the trabeculae can make interpretation difficult, because on initial appraisal the nevus cells may appear to be located in the nodal parenchyma,6 a location that is more characteristic of melanoma metastases. Connective tissue stains such as Masson trichrome and reticulin may help by disclosing the complex arborizing pattern of nodal stroma.
B Nevocytes in trabeculum of lymph node
Is there a role for SNB in the evaluation of melanocytic lesions of uncertain metastatic potential?
The morphology and immunophenotype of some primary cutaneous melanocytic lesions may be insufficiently typical to allow their certain assignment to the category of melanoma or nevus: lesions of uncertain malignant potential.1–5 The majority of lesions falling into this category are atypical cellular blue nevi, atypical spitzoid lesions, and deep penetrating nevi. In such cases, the surgeon will usually excise the lesion with a margin of local clearance appropriate for a primary melanoma of similar thickness, and
C Nevocytes in arborized trabeculae of lymph node
A
B
1397 Is there a role for SNB in the evaluation of melanocytic lesions of uncertain metastatic potential?
C
D
A
B
C
D
1398 Sentinel lymph node biopsies
review the pros and cons of SNB with the patient. If an SNB is performed and the SN shows no evidence of a melanocytic lesion, this may represent a nevus without capacity to extend to the nodes or a melanoma that has not (yet) metastasized to the regional nodes, but which may later develop clinically detectable metastases in distant sites. In such cases, CLND is not indicated. If a nodal melanocytic lesion is identified but is confined to the lymph node capsule or trabeculae, there is again no indication for immediate completion lymphadenectomy. If lesional cells are confined to the nodal capsule (other than the special case of melanoma cells in an afferent lymphatic) and
trabeculae, it is likely that they are collections of benign nevus cells (see above). If the node contains tumor that is truly located in the parenchyma, CLND and adjuvant therapy may be considered because a true parenchymal location strongly favors metastatic melanoma. The use of SNB in evaluation of melanocytic lesions of uncertain malignant potential is opposed by some, who argue that SNB is not appropriate for lesions with limited malignant potential that are not customarily treated by regional nodal surgery. The situation is further complicated by the fact that some patients with atypical spitzoid lesions atypical cellular blue nevi and pigmented epithelioid melanocytomas are found to have ostensibly parenchymal tumor deposits in the SN that closely resemble lymph node metastases and yet such lesions do not seem to extend to additional NSNs or to visceral sites. The biology and clinical management of these ‘borderline’ lesions is poorly understood and clearly needs more formal evaluation. Since the last edition of this book, the use of SNB in the management of melanocytic lesions of uncertain malignant potential has decreased. While a proportion of these patients may have lesional cells in the SN, the incidence of additional nodal tumor at CLND and the frequency of visceral metastases and melanoma death in these patients is essentially zero.
Molecular biology techniques in the assessment of sentinel nodes from melanoma patients
A B C
Since it is not possible histologically to examine the entire SN, it is possible that conventional microscopy may fail to detect some melanoma metastases in SNs of patients with limited tumor burden. This argues for more extensive nodal sampling1 and/or the introduction of novel approaches such as the RT-PCR.2 Molecular staging is currently standard in the management of hematological malignancies. The possibility that RT-PCR might identify melanoma cells in SNs in which extensive histologic and immunohistological evaluation reveals no evidence of tumor has attracted considerable interest. However, there is currently no compelling reason to abandon microscopy and analyze SN exclusively by RT-PCR. The techniques commonly used to extract mRNA for evaluation by RT-PCR destroy the tissue and prohibit identification of the specific cell from which the enhanced signal was derived. A molecular signal for a melanoma-associated marker, in addition to originating from a melanoma cell, might also derive from capsular and trabecular nevi, Schwann cells of intranodal nerves or macrophages that have ingested melanosomes or other organelles from melanoma cells. Concerns have been expressed that overinterpretation of RT-PCR results carries the
A
B
1399 Prediction of outcome based on the extent of nodal replacement by tumor and its distribution within the sentinel node
A
B
risk of overtreatment.3 Mocellin and coworkers, in a careful meta-analysis, have shown that a positive PCR reaction in the SNs of melanoma patients is significantly correlated with TNM stage, disease recurrence, and overall and disease-free survival.4 These authors did, however, find extensive heterogeneity between the results obtained in the 22 sizeable studies that they analyzed. They conclude that ‘the available evidence is somewhat conflicting and probably is not sufficient to conclude that PCR status is a prognostic indicator reliable enough to be implemented clinically in the therapeutic decision-making process’. However, they consider that their findings ‘justify additional investigations of the prognostic power of PCR analysis of sentinel lymph node (SLN) in patients with cutaneous melanoma’. The efficacy and clinical relevance of molecular analysis of SN are being studied in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II), sponsored by the National Cancer Institute in the United States.
Fig. 28.22 Metastatic tumor in afferent lymphatics: (A) melanoma in the intracapsular segment of an afferent lymphatic of a sentinel lymph node (H&E); (B) MART-1/Melan-A. In the presence of these appearances, the sentinel node should be reported as positive.
Fig. 28.23 Metastatic melanoma in the nodal parenchyma: (A) early extension of metastatic melanoma from the subcapsular sinus into the nodal parenchyma (HMB-45); (B) subcapsular metastatic melanoma with subjacent parenchymal melanoma metastases arranged as single tumor cells and a micrometastasis (MART-1/Melan-A); (C) single melanoma cells in the nodal parenchyma (MART-1/Melan-A); (D) macrometastasis in the nodal parenchyma (S100 protein-red chromogen-aminoethylcarbazole).
Fig. 28.24 Extracapsular extension of melanoma from a sentinel lymph node: tumor extends through the capsule and into the adjacent perinodal fat. By courtesy of R.R. Huang, MD, UCLA, California, USA.
Fig. 28.25 Nodal metastatic melanoma: the great majority of cells in this illustration are melanoma cells, but a minority have coarse granules of melanin and are regarded as melanin-containing macrophages (melanophages).
Prediction of outcome based on the extent of nodal replacement by tumor and its distribution within the sentinel node
Clinical outcome and the likelihood of death from melanoma correlate with the number of lymph nodes that contain melanoma metastases,1 but pathologists may further refine that assessment by measuring the size of nodal metastases and specifying their location within the SN. Building on earlier (pre-SN) studies2 of the morphometric assessment of the area and micrometer-assessed diameter of nodal melanoma metastases (Fig. 28.26), Starz and coworkers3 reported that the micrometer-measured depth of tumor penetration from the inner surface of the SN capsule correlated directly with the likelihood of metastases in NSNs in the same nodal drainage basin (Fig. 28.27). Wagner and coworkers4 correlated SN tumor volume
1400 Sentinel lymph node biopsies
A
B
C
D
1401 The impact of complete lymph node dissection after positive sentinel lymph node biopsy in melanoma-specific survival
parenchyma more often had additional nodes that contained metastases. Van Akooi and coworkers7 confirmed that the maximum dimension of the largest nodal tumor deposit is related to prognosis. They found that metastases < 0.1 mm in diameter were infrequently associated with metastases in NSNs or unfavorable clinical outcomes during short-term follow-up. Govindarajan and coworkers8 also reported that tiny SN metastases (< 0.2 mm in diameter in their study) were not associated with further disease, but Scheri and coworkers9 have shown that even very small SN metastases can be associated with reduced survival. These important issues remain under extensive study and should yield clearly applicable and clinically relevant criteria by which nodal tumor burden can be assessed.
Tumor
It is therefore likely that critical decisions regarding the need for CLND and deployment of adjuvant therapy will depend on the pathologist’s assessment of tumor burden and location in the SN.10,11 Currently, none of the available measures of tumor burden or disposition in the SN, individually or in combination, is sufficiently accurate that it can serve as the sole basis for treatment decisions. Such observations can effectively assist in the placement of patients in high- and low-risk categories for recurrence and death from melanoma. Pathologists may therefore wish to provide information on (for example) the Starz micrometer depth diameter of the largest metastasis and whether tumor is confined to the subcapsular zone or extends into the nodal parenchyma.12
A 7XPRUGLDPHWHU 6WDU]6VWDJLQJ B 7XPRUDUHD &RFKUDQHWDO
Fig. 28.26 Assessment of clinical outcome and the likelihood of death from melanoma correlate with the number of lymph nodes that contain melanoma metastases, but pathologists may further refine that assessment by measuring the size of nodal metastases. This can be recorded either as the proportional area of the lymph node occupied by tumor or using a micrometer to relate tumor maximum diameter to nodal maximum diameter.
Fig. 28.27 Approaches to the prediction of clinical outcome based on tumor burden and distribution in the sentinel node: (A) shows the Starz approach12, in which a micrometer measures the depth of penetration of the metastasis from the internal aspect of the nodal capsule to the deepest invasive tumor cell; (B) the measured area of the metastatic tumor is related to the area of the lymph node (proportional area). (C) A simpler approach is to record the diameter of the largest metastatic deposit; (D) the Dewar approach, in which it is determined whether the tumor is confined to the subcapsular sinus (relatively favorable) or also involves the parenchymal tissues (less favorable).