Context

Recent data suggest mesenteric tumor deposits (MTDs) indicate poor prognosis in small bowel well-differentiated neuroendocrine tumors (SB-NETs), including compared to positive lymph nodes, making their distinction crucial.

Objective

To study interobserver agreement in distinguishing SB-NET MTDs from positive nodes.

Design

Virtual slides from 36 locally metastatic SB-NET foci were shared among 7 gastrointestinal pathologists, who interpreted each as an MTD or a positive node. Observers ranked their 5 preferred choices among a supplied list of potentially useful histologic features, for both options. Diagnostic opinions were compared using Fleiss multirater and Cohen weighted κ analyses.

Results

Preferred criteria for MTD included irregular shape (n = 7, top choice for 5), perineural invasion/nerve entrapment (n = 7, top choice for 2), encased thick-walled vessels (n = 7), and prominent fibrosis (n = 6). Preferred criteria for positive nodes included peripheral lymphoid follicles (n = 6, top choice for 4), round shape (n = 7, top choice for 2), peripheral lymphocyte rim (n = 7, top choice for 1), subcapsular sinuses (n = 7), and a capsule (n = 6). Among 36 foci, 10 (28%) each were unanimously diagnosed as MTD or positive node. For 13 foci (36%), there was a diagnosis favored by most observers (5 or 6 of 7): positive node in 8, MTD in 5. Only 3 cases (8%) had a near-even (4:3) split. Overall agreement was substantial (κ = .64, P < .001).

Conclusions

Substantial interobserver agreement exists for distinguishing SB-NET MTDs from lymph node metastases. Favored histologic criteria in making the distinction include irregular shape and nerve/vessel entrapment for MTD, and peripheral lymphocytes/lymphoid follicles and round shape for positive nodes.

Well-differentiated neuroendocrine tumors of the small bowel (SB-NETs), in particular of the jejunum and ileum, have a propensity for locoregional as well as distant metastasis. Up to 72% of SB-NETs metastasize locally, often to mesenteric lymph nodes.1  While published clinical guidelines suggest that all mesenteric foci of disease from SB-NETs represent nodal metastases,2,3  several studies in the past decade have proposed that mesenteric foci of metastatic SB-NETs without histologic evidence of residual lymph nodes instead represent mesenteric tumor deposits (MTDs). The latter have been associated with advanced disease (ie, pT3/pT4 stage, nodal and distant metastases) and therefore may indicate a poor prognosis.4  These MTDs may be small and encountered in tissue sections submitted to identify mesenteric lymph nodes, or large and grossly evident, and sometimes also manifest as the initial presentation of disease, identified on abdominal imaging.5 

While earlier editions of American Joint Committee on Cancer (AJCC) staging manuals did not account for mesenteric lesions when staging SB-NETs, the current (8th) edition includes “large mesenteric masses (greater than 2 cm)” as a criterion for pN2 disease.1  “Mesenteric masses” are not further defined in the AJCC staging manual; however, the College of American Pathologists “Protocol for the Examination of Specimens from Patients with Well-Differentiated Neuroendocrine Tumors of the Jejunum and Ileum”6  describes them as “discrete but irregular mesenteric tumor nodules frequently located adjacent to neurovascular bundles and discontinuous from the primary neoplasm, and often associated with dense fibrosis, causing encasement of large mesenteric vessels.” Similarly, prior pathology studies defined MTDs as discrete but irregular mesenteric tumor nodules >1 mm with an irregular growth profile and indicated that common histologic features included entrapped nerves and adjacent large blood vessels.7,8 

Despite existing definitions, the histologic distinction between positive lymph nodes and MTDs can be difficult in many cases, and we have occasionally received extramural consultation cases around this question. While this has not been systematically evaluated in the literature, a recent survey on unresolved issues in digestive tract neuroendocrine neoplasia included photomicrographs of 3 locoregional foci of metastatic SB-NETs and asked respondents to interpret them as positive nodes or MTDs.9  For all 3 foci, the respondents favored 1 diagnosis over the other, but only moderately (roughly 70:30 split for each), indicating that interobserver variability still exists in the interpretation. Given the recent studies highlighting the poor prognosis of MTDs in SB-NETs, coupled with the paucity of published data looking at interobserver agreement in their diagnosis, we performed this study to assess interobserver agreement in distinguishing MTDs from positive lymph nodes in SB-NETs, as well as to ascertain what histologic criteria pathologists consider most helpful when making this distinction.

Two authors collaboratively drafted a list of 15 histologic features they considered potentially useful to establish a diagnosis of an MTD or a lymph node metastasis from an SB-NET. This list was emailed to 7 pathologists in this study (including the 2 who drafted the list), and each pathologist was asked to select and rank their 5 most preferred helpful features for each diagnostic option. The 7 pathologists all have an interest in digestive tract neuroendocrine neoplasms and practice in academic medical centers with a subspeciality sign-out model. They have been in practice for a mean of 14 years (range, 9–26 years), and all 7 completed a formal gastrointestinal pathology fellowship, except the pathologist in practice for the longest time.

One author reviewed existing gross descriptions and archival slides on all available SB-NET resection specimens from the author's institution and identified 36 locally metastatic foci (cases) in 30 tissue blocks. The foci were selected to represent a diagnostic spectrum, including cases that were felt not to be immediately classifiable as an MTD or a positive lymph node, as well as 7 cases felt to represent an “obvious” MTD and 7 felt to represent an “obvious” positive node. This was in keeping with the rough percentage (approximately 40%) of “easily classifiable” foci encountered in daily practice in the authors' experience. Fresh 4-μm hematoxylin-eosin–stained sections were cut from the blocks of these tissue sections, then scanned into whole-slide images and uploaded to a website (https://cbqareadout.ca). The virtual slides were shared with all 7 gastrointestinal pathologists in this study (including the author who selected the cases). All 7 pathologists rendered an independent diagnostic interpretation of MTD or positive lymph node for each case. All the authors (including the author who initially selected the cases) were blinded to the original interpretation as well as to the interpretation of the other pathologists. Additional information (eg, gross appearance, gross size) was not given for any case, and options such as obtaining additional levels or performing histochemical stains were not incorporated into the process; therefore, diagnostic interpretations purely relied on the histologic appearance of each individual scanned slide. The pathologists were also given the option to provide free-text comments about each case.

Each pathologist's interpretation of the 36 locally metastatic foci and notes as well as each pathologist's list for the 5 most helpful features (in order of importance) for diagnosis of positive node versus MTDs were sent to 1 author for collation; individual results were not shared among participants in any fashion. Fleiss multirater and Cohen weighted κ analyses were employed to assess agreement between pathologists. Additionally, a 2-way analysis of variance was employed to determine if the size of the neuroendocrine lesion impacted whether individuals classified the lesion as an MTD or an involved lymph node. These analyses were performed using SPSS statistical software (v.28, IBM, Armonk, New York). This study was exempt from Institutional Research Board approval, as no patient information was recorded or utilized.

The Table lists the 15 histologic features circulated to pathologists, along with how many pathologists selected each feature as one of their top 5 criteria for diagnosis of an SB-NET MTD or SB-NET nodal metastases. It also indicates the topmost preferred choice used by each pathologist when making this distinction. The chosen criteria for diagnosing SB-NET MTD included irregular shape/contour (n = 7), perineural invasion/nerve entrapment (n = 7), encasement of vessels (n = 7), the presence of thick-walled vessels (n = 7), and associated prominent fibrosis (n = 6). For making a diagnosis of SB-NET MTD, irregular shape/contour was the top choice for 5 pathologists and perineural invasion/nerve entrapment was the top choice for the remaining 2. The chosen criteria for diagnosing a positive lymph node included peripheral lymphoid follicles (n = 6), round shape/contour (n = 7), peripheral lymphocyte rim (n = 7, top choice for 1), subcapsular sinuses (n = 7), and a capsule (n = 6). For making a diagnosis of positive lymph node, peripheral lymphoid follicles were considered the most helpful feature by 4 pathologists; 2 considered round contour as the top feature, and 1 considered peripheral lymphocyte rim as the most helpful feature. Three criteria received no votes, including size of the focus, tumor in surrounding lymphovascular channels, and advanced pT-category stage. Given that preferred criteria were largely similar across the pathologists, we did not calculate ranks. One pathologist comment noted that they included a “multifocal” look under irregular shape/contour (namely, a lesion composed of different tumor foci, separated by fat or fibrosis). Another comment noted that the pathologist considered presence of lymphocytes/follicles in the middle of the lesion of equal importance as lymphocytes/follicles at the periphery of the lesion for supporting a diagnosis of SB-NET nodal metastases.

Preferred Histologic Criteria for Diagnosing Locoregional Metastases From Small Bowel Well-Differentiated Neuroendocrine Tumors Among 7 Gastrointestinal Pathologistsa

Preferred Histologic Criteria for Diagnosing Locoregional Metastases From Small Bowel Well-Differentiated Neuroendocrine Tumors Among 7 Gastrointestinal Pathologistsa
Preferred Histologic Criteria for Diagnosing Locoregional Metastases From Small Bowel Well-Differentiated Neuroendocrine Tumors Among 7 Gastrointestinal Pathologistsa

Of the 36 foci evaluated in the study, 10 (28%) were unanimously called MTDs (Figure 1, A and B), including all 7 cases considered “easily classifiable as MTD” by the pathologist who collected the cases, and 5 (14%) were favored to represent MTDs, receiving 5 or 6 votes out of 7 (Figure 1, C and D). Similarly, 10 (28%) were unanimously called positive lymph node (Figure 2, A and B), including all 7 “easily classifiable” cases per the collecting pathologist, and 8 (22%) were favored to represent a positive node (Figure 2, C and D). Only 3 (8%) had a near-even split, with 4 votes for one diagnosis and 3 for the other (Figure 3, A through C). Author notes usually commented on diagnostic challenges such as the possibility of a positive node with extranodal extension mimicking MTD, or an MTD secondarily engulfing a lymph node (Figure 3, D). All 36 foci used in the study are shown in the supplemental digital content with the same information supplied to the study participants, and the scores and provided comments for the 36 foci are provided in Supplemental Table 1 (all supplemental digital content is available at https://meridian.allenpress.com/aplm in the May 2024 table of contents).

Figure 1

A, This metastatic focus from a small bowel well-differentiated neuroendocrine tumor was interpreted as a mesenteric tumor deposit (MTD) by all 7 observers. A noncontributory piece of tissue was edited from the photomicrograph. B, This focus was also interpreted as an MTD by all observers. C, This focus was interpreted as an MTD by 6 observers. D, This focus was interpreted as an MTD by 5 observers. A noncontributory piece of tissue was edited from the photomicrograph (virtual slides, hematoxylin-eosin, original magnifications ×6.7 [A], ×9.1 [B], ×13.9 [C], and ×9.6 [D]).

Figure 1

A, This metastatic focus from a small bowel well-differentiated neuroendocrine tumor was interpreted as a mesenteric tumor deposit (MTD) by all 7 observers. A noncontributory piece of tissue was edited from the photomicrograph. B, This focus was also interpreted as an MTD by all observers. C, This focus was interpreted as an MTD by 6 observers. D, This focus was interpreted as an MTD by 5 observers. A noncontributory piece of tissue was edited from the photomicrograph (virtual slides, hematoxylin-eosin, original magnifications ×6.7 [A], ×9.1 [B], ×13.9 [C], and ×9.6 [D]).

Close modal
Figure 2

A, This metastatic focus from a small bowel well-differentiated neuroendocrine tumor was interpreted as a positive lymph node by all 7 observers. B, This focus was also interpreted as a positive lymph node by all observers. C, This focus was interpreted as a positive node by 6 observers. D, This focus was interpreted as a positive node by 5 observers (virtual slides, hematoxylin-eosin, original magnifications ×5.3 [A and D], ×7.9 [B], and ×10.4 [C]).

Figure 2

A, This metastatic focus from a small bowel well-differentiated neuroendocrine tumor was interpreted as a positive lymph node by all 7 observers. B, This focus was also interpreted as a positive lymph node by all observers. C, This focus was interpreted as a positive node by 6 observers. D, This focus was interpreted as a positive node by 5 observers (virtual slides, hematoxylin-eosin, original magnifications ×5.3 [A and D], ×7.9 [B], and ×10.4 [C]).

Close modal
Figure 3

A, This focus was called a mesenteric tumor deposit (MTD) by 4 observers and a positive lymph node by 3 observers. B, This focus was also called an MTD by 4 observers and a positive lymph node by 3 observers. C, This focus was called a positive lymph node by 4 observers and an MTD by 3 observers. D, This case was called a positive lymph node by 5 observers and an MTD by 2 observers, but multiple observers noted that the focus may represent either a positive lymph node with extranodal extension mimicking a tumor deposit, or a tumor deposit secondarily involving a lymph node (virtual slides, hematoxylin-eosin, original magnifications ×7.9 [A], ×6.6 [B], ×8.2 [C], and ×17.4 [D]).

Figure 3

A, This focus was called a mesenteric tumor deposit (MTD) by 4 observers and a positive lymph node by 3 observers. B, This focus was also called an MTD by 4 observers and a positive lymph node by 3 observers. C, This focus was called a positive lymph node by 4 observers and an MTD by 3 observers. D, This case was called a positive lymph node by 5 observers and an MTD by 2 observers, but multiple observers noted that the focus may represent either a positive lymph node with extranodal extension mimicking a tumor deposit, or a tumor deposit secondarily involving a lymph node (virtual slides, hematoxylin-eosin, original magnifications ×7.9 [A], ×6.6 [B], ×8.2 [C], and ×17.4 [D]).

Close modal

Utilizing Fleiss multirater analyses between all raters, the overall interobserver agreement for distinguishing MTD from positive nodes was substantial (κ = .64; P < .001). Cohen analyses between each individual rater and their peers showed that no single rater deviated significantly from the rest. The purpose of this assessment was to determine whether a single rater consistently deviated from the cohort or whether a particular question caused significant challenges. There were no significant disagreements (κ < .30), with all κ ranges between .44 and .78. The average size of the 36 foci was 2.2 cm (range, 0.1–7.5 cm). Raters indicated they did not consider size an important diagnostic criterion, and there was no statistically significant interaction between the size of a focus and whether individuals classified it as MTD or involved node (P = .41). However, the estimated marginal means showed that larger foci were generally classified as lymph nodes (average size 2.54 cm) compared to MTD (average size 1.73 cm). To determine whether an ad hoc “consensus” of voting patterns could be analyzed, each focus was assigned a diagnosis based on the majority of interpretations (namely, at least 4 out of 7 votes). This showed a voting tendency to classify larger lesions as lymph nodes (P = .04), but after Bonferroni correction, this did not quite reach statistical significance (namely, P < .025).

Tumor deposits have received the most attention in the setting of colorectal carcinoma (CRC).10,11  The definition of CRC tumor deposits changed between the 5th12  and 6th13  editions of the AJCC Cancer Staging Manual, and again between the 6th13  and 7th14  editions. Criteria changed from a size cutoff to an assessment of contour, and finally to lack of evidence of residual node. During this evolution, deposits went from a component of pT-category disease to pN-category disease. Given the changing definitions and applications, it is perhaps not surprising that colorectal tumor deposits may be challenging to distinguish from positive lymph nodes in some instances. Rock et al10  assessed this phenomenon by circulating images of 25 locoregional tumor metastases in cases of colorectal adenocarcinoma among 7 gastrointestinal pathologists and found moderate interobserver agreement (κ = .48), with most participating pathologists using rounded shape, a peripheral lymphocyte rim, peripheral lymphoid follicles, potential subcapsular sinus, residual adjacent nodal tissue, and a thick capsule to distinguish tumor deposits from involved nodes.

The current study was modeled on the study by Rock et al10  and aimed to perform a similar assessment of pathologist interobserver variability and preferred diagnostic histologic criteria in distinguishing MTDs from positive nodes in resected SB-NETs. We found that there exists substantial interobserver agreement among pathologists when distinguishing MTDs from positive lymph nodes in resection specimens for SB-NETs. This level of agreement is higher than that found among pathologists making a similar determination in a smaller number of cases of colorectal adenocarcinoma (κ = .64 versus κ = .48, and complete agreement in 56% of cases versus 44% of cases). However, we note that the Rock et al study10  specifically selected cases “to attempt to cover a wide breadth of potential pitfalls,” whereas our study aimed to cover the variety of cases encountered in daily practice, including easily classifiable examples. Additionally, some SB-NET MTDs may arguably be “easier” to identify than CRC tumor deposits, given that the former often demonstrate entrapped neurovascular bundles but this histologic landmark is not present in the latter. Given this, a percentage of cases encountered in daily clinical practice can easily be identified as representing a positive node or an MTD. These were represented in our cohort to confirm this observation, though of course the main aim of this study was to evaluate approaches to diagnostically challenging cases.

The pathologists in this study generally agreed on the most helpful diagnostic criteria for diagnosing an SB-NET involving a lymph node, including a round shape/contour of the tumor focus, the presence of peripheral lymphoid follicles and/or a peripheral lymphocyte rim, a subcapsular sinus, and a capsule. These 5 features were also among the top 6 findings used by pathologists to identify lymph node involvement by CRC.10  The presence of peripheral lymphoid follicles was considered the most useful single criterion by 57% of participants in this study and was the third most useful feature overall in the colorectal carcinoma study. Similarly, the pathologists generally agreed on histologic features of SB-NET MTDs, namely irregular shape/contour of the tumor focus, perineural invasion/nerve entrapment, encased vessels, thick-walled vessels in the proximity of the focus, and associated prominent fibrosis. The first 2 were selected as the main diagnostic criterion by 71% (5 of 7) and 29% (2 of 7) of the participants, respectively. The presence of nerves and thick-walled blood vessels within a lesional focus deserves particular mention, as in our experience these are quite uncommonly found within lymph nodes, meaning their presence suggests a lymph node was not present at that location. This was emphasized in some of the free-text comments provided by the reviewers (available in Supplemental Table 1), such as “favor MTD due to irregular shape with entrapped vessels and nerve” and “although it has a round shape, [a large vessel] in the center of the lesion makes a positive lymph node unlikely.” Similar definitional criteria (including entrapped neurovascular bundles and irregular contour) have been used in previous pathology studies assessing SB-NET MTDs.7,8,15  Combining our findings with the previously published criteria,7,8,15  we propose a working definition of SB-NET MTD as follows: “a locoregional SB-NET metastasis to the mesentery, of any size, with no definitive evidence of residual lymph node; they often demonstrate an irregular contour, entrapped nerves and thick-walled blood vessels, and fibrosis.” Size was not considered an important criterion by the participants in our study; however, larger lesions tended to more often be agreed upon as positive nodes, perhaps because structures such as lymphoid follicles and subcapsular sinuses were easier to visualize at such sizes, whereas irregular borders were harder to judge.

While some locoregional foci of metastatic SB-NETs are fairly easy to classify as MTD or positive node, some cases are extremely challenging, if not impossible. Some of these may actually represent a confluence of the 2 processes, namely either an MTD that extended into an adjacent node and secondarily involved it, or a nodal metastasis that spread beyond the node into surrounding tissue (extranodal extension), mimicking an MTD histologically. Many of the free-text comments provided by the reviewers raised this issue, with statements such as “this looks like a positive [lymph node] with extramural extension with trapped large vessels,” “left half is obviously [lymph node], but right half in isolation resembles MTD,” and “capsule and peripheral [lymphocytes] below, but encased vessel and dense fibrosis with ‘multifocal' appearance above; I think it is a [lymph node] below with extracapsular extension or separate MTD above. I would call it both [lymph node] and MTD, but if I had to pick I think it is a [lymph node], or at least it started as one.” It is difficult to provide guidance for such confounding lesions, as few data exist regarding their biologic potential and prognostic relevance, though all cases in our study where these issues were raised via free-text comments were ultimately interpreted as positive nodes by most if not all observers.

The study by Rock et al10  utilized ancillary techniques when evaluating their locoregional foci of colorectal carcinoma metastasis in an effort to further characterize their cases following review by the observers. Specifically, they ordered additional hematoxylin-eosin–stained levels on their cases, and they performed histochemical staining for elastin to identify associated blood vessels. For SB-NET foci, as for all challenging material, we agree that additional levels may aid an accurate diagnosis; however, we believe that histochemical and immunohistochemical stains are likely less useful in this setting. Small colorectal tumor deposits can demonstrate histologic overlap with lymphovascular invasion,10,16  especially given that the former likely arise from the latter.17  We have rarely encountered this particular issue in SB-NET cases. Furthermore, Rock et al10  found that elastin staining did not aid in the distinction between positive nodes and MTDs, supporting our decision not to perform it in our study.

The significance of tumor deposits in CRC has been thoroughly debated, with current evidence suggesting they are perhaps slightly worse prognostic factors than positive lymph nodes.18,19  In contrast, several recent studies have all convincingly shown that MTDs from SB-NETs are associated with aggressive disease and worse patient outcomes compared to lymph node metastases. Seven of these studies were summarized in a recent review article,4  and additional studies have reported similar findings.2022  Some of these studies strictly followed AJCC pN2 criteria that an “MTD” had to be located in the mesentery and measure >2 cm,21,23,24  whereas pathology-driven studies generally used criteria focusing on irregular contour and entrapment of nerves and vessels.7,8,15,25  Therefore, at the present time there exists sufficient evidence that the distinction between MTD and positive nodes can have a significant impact on prognostication for SB-NET patients. However, this currently has limited relevance to AJCC staging, as pN1 disease is defined as 1 to 11 lymph nodes involved by metastatic disease and pN2 disease is defined as “large mesenteric masses” (>2 cm) and/or >12 nodal “deposits,” both of which indicate overall stage III disease.1  This is not the case for CRC, wherein the number of lymph nodes (and deposits misinterpreted as lymph nodes) can alter overall patient stage.26  With continued prospective accumulation of accurate data, the role of MTDs in staging SB-NETs may be updated in the future.

To conclude, pathologists can often reach agreement on whether a local SB-NET metastasis represents a positive lymph node or an MTD, though a minority of cases remain diagnostically challenging due to biologic behavior and/or a composite appearance suggesting a confluence of both processes, leading to some interobserver variability. Positive lymph nodes appear most likely in tumor foci with a round contour and peripheral lymphoid tissue, while MTDs appear most likely in tumor foci with an irregular contour and entrapped/involved nerves. These features should be carefully assessed by practicing pathologists, as recent data suggest that MTDs appear to portend a worse prognosis than nodal disease in SB-NETs.

The authors thank Geoffrey Smith, MD, for assistance in scanning the slides; Emina E. Torlakovic, MD, PhD, and Ryan Haupt for hosting the slides for review; and Wendy L. Frankel, MD, for permission to use a manuscript title similar to hers.

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Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the May 2024 table of contents.

Competing Interests

The authors have no relevant financial interest in the products or companies described in this article.

Supplementary data