GI Lymphoproliferative Disorders: Not Your Usual Suspects

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1 GI Lymphoproliferative Disorders: Not Your Usual Suspects The Hawaii Pathology Conference Update in Gynecologic & Breast Pathology, Cytopathology and Hematopathology October 2018 Teri A. Longacre, M.D., Department of Pathology, Stanford Medicine Stanford, California

2 Disclosures: US Pathology Biomarker Advisory Board, Merck

3 GI Lymphoproliferative Disorders Small biopsy Crush artifact Access to flow not the best Clonality may be problematic Rare, uncommon, or underecognized entities

4 Case 1 56 year old with fever, weight loss and diarrhea

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8 CD30

9 Enteropathy Associated T Cell Median age 60 Lymphoma Abdominal pain, fever, weight loss, perforation, obstruction, history of malabsorption (+/-) Jejunum - often multiple circumferential ulcers with no mass lesion Poor prognosis

10 Enteropathy Associated T Cell Lymphoma (EATCL) May not have history of celiac disease May present with celiac at time of EATCL May present first with refractory celiac disease Arch Pathol Lab Med 2018;142:44 52

11 Enteropathy Associated T Cell Lymphoma Medium & large atypical cells Mixed inflammatory infiltrate CD3+, CD7+, CD4-, CD8-/+, CD30+, granzyme B, perforin T cell receptor beta gene rearrangement Typically negative for CD56 Adjacent mucosa shows celiac changes Arch Pathol Lab Med 2018;142:44 52

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14 Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL) Not assoc with celiac Asian predominance Monomorphic small & medium cells Absent mixed inflammatory infiltrate Express CD3, CD8, & CD56. TCR alpha-beta or gamma-delta Arch Pathol Lab Med 2018;142:44 52

15 Refractory Sprue Dietary indiscretion Collagenous sprue Lymphoma/ ulcerative jejunoileitis Right diagnosis, secondary problem Wrong diagnosis

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17 Median age 60 Collagenous Sprue Markedly thickened, amorphous subepithelial collagenous band Response to gluten withdrawal poor: requires steroids Very rare: exclude lymphoma

18 Ulcerative jejunoilietis Median age 60 Abdominal pain, fever, weight loss Probably a manifestation of enteropathy associated T cell lymphoma Exclude infection, Crohn s, vasculitis, drugs, ischemia

19 Refractory Celiac Disease Persistent (primary) or recurrent (secondary) malabsorption symptoms Villous blunting (atrophy) Adherence to gluten-free diet at least 6-12 months All other causes excluded

20 Refractory Celiac Disease Type 1: normal IELs Good response to aggressive nutritional support, gluten free diet, & alternative pharmacologic therapy Type 2: abnormal IELs Poor prognosis; uncertain response to alternative pharmacologic therapy; subset develop EATCL or ulcerative jejunitis Gut 2010; 59:

21 Criteria for Types 1/2 Refractory Celiac Disease IHC: >50% CD3-CD8- IELs (cytoplasmic CD3 may be present) Flow cytometry: >20-25% CD3-CD8- IELs Clonal T-cell rearrangement (gamma, delta) Gut 2010; 59:

22 Case 2 44 year old male with unexplained diarrhea

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27 CD117

28 CD117

29 Mast cell tryptase

30 CD25

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32 Systemic Mastocytosis: GI Tract Diarrhea may be presenting symptom (67%) Other symptoms: abdominal pain, nausea, weight loss, bloating, vomiting, reflux Sites of involvement colon (95%), ileum (86%), duodenum (80%), & stomach (54%) Am J Surg Pathol 2014;38:832-42

33 Systemic Mastocytosis: GI Tract Pathology often subtle Often associated with prominent eosinophils, which may obscure the mast cell infiltrate CD117, mast cell tryptase (MCT), & CD25 will highlight dense aggregates, plaque-like collections or nodules of mast cells in lamina propria or subepithelium Am J Surg Pathol 2014;38:832-42

34 Classification of Mast Cell Disorders Mast cell hyperplasia Mastocytosis Mast cell activation syndrome Myelomastocytic conditions (leukemia) Int Arch Allergy Immunol 2012;157:

35 Mast Cell Hyperplasia Non-clonal, reactive Underlying disease No signs of mast cell activation Presence of round & loosely scattered mast cells is best interpreted as mast cell hyperplasia No widely accepted criteria for normal or increased numbers of mast cells in various tissue sites Int Arch Allergy Immunol 2012;157:

36 Mastocytosis Cutaneous mastocytosis* Systemic mastocytosis* Mastocytoma *Mutually exclusive Int Arch Allergy Immunol 2012;157:

37 CD117

38 CD117 Is Not Specific for GIST Spindled Solitary fibrous tumor Dermatofibrosarcoma Synovial sarcoma Angiosarcoma Mesenteric fibromatosis* Endometrial stromal sarcoma Reactive nodular fibrous pseudotumor* Epithelioid Mastocytoma Seminoma Melanoma Clear cell sarcoma Ewing sarcoma Epithelioid angiosarcoma PEComa Extramedullary myeloid tumor *Controversial: may be due to antibody titer, antigen retrieval, etc

39 Mast Cell Activation Syndrome Typical clinical signs & symptoms Substantial & transient increase in a mast cellderived mediator in biological fluids during or shortly after the acute event compared to a baseline level recorded either before the acute event or at least 24 hr after all clinical signs have completely resolved An objective major response of clinical symptoms to therapy Int Arch Allergy Immunol 2012;157:

40 Mast Cell Activation Syndrome Acute urticaria (hives) Flushing Pruritus Headache Abdominal cramping, diarrhea, vomiting Respiratory symptoms and hypotension Int Arch Allergy Immunol 2012;157:

41 Mast Cell Activation Syndrome Primary Secondary Idiopathic Int Arch Allergy Immunol 2012;157:

42 Primary MCAS Monoclonal mast cells (KIT D816V or other KIT exon 17 mutations) Int Arch Allergy Immunol 2012;157:

43 Secondary MACS Type I allergy of another underlying disease leading to MCA Int Arch Allergy Immunol 2012;157:

44 Idiopathic MAC No allergy No other underlying disease No monoclonal mast cells No mast cells in skin detected Int Arch Allergy Immunol 2012;157:

45 Systemic Mastocytosis Main criterion Compact infiltrate in an extramedullary organ (>15 mast cells) Minor criteria Prominent spindling of mast cells (>25% in a compact infiltrate) Aberrant immunophenotype of mast cells (CD2 and/or CD25) Activating point mutation of c-kit at codon 816 (usually KIT D816V) Elevated baseline serum tryptase (>20 ng/ml) Int Arch Allergy Immunol 2012;157:

46 Systemic Mastocytosis The major and at least 1 minor criterion or At least 3 minor criteria Int Arch Allergy Immunol 2012;157:

47 GI biopsy Rule out mast cell activation syndrome

48 Role of Pathologist Identify compact mast cell infiltrates in extracutaneous tissue Tryptase and CD117 (KIT) IHC Expression of CD25 by mast cells to demonstrate aberrant immunophenotype Int Arch Allergy Immunol 2012;159:1 5

49 Caveats: False Positives Many CD25+ lymphocytes & histiocytes Cross reactivity with tryptase Int Arch Allergy Immunol 2012;159:1 5

50 Case 3 60 year old male with CLL and diarrhea Rule out progession

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54 Idelalisib-Associated Enterocolitis PI3Kδ inhibitor for treatment of CLL/SLL and follicular lymphoma Can cause severe diarrhea & colitis Symptoms decrease following removal of drug Am J Surg Pathol 2015;39: ; Surg Pathol 2015;39:

55 Idelalisib-Associated Enterocolitis Crypt apoptosis with loss of goblet cells Focal active cryptitis Mild architectural distortion Intraepithelial lymphocytosis (CD8+) Am J Surg Pathol 2015;39: ; Surg Pathol 2015;39:

56 Idelalisib-Associated Enterocolitis Mimics Autoimmune enteropathy Common variable immune deficiency Viral (CMV) infection

57 Other Antineoplastic Drugs Mycophenolate mofetil Acute GVHD IBD Pactlitaxel Ring chromosomes

58 Case 4 28 year old male with anal pain and induration

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64 IHC for spirochetes

65 Warthin-Starry maybe positive?

66 Primary Perianal Syphilis Anal canal ulcers, anorectal inflammatory masses, or proctitis HIV+ males or men who have sex with men Often not clinically suspected

67 Primary Perianal Syphilis Sharply punched out painless ulcer chancre Marked acanthosis at periphery of lesion Dermal infiltrate of lymphocytes and plasma cells Perivascular inflammatory infiltrate rich in plasma cells with endothelial cell swelling Arch Pathol Lab Med 2015;139:

68 Colorectal Syphilis Bleeding, pain, tenesmus Ulcerations, mass like lesion HIV+ males or men who have sex with men Often not clinically suspected Often secondary Am J Surg Pathol 2013; 37:38-46

69 Secondary Syphilis Type seen in colorectal lesions Maculopapular lesions Band-like infiltrate in upper dermis Much more superficial infiltrate of lymphocytes, histiocytes, plasma cells Parakeratosis, necrotic keratinocytes Poorly formed granulomas may be present

70 Primary vs. Secondary Mucocutaneous Syphilis 8 cases of primary syphilis: All cases were ulcers 26 cases of secondary syphilis: Most cases were maculopapular lesions with 4 cases of erosions Hum Pathol 2009; 40:

71 Spirochete Detection: Primary vs Secondary Syphyilis Warthin Starry 4/8 cases of primary syphilis 13/26 cases of secondary syphilis IHC for spirochetes 8/8 cases of primary syphilis 21/26 cases of secondary syphilis Hum Pathol 2009; 40:

72 Spirochete Detection: Primary vs Secondary Syphylis Primary: perivascular distribution Secondary: intraepithelial distribution

73 GI Syphilis Consider primary syphilis in an anal ulcer/mass with perivascular plasma cells Secondary syphilis if colorectal IHC should be done in all cases of suspected syphilis but sensitivity is not 100%

74 Not the same as intestinal spirochetosis

75 Intestinal Spirochetosis Brachyspira aalborgi & Brachyspira pilosicoli Homosexuals and HIV-infected individuals are at high risk of being colonized But may see it incidentally on a routine screen, on SSPs, CRC, UC, etc

76 Intestinal Spirochetosis Symptoms (abdominal pain, diarrhea, bleeding) may or may not occur Clinical significance in individual cases is uncertain Gastrointestinal symptoms may respond to antibiotic treatment (metronidazole)

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79 Differential Diagnosis Plasmacytoma Rectal tonsil

80 Rectal Tonsil Localized reactive lymphoid hyperplasia Middle age adults Rectal bleeding, pain, mass on screening endoscopy Dense lymphoid infiltrate and follicular hyperplasia of mucosa with congestion; no ulceration; no neutrophils Benign

81 Case 5 42 year old with diarrhea and abdominal pain

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87 Nodular Lymphoid Hyperplasia Multiple small nodules (2-10 mm) in the small intestine (more often), stomach, large intestine, or rectum Markedly hyperplastic, mitotically active germinal centers, & well defined lymphocyte mantles in lamina propria &/or in the superficial submucosa World J Gastrointest Endosc 2014; 6:

88 Nodular Lymphoid Hyperplasia Asymptomatic disease (in the majority of the patients) Abdominal pain Chronic diarrhea Bleeding Intussusception or intestinal obstruction World J Gastrointest Endosc 2014; 6:

89 Differential Diagnosis Mantle cell lymphoma Extranodal marginal zone lymphoma Mucosa-associated lymphoid tissue (MALT) Follicular lymphoma World J Gastrointest Endosc 2014; 6:

90 Distinguishing Features Polymorphic infiltrate Absence of significant cytologic atypia Reactive follicles within the lesion World J Gastrointest Endosc 2014; 6:

91 Nodular Lymphoid Hyperplasia Pediatric Adult With immunodeficiency Without immunodeficiency World J Gastrointest Endosc 2014; 6:

92 Nodular Lymphoid Hyperplasia Common variable immunodeficiency IgA deficiency HIV Giardia lamblia Helicobacter pylori World J Gastrointest Endosc 2014; 6:

93 Nodular Lymphoid Hyperplasia Risk for lymphoma (adults) Treat underlying cause if known Surveillance World J Gastrointest Endosc 2014; 6:

94 Case 6 92 year old man with history of squamous cell carcinoma and new PET CT nodule in right colon undergoes colonoscopy with biopsy.

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98 Diagnosis Anti-PDL-1 therapy induced colitis

99 Anti-PDL-1 Therapy Induced Colitis Mixed acute and chronic inflammation (lymphocyte predominant) Crypt microabscesses Numerous intra-epithelial lymphocytes, and enterocyte apoptotic bodies. Surface epithelial injury Am J Surg Pathol 2017; 41:

100 Anti-PDL-1 Therapy Induced Colitis As anti-pd-1 agents are increasingly used in oncology, anti-pd-1 colitis should be considered in any patient with a history of disseminated malignancy, especially if there is a history of chronic diarrhea. Treatment consists of withdrawal of anti- PD-1 therapy and initiation of corticosteroids. Am J Surg Pathol 2017; 41:

101 1. Chen JH et al. Am J Surg Pathol 2017 (epub ahead of print). Anti-PDL-1 Colitis Two common histologic patterns: 1. Active colitis pattern (5 of 8 patients): Cryptitis and crypt abscess formation Crypt atrophy/dropout Crypt epithelial apoptoses 2. Lymphocytic colitis-like pattern (3 of 8 patients) Am J Surg Pathol 2017; 41:

102 Case 7 65 year old male with intractable diarrhea

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106 Autoimmune Enteropathy Predominantly pediatric (M>F), but occurs in adults Intractable diarrhea Nonresponsive to bowel rest, diet restriction, TPN (30% mortality) Virchows Arch 2018;472:55-66

107 Autoimune Enteropathy Variable, often severe villous atrophy Marked inflammatory destruction of crypts Marked apoptosis Few intraepithelial lymphocytes Concomitant gastritis and colitis Virchows Arch 2018;472:55-66

108 Autoimmune Enteropathy Anti-enterocyte antibodies (usually IgG) linear pattern along apex or brush border on indirect immunofluroescence Anti-goblet cell antibodies in goblet cell (less specific) Virchows Arch 2018;472:55-66

109 Autoimmune Enteropathy: Extraintestinal Associations Insulin dependent DM Thyroid insufficiency Membranous glomerulonephrititis Coombs-positive hemolytic anemia Autoantibodies: AMA, ANA, antiparietal cell Virchows Arch 2018;472:55-66

110 Autoimmune Enteropathy Predominantly CD3 and CD4 positive T cells T cell receptor αβ Consequence of hyperactive immune system Virchows Arch 2018;472:55-66

111 Pediatric Autoimmune Enteropathy 1. APECED (Autoimmune Phenomena, Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy) Mutations in AIRE 2. IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked) Mutation in FOXP3 3.Immunodeficiency (CVID)

112 Adult Autoimmune Enteropathy Underlying autoimmune disease Thymoma may be malignant Diabetes mellitus type 1 Rheumatoid arthritis Autoimmune thyroiditis Autoimmune hepatitis

113 Thank you Stanford University