Indolent NK/T Cell Lymphoproliferative

Disorders of GI Tract

Chung-Che (Jeff) Chang, M.D., Ph.D.

Medical Director, Hematology and Molecular Pathology

Florida Hospital

Professor of Pathology, College of Medicine

University of Central Florida

407-303-1879

c.jeff.chang.md@flhosp.org

Important!

Many of these cases had been diagnosed as

aggressive T/NK cell lymphomas or as

celiac disease or inflammatory bowel

disease and then needlessly, and usually

ineffectively, treated.

30 year old asymptomatic white

male triathlete and marathon

runner underwent endoscopy ex.

because of a positive family

history of colon cancer and

colonic polyps.

Case report

Am J Surg Pathol 2006;30:539

Persistent multiple erythematous bull-eye lesions in the stomach, small bowel, and large bowel for 3 years.

CD3

CD56

TIA1

Br J Haematol 2003;120:1026

NK Cell-Associated Antigens

for NK cell lymphomas

NK cells with heterogeneous expression of

the immunoglobulin-like receptors CD158

isoforms suggesting a non-clonal process.

PCR for rearrangement of the TCR-

gamma gene showed no evidence of a

clonal T-cell population.

In situ hybridization for Epstein-Barr virus

encoded RNA (EBER) was negative.

There was no evidence of the involvement

beyond GI tract.

The patient was found to have high titers of antigliadin antibodies with no other evidence of celiac disease.

After instituting a gluten-free diet, many of the lesions regressed.

“Atypical NK-cell Proliferation of the Gastrointestinal Tract” may be driven by an anomalous immune response.

NK-cell enteropathy:

clinical/endoscopical findings

8 patients (2 men; 6 women; ages 27-68

years) with vague gastrointestinal

symptoms, abdominal pain, constipation,

diverticulosis, and reflux, with lesions

involving stomach, duodenum, small

intestine, and colon by endoscopy.

The lesions exhibited superficial

ulceration, edema, and hemorrhage.

Blood 2011;117:1447

Histopathological findings

A mucosal infiltrate (rarely submucosal) of intermediate to large cells with irregular nuclei and moderate amount of pale cytoplasm) with an NK-cell phenotype (CD56+/TIA-1+ /Granzyme B+/cCD3+/CD2-/+, but not CD5, CD4, CD8, CD20, CD30, or CD68).

Not invading the glandular epithelium.

No angiocentricity/agniodestruction.

At periphery, inflammatory infiltrate.

Focal apoptotic bodies but no necrosis except ulcerated area.

Ki67 low (average 25%)

EBV–encoded RNA in situ hybridization:

negative.

TCR-γ gene rearrangement: Negative.

Clinical outcomes

Three patients received aggressive chemotherapy followed by autologous bone marrow transplantation in 2.

Five patients were followed without treatment with no patient developed progressive disease or died of lymphoma (median follow-up, 30 months).

Repeat endoscopies in 6 of 8 patients showed persistence or recurrence of superficial gastrointestinal lesions.

“NK-cell enteropathy” of as yet unknown etiology.

Relatively high expression of Granzyme B and/or TIA-1 suggesting that the NK cells in these lesions were primed for the cytotoxic function, most probably responding to local inflammation, autoimmunity, or viruses.

Lymphomatoid gastropathy: a distinct

clinicopathologic entity of self-limited

pseudomalignant NK-cell proliferation

10 cases of unrecognized self-limited natural

killer–cell proliferation in the stomach

5 men and 5 women

Age; 46-75 years

No gastric symptoms.

Gastroscopy for screening for gastric cancer.

Gastroscopy showed ulcers or flat elevations

with a shallow depression (diameter, ∼ 1 cm).(Blood, 116:5631, 2010)

(Blood, 116:5631, 2010)

Lymphomatoid gastropathy

• Diffuse “atypical” infiltrate of medium to

large lymphoid cells, some with prominent

nucleoli, in the lamina propria.

• Necrosis present in some, not angiocentric or

angiodestructive, no apoptotic bodies.

• Occasionally extends into glands

• All cases with variable % (20 to 90%) with

eos. granules

• 9/10 H. pylori.

Atypical NK cells occasionally infiltrate the glandular epithelium (arrow), showing lymphoepithelial-like lesions by NK cells (B). Some atypical cells harbor large eosinophilic granules in the cytoplasm (C). In some cases, the nucleoli are prominent (arrow; D). (Blood, 116:5631, 2010)

Immunophenotypign typing identical to

that of NK-enteropathy

EBER−

Clinical outcome: most lesions underwent

self-regression. Three cases relapsed, but

none of the patients died

Differential diagnosis

Extranodal natural killer (NK)-/T-cell lymphomas: angiocentric and angiodestructive growth pattern with frequent necrosis and apoptosis; EBER+;

CD56+ T-cell neoplasm with extensive loss of T-cell markers may be considered: enteropathy-associated T-cell lymphoma (EATL type II): Clonal TCR gene rearrangement

Indolent T-cell LPD

• 6 M, 4 F, young-middle age (median age: 48 years)

• 5 white, 1 African American, 1 Asian

• Varied GI complaints (diarrhea &/or abd. pain, food intolerance, and dyspepsia, wt. loss, some “malabsorption”), rarely asymptomatic

• Small intestine (8), colon (6), oral cavity (3), esophagus (1) , stomach (2)

• Four patients :1 site; multiple sites: 6 patients

• None of the patients had a history of celiac sprue

• Some with history of IBD (Crohn disease, ulcerative colitis)

Blood 2013, 122:3599

4 patients: no lymphadenopathy, organomegaly,

or masses; 3 patient: mildly enlarged mesenteric

/para-arotic lymph nodes and/or mild

splenomegaly

Bone marrow examination: negative

1 Patient: the peripheral blood showed TCR-γ

chain gene rearrangement revealed a small clone

identical to the 1 in the colonic biopsy, no

evidence of disseminated clinical disease.

duodenal mucosa showed an “irregular” appearance (A). In the colon, numerous small polyps with associated mucosal erythema

Blood 2013, 122:3599

Indolent T-cell LPD

• Expansion of lamina propria by dense nondestructive infiltrate of predominantly small, montonous lymphocytes with slightly irregular nuclei and scant cytoplasm that displaces and distorts glands & occasionally extends into the submucosa.

• Do not usually involve the full thickness of the bowel and does not form tumor masses

• Occasional B-cell nodules at periphery.

• Some pleomorphism.

• Deeper extension but still with predominantly superficial involvement.

• May have some villous atrophy, crypt hyperplasia described by some, some infiltration into epithelium, 1 with “lymphocytic gastritis”.

• Some have granulomas & numerous eosinophils, other inflammatory cells.

• Diffuse LN & interstitial BM involvement (1 case)

TIA1

CD4CD8

Blood 2013, 122:3599

CD4CD8

Blood 2013, 122:3599

Phenotype/genotype: T-LPD

• CD3+, CD2+, CD5±, CD7±, CD56-, TCRβ+,

TCRγ-, EBER-, CD30-, Ki-67 up to 5-10%.

• Eight cases were CD4−/CD8+, 1 was

CD4+/CD8−, and another was CD4−/CD8−

• CD8+ cases: TIA1+, granz B-

• CD4+ cases: cytotoxic marker negative

• Clonal TCRγ rearrangements (1 oligoclonal)

Clinical outcome

• One patient (with “IBD” & multiple surgeries) ANED, all others whether or not treated with chemotherapy alive with persistent disease (9-175 month f/u, median 38 mo.)

• Of the 12 other patients reported (CD4+ in 11) , most go varied chemotherapy, some just steroids

• 9 alive, all but 1 with disease (1->15 years)±symptoms ± varied therapies (pt. in CR got chemorx)

• 3 died (2 of disease at 11-14 years including one who had not received lymphoma therapy that transformed.)

Differential diagnosis

Grossly:

EATL: Extensive mucosal ulcerations,

deep infiltration of the bowel wall,

multifocal involvement, infiltration of

adjacent abdominal structures, associated

ascites.

Indolent T-LPD usually presents as 1 or

more shallow mucosal ulcers with

associated erythema or as multiple small

polyps.

Histologically/

immunophenotypically

Indolent T-LPD: nondestructive, involving the

lamina propria and muscularis mucosae, small

mature cells.

Type I EATL : large and destructive infiltrate.

medium- to large-sized pleomorphic cells with

prominent nucleoli; the intestinal mucosa

adjacent to the main tumor mass frequently

shows evidence of enteropathy (Not indolent

T-LPD)

Type II EATL: destructive infiltrate,

monotonous and small to medium-sized

cells, florid infiltration of the intestinal

crypt epithelium and adjacent intestinal

mucosa by lymphoma cells (Not indolent

T-LPD).

Type II EATL: CD3+, CD8+, CD56+,

often TCR-G+, CD4-.

CD56- in indolent T-LPD also aids in the

distinction from NK cell enteropathy.

IBD (primarily ulcerative colitis)

– crypt distortion in indolent T-LPD,

– but no cryptitis, crypt abscesses, reduced

intraepithelial mucin, basal plasmacytosis,

submucosal fibrosis, hypertrophic muscularis

mucosae, and Paneth cell hyperplasia.

Celiac sprue

– Duodenal involvement with an increase in villous

intraepithelial lymphocytes in indolent T-LPD

– Lacking lymphocytes clustering at the tip of the

villi , villous atrophy, hyperplastic and elongated

crypts, increase in plasma cells in lamina propria

Other indolent T-cell lymphoproliferative

disorders/lymphomas

• Indolent CD8+ cutaneous T-cell lymphomas of the ear/other (acral) sites

• “Indolent PTCL – 10 cases with small-sized cells with slight nuclear atypia & very low Ki-67 found among 277 PTCL, NOS. (Hum Pathol 44:1927, 2013)

• 8 extranodal± nodal (most often spleen or thyroid), CD4± (5) or cytotoxic CD8+ (5), Some treated with surgery alone

• PTCL, NOS of thyroid with autoimmune thyroiditis(Br J Haem 161:214, 2013)

• Primary cutaneous CD4+ small/medium TCL

The bottom line

• Lymphomatoid gastropathy/NK enteropathy &

the indolent GI T-cell LPD need to be

recognized (?new provisional entities in the

new WHO book), at least T-cell cases may

sometimes progress.

• Careful integration of the history, endoscopic,

histologic, and immunophenotypic features is

necessary to make the correct diagnosis

• Best therapy for the disease or at least the

symptoms is not well-established.