Intestinal T cell Lymphoma

Question 1

What are the major

intestinal T cell lymphomas?

Answer 1

• EATL
• MEITL
• Intestinal T cell lymphomas, NOS
• Indolent T-cell lymphoproliferative disorder of the GI tract

Question 2

What is a key genetic difference

between EATL and MEITL?

Answer 2

• MEITL cases show a high proportion of gains in chromosome 8q24.2, which involves the MYC gene
  
  • this is not seen in EATL

Question 3

What is the prognosis of both EATL and MEITL ?

Answer 3

• both lymphomas are clinically aggressivce
• occur in adults
• negative for EBV

Question 4

What is a key difference in the intestinal T-cell

lymphoma, NOS ?

Answer 4

• generally lacks epitheliotropism
• still is clinically aggressive and has a cytotoxic immunophenotype

Question 5

What is the definition of EATL ?

Answer 5

• aggressive, neoplasm of intraepithelial T cells
• associated with Celiac disease
• exhibits various degrees of pleomorphism
• adjacent mucosa
  
  • villous atrophy
  • crypt hyperplasia
  • increased intraepithelial lymphocytes

Question 6

What is the epidemiology of EATL?

Answer 6

• most common subtype of primary intestinal T cell lymphoma
  
  • accounts for ~2/3 of all cases
• occurs in patients with celiac disease
  
  • may be diagnosed before or alongside EATL
• slight male predominance
• 6-7th decade

Question 7

What is the localization of EATL ?

Answer 7

• small intestine is involved in >90% of cases (jejunum and ileum are most common) - multi focal lesions are seen in up to 50% of cases - can occur in other GI sites including colon and stomach - rarely can have extra-GI involvement including the skin, CNS, and LN

Question 8

What are the clinical presentations of EATL ?

Answer 8

• most frequently presents with abdominal pain and gluten insensitivity (adult onset and only rarely in kids) - may have other symptoms of weakness, anorexia, intestinal perforation, hemorrhage, B symptoms can occur in up to 1/3 of patients - symptom duration is variable but usually is < 3 months - in a proportion of patients there is a prodrome of refractory celiac disease - HLH can occur in up to 40% of patients

Question 9

What are frequent sites of disease dissemination ?

Answer 9

• most common are the intra-abdominal lymph nodes - followed by bone marrow, mediastinal LN/lungs, liver, and skin

Question 10

What are the key microscopic findings of EATL ?

Answer 10

• cytomorphology can be quite variable - most lymphomas are: medium to large in size, vesicular chromatin, prominent nucleoli, round, and abundant pale-staining cytoplasm - but 40% of cases show large or anaplastic morphology - IMP: angiocentricity and angioinvasion are frequently seen - tumor cells can be difficult to see due to a moderate to striking infiltrate of histiocytes and eos - adjacent background mucosa has features of celiac disease, occasionally the jejunum may appear normal

Question 11

What is the immunophenotype of EATL ?

Answer 11

• Most common: CD3+, CD7+, CD103+, cytotoxic molecules + while negative for CD5, CD4, CD8 - IMP: up to 30% can be positive for CD8 with a higher frequency in patients with refractory celiac disease - CD30 is often seen when there is large cell morphology

Question 12

What is the postulated normal counterpart to the lymphoma cells of EATL ?

Answer 12

• small intestinal, intraepithelial lymphocytes, which sometimes share a similar immunophenotype to EATL * expressing CD8, alpha-beta heterodimer

Question 13

What are the precursor lesions to EATL ?

Answer 13

• precursor: refractory sprue with symptoms of disease and abnormal small intestine morphology for >6-12 months (2 types exist based on immunophenotype and molecular) * Type I * Type II

Question 14

What are the features of Type I refractory celiac disease?

Answer 14

• small intestinal lymphocytes have a normal immunophenotype: sCD3 and CD8+ and TCR - polyclonal products are detected on TR rearrangement - small intestine histology is that seen in uncomplicated celiac disease - this type accounts for 70-80% of celiac disease - no genetic or molecular alterations have been identified - mild symptoms - high 5 year survival rate with low risk of developing EATL

Question 15

What are the features of type 2 Celiac Disease ?

Answer 15

• immunophenotype of the lymphocytes is similar to EATL with maybe a subset of CD8+ lymphocytes - IMP: expression of CD30 is considered an indication of transformation to EATL - severe villous atrophy - TR gene rearrangements can show clones (usually alpha beta lineage) - deregulated expression of IL-15 disrupts homeostasis of the intestinal immune system and increases the survival of the intraepithelial lymphocytes - recurrent gains of chromosome 1q22-44 are detected in type 2 celiac disease, which is similar to EATL - aberrant nuclear p53 expression can be detected in 50% of cases in the absence of molecular lesions of TP53 - most patients have severe symptoms and malnutrition (protein losing enteropathy) - low 5 year survival with up to 50% developing EATL (chemo and BMT cannot eradicate the atypical lymphocytes)

Question 16

What is the genetic profile of EATL?

Answer 16

• TRB or TRG genes are cleanly re-arranged in virtually all cases - gains of the 9q34 region or deletions of 16q12.1 (different from PTCL, NOS) *this is also seen in a large proportion of MEITLs - different from MEITL, EATL frequently has gains of 1q and 5q - 56% of cases have LOH at 9p21 which causes a loss of p16 expression

Question 17

What are the genetic predispositions to development of EATL ?

Answer 17

• celiac or gluten sensitive enteropathy - associated with HLA loci: * HLA-DQA1 * HLA-DQB1

Question 18

What is the prognosis and predictive factors of EATL?

Answer 18

• poor prognosis due to multifocal intestinal involvement - median survival is 7 months - better outcomes have been reported in patients receiving chemotherapy and BMT - prognostic factors are not well-established, but malnourishment plays a role in the poor outcomes

Question 19

What is the definition of MEITL ?

Answer 19

• primary intestinal lymphoma derived from intraepithelial lymphocytes - no clear association with celiac disease - cells are medium in size with a rim of pale cytoplasm, no clear necrosis should be seen - florid infiltration of the intestinal epithelium is present - IMP: inflammatory background is absent

Question 20

What is the epidemiology of MEITL ?

Answer 20

• accounts for the majority of primary intestinal T cell lymphomas in Asia and is common in Hispanic individuals - males are affected more than females

Question 21

What is the localization of MEITL ?

Answer 21

• small intestine is the most frequent site (jejunum > ileum) - tumor mass with/without ulceration can be seen as well as diffuse mucosal infiltration - involvement of the mesenteric LN is common and dissemination to other sites of the GI tract can be seen including the large intestine and stomach

Question 22

What are the clinical features of MEITL ?

Answer 22

• symptoms are in accordance with the tumor: pain, obstruction, perforation, diarrhea - dissemination can and does frequently occur

Question 23

What are the microscopic features of MEITL ?

Answer 23

• lymphocytes are medium in size with moderate amounts of pale cytoplasm - round nuclei, fine chromatin and inconspicuous nucleoli - generally uniform in appearance - tumor cells show prominent epitheliotropism - villous architecture is distorted with expanded villi - IMP: an inflammatory background as well as necrosis are notably absent

Question 24

What is the immunophenotype of MEITL ?

Answer 24

• very distinct IHC: CD3, CD8 and CD56 positive with lack of CD5 (gamma delta T cell immunophenotype) - TIA-1 is consistently expressed while other cytotoxic markers are inconsistent - CD20 can be positive in up to 20% of cases - MATK (marker helps differentiate from EATL if positive in >80% of cells)

Question 25

What is the cell of origin and important to know about grading ?

Answer 25

• arises form intestinal T lymphocytes, can be a/b or g/d in derivation - grading is not performed because the lymphoma is clinically aggressive regardless of cell size

Question 26

What is key about the genetic profile of MEITL ?

Answer 26

• clonal rearrangement of the TR genes is seen in >90% of the cases - extra signals of MYC at 8q24.2 are often seen - gains at 9q34.3 are the most common copy number gains in 75% of cases - activating mutations at STAT5B have been identified in a high proportion of cases * seen in both a/b and g/d cases - EBV should be negative (otherwise it is extranodal NK/T cell lymphoma) * but can see EBV positive background B cells - IMP: no association with celiac disease or HLA subtypes

Question 27

What are the prognostic and predictive factors of MEITL ?

Answer 27

• clinical outcome is poor, 7 months (median survival) - better outcomes were observed in patients with better performance status and initial response to treatment

Question 28

What is the definition of intestinal T cell lymphoma, NOS ?

Answer 28

• used to diagnose T cell lymphoma arising in the small intestine and other GI tract sites that does not fit the definition of EATL or MEITL. - sometimes used if there is insufficient tissue on biopsy or the immunophenotype cannot be completely evaluated - not a specific disease category

Question 29

What is the definition of indolent T-cell lymphoproliferative disorder of the GI tract ?

Answer 29

• LPD can involve the mucosa at all sites but is most common in the small bowel and colon - cells infiltrate the laminate propria but do not invade the epithelium - indolent disease but patients do not respond to chemotherapy

Question 30

What is the epidemiology of Indolent T cell LPD of the GI tract ?

Answer 30

• presents in adulthood, M > F - a small proportion of patients have a history of Crohn’s disease

Question 31

What is the localization of indolent T cell LPD of the GI tract ?

Answer 31

• small bowel and colon - but the esophagus and the stomach can also be involved NOTE: * bone marrow and peripheral blood are usually not involved

Question 32

What are the clinical symptoms of the indolent T cell LPD ?

Answer 32

• abdominal pain, diarrhea, dyspepsia, and weight loss - the clinical course is chronic and rarely can be progressive - peripheral lymphadenopathy is not encountered although occasional mesenteric LN can be involved

Question 33

What are the microscopic features of indolent T cell LPD ?

Answer 33

• lamina propria is expanded by a dense lymphocytic infiltrate, this can extend beyond the muscularis mucosa and into the submucosa - mucosal glands can be displaced but no destroyed by the infiltrate - monomorphic cell infiltrate of small lymphocytes - admixed inflammation is rare and occasional epithelioid granulomas can be seen IMP: some of the features can resemble Crohn’s disease

Question 34

What is the immunophenotype of indolent T cell LPD ?

Answer 34

• most are a mature T cell immunophenotype (CD3 positive) and predominantly CD8 but CD4+ cases have been described - generally express TIA-1 but granzyme B is usually negative - CD2 and CD5 are positive with variable CD7 - CD56 is negative - CD103 has been described as positive in some cases - proliferation index is ver low by ki67

Question 35

What is the postulated cell of origin of indolent T cell LPD ?

Answer 35

• mature peripheral T cell

Question 36

What is the genetic profile of indolent T cell LPD ?

Answer 36

• recurrent mutations or translocations have not been identified - EBV has been negative in all cases

Question 37

What is the prognosis and predictive factors of indolent T cell LPD ?

Answer 37

• chronic relapsing clinical course with poor response to conventional chemotherapy - prolonged survival with persistent disease - cases with CD4 rather than CD8 expression seem to have a higher risk of progression of disease, but data is limited