Gastric Carcinomas With Lymphoid Stroma: Categorization and Comparison With Solid-Type Colonic Carcinomas

Raul S Gonzalez; Justin M M Cates; Frank Revetta; Loralee A McMahon; Kay Washington

doi:10.1093/ajcp/aqx096

. 2017 Nov 8;148(6):477–484. doi: 10.1093/ajcp/aqx096

Gastric Carcinomas With Lymphoid Stroma

Categorization and Comparison With Solid-Type Colonic Carcinomas

Raul S Gonzalez ^1,^✉, Justin M M Cates ², Frank Revetta ², Loralee A McMahon ¹, Kay Washington ²

PMCID: PMC6543885 PMID: 29126141

Abstract

Objectives

To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, “medullary carcinomas”), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither.

Methods

We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas.

Results

In the stomach, EBV-associated carcinomas (n = 8) contained intratumoral germinal centers (P = .024) and eosinophils (P = .030) and lacked necrosis (P = .019) compared with MSI-associated carcinomas (n = 5) and non-EBV, non-MSI carcinomas (n = 4). In the colon, MSI-driven carcinomas (n = 40) more frequently contained intratumoral lymphocytes (P = .017) and neutrophils (P = .0050) and less often metastasized to distant sites (P = .0040) than poorly differentiated carcinomas lacking MSI (n = 11).

Conclusions

Morphology may help classify gastric carcinomas with lymphoid stroma, although ancillary testing appears more reliable. Lymphoepithelioma-like carcinoma and medullary carcinoma should not be used interchangeably.

Keywords: Stomach, Medullary carcinoma, Lymphoepithelioma-like carcinoma, Microsatellite instability, Epstein-Barr virus

Most carcinomas of the gastrointestinal tract are adenocarcinomas, with clearly defined gland formation and evidence of mucin production. Some subtypes, however, assume a solid growth pattern, with malignant cells growing in sheets or nests. The prototypical solid-type carcinoma in the colon is medullary carcinoma, a well-studied tumor characterized by abundant tumor-infiltrating lymphocytes and microsatellite instability (MSI).^1-3 It is often reported as representing less than 1% of colorectal carcinomas.⁴ Colonic carcinomas with a somewhat similar morphologic appearance but no evidence of MSI and fewer infiltrating inflammatory cells are generally regarded as poorly differentiated carcinoma not otherwise specified, which has a worse prognosis than colonic medullary carcinoma.⁵

Solid-type carcinomas of the stomach generally have morphologic appearances similar to their colonic counterparts but are less frequently seen (as gastric carcinoma is less common than colorectal carcinoma in the West); they comprise roughly 3% of gastric carcinomas.⁶^,⁷ Although MSI has been reported in some such gastric carcinomas,⁷^,⁸ up to 86% instead are microsatellite stable and Epstein-Barr virus (EBV) positive^9-12; others are MSI and EBV negative. The World Health Organization advocates use of the term gastric carcinoma with lymphoid stroma¹³ to describe these solid-type, non-gland-forming carcinomas with abundant intratumoral inflammatory cells. This term encompasses both lymphoepithelioma-like carcinoma and medullary carcinoma. Despite the established associations between MSI and medullary carcinoma in the colon and EBV positivity and lymphoepithelioma-like carcinoma in other organ systems,¹⁴ most reports on gastric carcinoma with lymphoid stroma conflate the terms medullary carcinoma and lymphoepithelioma-like carcinoma and/or classify carcinomas arising from MSI or EBV into the same group.^15-20 The Cancer Genome Atlas (TCGA) Research Network recently published a comprehensive molecular categorization of gastric carcinomas, in which EBV and MSI status defined two of the four proposed subtypes,²¹ further underscoring the importance of these factors in gastric carcinogenesis and potential future treatment regimens. In addition, TCGA and other investigators have established that EBV and MSI are generally mutually exclusive in gastric carcinomas, suggesting that tumors with these etiologies should not be categorized together.¹⁵^,²¹ However, despite their different molecular underpinnings, gastric adenocarcinomas with EBV, MSI, or neither generally resemble one another morphologically.²²^,²³ This holds true for gastric carcinomas with lymphoid stroma as well.

As relatively few authors have explicitly argued for a clear distinction among gastric carcinomas with lymphoid stroma based on etiology,⁸^,^24-26 we examined the clinicopathologic features in a series of these tumors, with an emphasis on subtype categorization. Since solid-type carcinomas with lymphoid stroma of the colon are more common than those of the stomach, we also identified cases of medullary carcinoma and poorly differentiated solid-type carcinoma of the colon to determine whether these lesions had observable differences from their gastric counterparts.

Materials and Methods

With appropriate institutional research board approval, we searched the surgical pathology archives of the University of Rochester Medical Center and Vanderbilt University Medical Center, identifying 68 carcinomas (17 gastric and 51 colonic) with at least 50% solid growth pattern and some degree of intratumoral lymphocytic inflammation. This represented 7% (13/189) of all gastric carcinomas and 2% (34/1,719) of all colonic carcinomas searched at Vanderbilt; total carcinoma numbers were not available from the University of Rochester.

Clinicopathologic data were gathered on each case, including patient age, sex and race; tumor site and size; treatment history, including neoadjuvant and adjuvant therapy; nodal and distant metastases; overall American Joint Committee on Cancer seventh edition stage; and patient outcomes, including dates of resection, recurrence, and death or last clinical follow-up. Original H&E-stained slides from each tumor were reviewed to document the appearance of advancing tumor border (pushing vs infiltrating), tumoral necrosis, mucosal ulceration, abundant mitotic activity (defined as ≥3 per high-power field [0.55 mm²]), prominent nucleoli, nuclear pleomorphism, prominent intratumoral lymphocytes (>10 per high-power field), intratumoral germinal center formation, intratumoral neutrophils (including microabscesses), intratumoral eosinophils, other (nonsolid) components, tumor budding, lymphovascular invasion, perineural invasion, and histologic appearance of metastases. Gastric cases were also scrutinized for microscopic growth pattern, which was categorized as syncytial (sheets of cells, often with indistinct cell borders) or clustered (tight, delineated aggregates of cells, often with more distinct cell borders).

Immunohistochemical staining for MLH1 (clone G168-15, dilution 1:50; Biocare Medical, Concord CA), MSH2 (clone FE11, dilution 1:50; Biocare Medical), MSH6 (clone BC/44, dilution 1:50; Biocare Medical), and PMS2 (clone A16-14, dilution 1:100; Biocare Medical) was performed using high pH (pH 9) heat-induced epitope retrieval on an Omnis Automated staining platform and the Flex Detection System (Agilent Technologies, Santa Clara, CA). This was performed on 16 gastric cases and 43 colonic cases (the remaining gastric case had previously been determined to be EBV positive, and the remaining eight colonic cases had previously undergone polymerase chain reaction [PCR]–based testing for MSI for clinical purposes), with total loss of protein expression by tumor nuclei interpreted as a positive result. Epstein-Barr encoding region (EBER) in situ hybridization was performed on all cases and was detected using the RISH HRP Detection Kit (Biocare Medical), with any staining within tumor nuclei interpreted as a positive result. Immunohistochemical staining for CDH17 (clone 1262C, dilution 1:750; Novus Biologicals, Minneapolis, MN) and CDX2 (dilution 1:400; Cell Signaling Technology, Danvers, MA) was performed on 16 colon cases and 16 stomach cases using pH 6 antigen retrieval using the EnVision+ System with HRP-labeled polymer (Agilent Technologies), with any staining of tumor cells interpreted as a positive result. Molecular testing for EBV positivity (eg, PCR) was not performed, nor was molecular testing for MSI in cases not previously tested for clinical purposes.

The carcinomas were categorized based on whether they were MSI-high/mismatch repair protein deficient (by immunohistochemistry or by molecular assay performed as part of prior patient care), EBER positive, or neither. MSI-high/mismatch repair protein-deficient cases from both organs were designated medullary carcinoma, while EBER-positive cases were designated lymphoepithelioma-like carcinoma; the remaining cases were considered poorly differentiated carcinoma not otherwise specified.

Clinicopathologic variables were compared among different diagnostic groups using standard bivariate statistical tests (Fisher’s exact and Kruskal-Wallis tests) in Stata version 13 (StataCorp, College Station, TX). All hypothesis tests were two-sided, with α = .05.

Results

Among the 68 cases, there were five gastric medullary carcinomas, eight gastric lymphoepithelioma-like carcinomas, four gastric poorly differentiated carcinomas, 40 colonic medullary carcinomas, and 11 colonic poorly differentiated carcinomas. MSI-high status and EBER positivity were mutually exclusive for gastric cases, and no colonic cases were EBER positive.

Three of the MSI-high gastric carcinomas demonstrated loss of MLH1 and PMS2 by immunohistochemistry, and the other two demonstrated loss of MSH2 and MSH6; three of these patients were determined to have Lynch syndrome. Thirty of the MSI-high colonic carcinomas demonstrated loss of MLH1 and PMS2 by immunohistochemistry, one demonstrated loss of MSH2 and MSH6, one demonstrated loss of only PMS2, and eight had germline mutations, MSI-high status, or MLH1 hypermethylation by previous PCR testing; five of these patients were determined to have Lynch syndrome.

Clinicopathologic features are summarized in Table 1 . The gastric cases showed a predominantly nested growth pattern, with the cells arranged into clusters and/or syncytial sheets within the nests. Also common were pushing borders (12/17, 71%) and overlying ulceration (15/17, 88%). Tumor cells demonstrated mild to moderate pleomorphism, vesicular nuclei, and prominent nucleoli. Mitoses were abundant in the majority of cases (10/17, 59%). Intratumoral inflammation was usually present but was mild in about half of cases. Lymphocytes were prominent in roughly two-thirds of cases (12/17, 71%), while fewer cases demonstrated neutrophils (6/17, 35%) or eosinophils (6/17, 35%). When present, the neutrophils typically (4/5, 80%) formed microabscesses. Peritumoral inflammation (ie, “Crohn-like reaction”) usually accompanied intratumoral inflammation.

Table 1.

Clinicopathologic Features of Gastric Carcinomas With Lymphoid Stroma and Colonic Solid-Type Carcinomas, by Subtype^a

Characteristic	Gastric				Colonic
Characteristic	MC (n = 5)	LEC (n = 8)	PDC (n = 4)	P Value	MC (n = 40)	PDC (n = 11)	P Value
Mean age, y	74	65.4	70.3	.39	69.5	61.6	.071
Female sex	3 (60)	1 (13)	1 (25)	.19	25 (63)	7 (64)	1.0
White race	4 (80)	4 (50)	4 (100)	.11	39 (98)	10 (91)	.39
Median tumor size, cm	9.2	7.6	5.5	.50	7.2	4.8	.042^b
Syncytial growth (vs clustered)	3 (60)	5 (63)	2 (50)	.92	NA	NA	NA
Pushing border (vs infiltrative)	4 (80)	6 (75)	2 (50)	.59	31 (78)	6 (55)	.15
Tumoral necrosis	4 (80)	1 (13)	3 (75)	.019^b	29 (73)	10 (91)	.42
Mucosal ulceration	5 (100)	6 (75)	4 (100)	.19	36 (90)	8 (73)	.16
Abundant mitotic activity	3 (60)	4 (50)	3 (75)	.71	22 (55)	7 (64)	.61
Prominent nucleoli	5 (100)	8 (100)	3 (75)	.21	39 (98)	11 (100)	1.0
Nuclear pleomorphism	3 (60)	1 (13)	2 (50)	.17	11 (28)	5 (45)	.26
Abundant intratumoral lymphocytes	3 (60)	7 (88)	2 (50)	.32	20 (50)	1 (9)	.017^b
Follicles with germinal centers	0 (0)	4 (50)	0 (0)	.024^b	1 (3)	0 (0)	1.0
Intratumoral neutrophils	1 (20)	4 (50)	1 (25)	.48	18 (45)	0 (0)	.0050^b
Neutrophilic microabscesses	1 (20)	3 (38)	0 (0)	.23	13 (33)	0 (0)	.046^b
Intratumoral eosinophils	0 (0)	5 (63)	1 (25)	.030^b	7 (18)	3 (27)	.67
Nonsolid component	1 (20)	4 (50)	3 (75)	.25	25 (63)	8 (73)	.53
Tumor budding	1 (20)	2 (25)	2 (50)	.59	26 (65)	9 (82)	.47
Lymphovascular invasion	1 (20)	3 (38)	2 (50)	.63	19 (48)	6 (55)	.74
Perineural invasion	3 (60)	2 (25)	1 (25)	.40	2 (5)	1 (9)	.50
Nodal metastases	2 (40)	5 (63)	2 (50)	.72	18 (45)	6 (55)	.57
Distant metastases	0 (0)	2 (25)	0 (0)	.19	4 (10)	6 (55)	.0040^b
CDH17 positivity	4 (80)	4/7 (57)	2 (50)	.61	13/15 (87)	1/1 (100)	1.0
CDX2 positivity	2 (40)	2/7 (29)	4 (100)	.064	7/15 (47)	1/1 (100)	1.0

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LEC, lymphoepithelioma-like carcinoma; MC, medullary carcinoma; PDC, poorly differentiated carcinoma; NA, not evaluated.

^aValues are presented as number (%) unless otherwise indicated. All statistical comparisons made using Fisher’s exact test (two-sided).

^bIndicates statistical significance (P < .05).

Despite morphologic overlap among the gastric carcinoma, a few observable differences were noted among different diagnostic subgroups Image 1 . Necrosis was least common in lymphoepithelioma-like carcinoma (1/8, 13%; P = .019), whereas intratumoral eosinophils were most commonly seen in lymphoepithelioma-like carcinoma (5/8, 63%; P = .030). Germinal center formation was seen in four (50%) of eight lymphoepithelioma-like carcinomas but not in any medullary carcinomas or poorly differentiated carcinomas (P = .024). Poorly differentiated carcinoma had no particular distinguishing characteristics upon examination of H&E-stained slides.

Gastric carcinomas with lymphoid stroma generally resemble one another on H&E-stained sections, but minor histopathologic differences do exist. A, Gastric lymphoepithelioma-like carcinoma shows malignant cells vaguely clumped into small clusters. The cells show prominent nucleoli and abundant amphophilic cytoplasm. Mitotic figures are readily identified. Intratumoral inflammation is present, including lymphocytes and occasional eosinophils. Necrosis was typically not seen in these tumors (H&E, ×400). B, Gastric lymphoepithelioma-like carcinoma often shows focally prominent intratumoral lymphoid aggregates containing germinal centers (H&E, ×200). C, By definition, gastric lymphoepithelioma-like carcinomas demonstrated EBER positivity (in situ hybridization, ×200). D. The cells of gastric medullary carcinoma resemble those of lymphoepithelioma-like carcinoma, although in this example, they are arranged in a more syncytial, rather than clustered, manner (H&E, ×400). E, Medullary carcinomas demonstrate some evidence of microsatellite instability; this case showed MLH1 loss by immunohistochemistry, with staining retained in tumor-infiltrating lymphocytes (immunohistochemical stain, ×200). F, Gastric poorly differentiated carcinoma is composed of sheets of malignant cells and occasional inflammatory cells (H&E, ×400). In these cases, EBER was negative and microsatellite instability was not detected.

The two colonic carcinoma subtypes generally resembled one another and resembled the gastric carcinomas, although some differences were appreciable Image 2 . Intratumoral inflammation was more common in medullary carcinoma than poorly differentiated carcinoma (lymphocytes, 20/40 [50%] vs 1/11 [9%], P = .017; neutrophils, 13/40 [33%] vs 0/9 [0%], P = .0050). Distant metastases were more common in colonic poorly differentiated carcinoma (6/11, 55%) than medullary carcinoma (4/40, 10%; P = .0040). The aforementioned morphologic differences between solid-type colonic tumors were not observed in their gastric counterparts and vice versa. Perineural invasion was more common in gastric medullary carcinoma than colonic medullary carcinoma (3/5 [60%] vs 2/40 [5%], P = .0030), but otherwise there were no significant morphologic differences between gastric and colonic medullary carcinoma or between gastric and colonic poorly differentiated carcinoma. Tumor budding was common in colonic cases (35/51, 69%) but not in gastric cases (5/17, 29%; P = .0091).

Solid-type colonic carcinomas generally resemble one another, but histopathologic differences do exist. A, Colonic medullary carcinoma demonstrates prominent intratumoral neutrophils forming microabscesses (H&E, ×400). MLH1 expression was lost in this case. B, In colonic poorly differentiated carcinomas, intratumoral inflammatory cells are present but are less abundant than in typical colonic medullary carcinoma (H&E, ×400). EBER in situ hybridization was negative, and MLH1 expression was retained.

Most tumors tested (24/32, 75%) were CDH17 positive, and half at each site (16/32, 50%) were CDX2 positive; all four gastric poorly differentiated carcinomas showed CDX2 positivity (P = .064).

Limited sample size precluded robust statistical analysis of patient survival.

Discussion

The term medullary carcinoma generally refers to microsatellite-unstable solid-type carcinomas with numerous tumor-infiltrating lymphocytes in the colon, and the term lymphoepithelioma-like carcinoma implies an EBV-driven solid-type carcinoma in many organ systems. The nomenclature for gastric carcinomas with lymphoid stroma is more muddled. Both EBV and MSI have been linked to malignancies having a solid, syncytial-type growth pattern, but unlike in other organ systems, these tumors are often classified together, thereby implying that they are the same entity. This confusion is exacerbated by the fact that medullary carcinoma and lymphoepithelioma-like carcinoma are often listed as synonyms that refer to the same tumor type in the stomach.^15-20

This situation is somewhat understandable, given the relative rarity of gastric carcinoma with lymphoid stroma compared with solid-type colorectal carcinoma and the fact that MSI-driven (medullary) and EBV-driven (lymphoepithelioma-like) gastric carcinomas with lymphoid stroma resemble each other microscopically and also resemble gastric MSI-negative, EBV-negative poorly differentiated carcinoma not otherwise specified. All three tumor types feature nests of cells with prominent nucleoli and ample amphophilic cytoplasm. Mitotic figures, ulceration, and necrosis are frequent, and inflammatory cells infiltrate among tumor cells and surround the tumor.

Some have argued that gastric lymphoepithelioma-like carcinoma and medullary carcinoma can be distinguished morphologically. In a review article, Chetty²⁴ noted that gastric medullary carcinoma demonstrates a syncytial growth pattern, bears robust peritumoral inflammation, and has a well-defined border, while lymphoepithelioma-like carcinoma is formed by small clusters of cells that “do not correspond to the syncytial growth patterns seen in medullary carcinoma,” has more prominent intratumoral than peritumoral inflammation, and has an infiltrative border. However, we found that syncytial and clustered growth patterns exist on a morphologic spectrum, and both tumor types often showed nests of tumor cells exhibiting both arrangements, with one perhaps predominating over the other. In addition, these tumors often showed inflammation both within and around the lesion itself, and both tended to show a pushing rather than infiltrative border.

We found other significant morphologic differences in our analysis of these gastric lesions. Necrosis is least common in lymphoepithelioma-like carcinoma, and lymphoid follicles with germinal centers and intratumoral eosinophils are most common in lymphoepithelioma-like carcinoma. The reliability of these observations is unclear, given the admittedly small number of cases in this study. Considering this limitation, as well as the overlap in syncytial and clustered architecture and the fact that intratumoral and peritumoral inflammation are not mutually exclusive, we do not recommend relying on histologic criteria alone to distinguish among medullary carcinoma, lymphoepithelioma-like carcinoma, or poorly differentiated carcinoma in the stomach. Therefore, the term gastric carcinoma with lymphoid stroma should best serve as a categorizing diagnosis after initial histologic review. Determining MSI and EBV status via ancillary testing currently appears to be the most reliable way to distinguish among these three entities and to arrive at a final diagnosis.

The driving factor behind non-MSI, non-EBV poorly differentiated carcinoma with lymphoid stroma remains unclear, although one study found frequent ERBB2, TP53, and LRP1B mutations in these tumors.²⁷

Less confusion exists regarding solid-type carcinomas of the colon. The existence of medullary carcinoma and its association with MSI is well established, and colonic medullary carcinoma is more likely to demonstrate intratumoral lymphocytes than poorly differentiated carcinoma. Our study found that neutrophils are also common within medullary carcinoma, which was not discussed in prior case series¹^,²⁸ but was recently posited as a potential criterion for the diagnosis.²⁹ The existence of lymphoepithelioma-like carcinoma in the colon is somewhat dubious, as the few existing case reports are not especially convincing in establishing an association with EBV infection.²⁴

The main reason for proper categorization of solid-type colonic carcinomas and gastric carcinomas with lymphoid stroma is to establish optimal treatment options and predict prognosis. Colonic medullary carcinoma is known to have a good prognosis, and we found that metastasis to other organs occurs significantly less often than colonic solid-type poorly differentiated carcinoma, as previously reported.⁵ At the present time, however, the biological behavior of the various types of gastric carcinoma with lymphoid stroma is less clear. While our study was too small for proper survival analysis, larger studies have shown that EBV-associated gastric carcinomas have a relatively good prognosis, whether considering all gastric carcinomas together or only considering gastric carcinomas with lymphoid stroma.¹¹^,³⁰^,³¹ Other indicators of good prognosis include MSI,¹⁷ tumor-infiltrating lymphocytes,¹⁷ and a diagnosis of medullary carcinoma in comparison to poorly differentiated carcinoma.²⁵ It has also been reported that among early gastric carcinomas, those with lymphoid stroma invade submucosa more deeply but metastasize less frequently.³²

Regarding patient treatment options, microsatellite-unstable carcinomas respond to chemotherapeutic regimens differently than microsatellite-stable tumors.³³ Targeted therapy for carcinomas induced by EBV infection currently remains experimental but may become available in the future.³⁴^,³⁵ In addition, both EBV-associated and MSI-associated carcinomas are promising candidates for immunotherapy,³⁶ such as targeted antibodies against PD-1 and PD-L1, which have received intense scrutiny recently as therapeutic options for malignancies with numerous intratumoral lymphocytes, such as melanoma.³⁷ Others have reported that gastric carcinomas with lymphoid stroma usually express PD-L1 within tumoral cells,²⁰^,³⁸ which suggests that PD-1 and PD-L1 inhibitors may be useful in treating gastric and colorectal carcinomas with lymphoid stroma in the future.

As CDX2 is often lost in colonic medullary carcinoma and poorly differentiated carcinoma,³ and CDH17 is often expressed in colonic medullary carcinoma,³⁹ we stained several of our cases with these markers. CDX2 positivity was present in a minority of gastric medullary carcinomas and lymphoepithelioma-like carcinomas and in all poorly differentiated carcinomas, although this result did not reach statistical significance. CDH17 positivity was present in roughly half of cases from all three gastric categories. Thus, these markers are not useful diagnostically in this setting.

Most of our ancillary testing was based on staining techniques rather than molecular testing, an approach that has been recently popularized with respect to gastric cancer. Multiple groups⁴⁰^,⁴¹ have used staining as a method for classifying gastric cancer into schema similar to the molecular categorizations established by TCGA and others.

Given the small number of cases in our study, further research with larger cohorts is necessary to clearly define the clinicopathologic characteristics of gastric medullary carcinoma, lymphoepithelioma-like carcinoma, and poorly differentiated carcinoma with lymphoid stroma. This can only be accomplished through accurate characterization using precise diagnostic definitions, as these entities have overlapping features. Our series serves as a “proof of concept” that gastric carcinoma with lymphoid stroma can be divided into cases associated with EBV, MSI, and neither, with histology likely serving at most a minor role in making this distinction compared with ancillary testing. Whether the straightforward criteria in our study are used or more nuanced criteria are adopted, such distinction may be relevant to patients in the future as these entities are further characterized and specific treatment options become available.

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PERMALINK

Gastric Carcinomas With Lymphoid Stroma

Raul S Gonzalez, MD

Justin M M Cates, MD, PhD

Frank Revetta

Loralee A McMahon, HT

Kay Washington, MD, PhD