Intestinal T cell Lymphoma Flashcards
1
Q
What are the major
intestinal T cell lymphomas?
A
- EATL
- MEITL
- Intestinal T cell lymphomas, NOS
- Indolent T-cell lymphoproliferative disorder of the GI tract
2
Q
What is a key genetic difference
between EATL and MEITL?
A
- MEITL cases show a high proportion of gains in chromosome 8q24.2, which involves the MYC gene
- this is not seen in EATL
3
Q
What is the prognosis of both EATL and MEITL ?
A
- both lymphomas are clinically aggressivce
- occur in adults
- negative for EBV
4
Q
What is a key difference in the intestinal T-cell
lymphoma, NOS ?
A
- generally lacks epitheliotropism
- still is clinically aggressive and has a cytotoxic immunophenotype
5
Q
What is the definition of EATL ?
A
- aggressive, neoplasm of intraepithelial T cells
- associated with Celiac disease
- exhibits various degrees of pleomorphism
- adjacent mucosa
- villous atrophy
- crypt hyperplasia
- increased intraepithelial lymphocytes
6
Q
What is the epidemiology of EATL?
A
- 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
7
Q
What is the localization of EATL ?
A
- 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
8
Q
What are the clinical presentations of EATL ?
A
- 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
9
Q
What are frequent sites of disease dissemination ?
A
- most common are the intra-abdominal lymph nodes - followed by bone marrow, mediastinal LN/lungs, liver, and skin
10
Q
What are the key microscopic findings of EATL ?
A
- 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
11
Q
What is the immunophenotype of EATL ?
A
- 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
12
Q
What is the postulated normal counterpart to the lymphoma cells of EATL ?
A
- small intestinal, intraepithelial lymphocytes, which sometimes share a similar immunophenotype to EATL * expressing CD8, alpha-beta heterodimer
13
Q
What are the precursor lesions to EATL ?
A
- 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
14
Q
What are the features of Type I refractory celiac disease?
A
- 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
15
Q
What are the features of type 2 Celiac Disease ?
A
- 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)
16
Q
What is the genetic profile of EATL?
A
- 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
17
Q
What are the genetic predispositions to development of EATL ?
A
- celiac or gluten sensitive enteropathy - associated with HLA loci: * HLA-DQA1 * HLA-DQB1
18
Q
What is the prognosis and predictive factors of EATL?
A
- 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
19
Q
What is the definition of MEITL ?
A
- 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
20
Q
What is the epidemiology of MEITL ?
A
- accounts for the majority of primary intestinal T cell lymphomas in Asia and is common in Hispanic individuals - males are affected more than females
21
Q
What is the localization of MEITL ?
A
- 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
22
Q
What are the clinical features of MEITL ?
A
- symptoms are in accordance with the tumor: pain, obstruction, perforation, diarrhea - dissemination can and does frequently occur
23
Q
What are the microscopic features of MEITL ?
A
- 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
24
Q
What is the immunophenotype of MEITL ?
A
- 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)
25
Q
What is the cell of origin and important to know about grading ?
A
- 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
26
Q
What is key about the genetic profile of MEITL ?
A
- 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
27
Q
What are the prognostic and predictive factors of MEITL ?
A
- clinical outcome is poor, 7 months (median survival) - better outcomes were observed in patients with better performance status and initial response to treatment
28
Q
What is the definition of intestinal T cell lymphoma, NOS ?
A
- 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
29
Q
What is the definition of indolent T-cell lymphoproliferative disorder of the GI tract ?
A
- 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
30
Q
What is the epidemiology of Indolent T cell LPD of the GI tract ?
A
- presents in adulthood, M > F - a small proportion of patients have a history of Crohn’s disease
31
Q
What is the localization of indolent T cell LPD of the GI tract ?
A
- small bowel and colon - but the esophagus and the stomach can also be involved NOTE: * bone marrow and peripheral blood are usually not involved
32
Q
What are the clinical symptoms of the indolent T cell LPD ?
A
- 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
33
Q
What are the microscopic features of indolent T cell LPD ?
A
- 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
34
Q
What is the immunophenotype of indolent T cell LPD ?
A
- 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
35
Q
What is the postulated cell of origin of indolent T cell LPD ?
A
- mature peripheral T cell
36
Q
What is the genetic profile of indolent T cell LPD ?
A
- recurrent mutations or translocations have not been identified - EBV has been negative in all cases
37
Q
What is the prognosis and predictive factors of indolent T cell LPD ?
A
- 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
