SLIDE SEMINAR CASES 11th Digestive Pathology Course

Bucharest, November 2nd 2018

Alessandro Lugli, MD

Institute of Pathology

University of Bern

Switzerland

61 year old man

Known soor esophagitis

Endoscopically suspicious for eosinophilic esophagitis

Number eos / HPF ?

Biopsies from the middle and distal part of the esophagus

CASE 1 Clinical information

HISTOLOGY Distal esophagus

HISTOLOGY Distal esophagus

HISTOLOGY Middle esophagus

HISTOLOGY Middle esophagus

HISTOLOGY Diagnostic findings

Slight basel cell hyperplasia

Single eosinophils (max. 2 / HPF)

Presence of neutophils and lymphocytes

Special stains (PAS, Grocott): no sign for fungal infection

No dysplasia

HISTOLOGY Diagnosis, but………

Unspecific acute esophagitis

CLINICO-PATHOLOGICAL CONFERENCE Gastroenterology & Pathology

Endoscopically suspicious for an eosinophilic esophagitis

Known HSV infection (Urinary tract)

Reevaluation

HISTOLOGY – DISTAL ESOPHAGUS Peripapillary lymphocytic inflammation

HISTOLOGY – MIDDLE ESOPHAGUS Peripapillary lymphocytic inflammation

MIDDLE ESOPHAGUS IHC: CD3 (57 / HPF)

MIDDLE ESOPHAGUS Immunohistochemistry: additional analysis

Lymphocytes positive additionally for

CD2,CD4, CD7 and CD8

HSV 1 and 2 negative

DIAGNOSIS

Lymphocytic esophagitis

2ND CLINICOPATHOLOGICAL CONFERENCE Gastroenterology & Pathology

Endoscopy: Trachealisation of the esophagus

Antibiotic therapy for urinary tract infection

Therapy with Budenosid

Soor esophagitis suspected

Recovery of the lymphocytic esophagitis ?

HISTOLOGY – DISTAL ESOPHAGIS Soor esophagitis

HISTOLOGY – DISTAL ESOPHAGUS Intraepithelial lymphocytosis

HISTOLOGIE – DISTAL ESOPHAGUS IHC: CD3 (34 / HPF)

FOLLOW UP Clinico-pathological interpretation

Improvement under therapy with Budenosid

Histologically decreased lymphocytic infiltration

Antibiotic therapy for urinary tract infection

Therapy of the soor esophagitis

Clinical and endoscopical follow up

LYMPHOCYTIC ESOPHAGITIS Clinical aspects

More frequent in elderly women

Mean age: 63 years

Dysphagia, odynophagia

Reflux, retrosternal burning

Vomiting, foreign body sensation

Therapy not clear yet (PPI ?)

Haque, Genta, GUT 2012

LYMPHOCYTIC ESOPHAGITIS Endoscopic aspects

Especially peripapillary lymphocytic infiltration

Immunophenotype of T-cells not clear yet

Only few neutrophils and eosinophils

Intercellular edema and spongiosis

Basal cell hyperplasia

LYMPHOCYTIC ESOPHAGITIS Histological aspects

Reflux disease

Infections

Motility disorders

Allergy / Asthma

Autoimmune / dermatologic diseases

Immune suppression (HIV, CVID)

Crohn’s disease (especially in children)

Celiac disease

LYMPHOCYTIC ESOPHAGITIS Etiologic associations

SELECTED LITERATURE

1: Rubio CA, Ichiya T, Schmidt PT. Lymphocytic oesophagitis, eosinophilic oesophagitis and compound

lymphocytic-eosinophilic oesophagitis I: histological and immunohistochemical findings. J Clin Pathol.

2016 Jul 28. pii: jclinpath-2016-203782.

2: Genta RM. Lymphocytic Esophagitis. Gastroenterol Hepatol (N Y). 2015 Aug;11(8):559-61.

3: Xue Y, Suriawinata A, Liu X, Li Z, Gabbard S, Rothstein R, Lacy B, Lisovsky M. Lymphocytic

Esophagitis With CD4 T-cell-predominant Intraepithelial Lymphocytes and Primary Esophageal Motility

Abnormalities: A Potential Novel Clinicopathologic Entity. Am J Surg Pathol. 2015 Nov;39(11):1558-67.

4: Haque S, Genta RM. Lymphocytic oesophagitis: clinicopathological aspects of an emerging

condition. Gut. 2012 Aug;61(8):1108-14.

5: Purdy JK, Appelman HD, Golembeski CP, McKenna BJ. Lymphocytic esophagitis: a chronic or

recurring pattern of esophagitis resembling allergic contact dermatitis. Am J Clin Pathol. 2008

Oct;130(4):508-13.

6: Rubio CA, Sjödahl K, Lagergren J. Lymphocytic esophagitis: a histologic subset of chronic

esophagitis. Am J Clin Pathol. 2006 Mar;125(3):432-7.

52 year old woman

Ulcerative colitis since 2007

Complete remission under therapy with Infliximab since September 2015

Endoscopically mucosal healing, no activity

Chromoendoscopy negative

Ileal polypoid lesion

DD: Adenoma, GIST, NET/NEC

CASE 2 Clinical information

ENDOSCOPY Ileal polypoid lesion (size: 1.5cm)

HISTOLOGY Overview

HISTOLOGY Submucosal spindle cell proliferation

HISTOLOGY Spindle cells not atypic

HISTOLOGY Collagenous stroma

HISTOLOGY No mitoses

HISTOLOGY Scattered blood vessels

HISTOLOGY Immunhistochemistry

S100

SMA

CD34

No expression of c-kit,

DOG1, ALK or Stat6.

Regular expression of

ß-Catenin

HISTOLOGY Diagnosis, but………

Benign mesenchymal proliferation NOS

HISTOLOGY Expression of PDGFα

MOLECULAR PATHOLOGY ANALYSIS PDGFRα Mutation

Molecular Pathology results

Mutation analysis of KIT and PDGFRA:

PCR: KIT exons 9 and 11

Sanger sequencing: KIT Exons 9, 11, 13, 17 and PDGFR exons 12,

14 and 18

KIT mutation analysis: No mutation

PDGFRA mutation analysis:

mutation in exon 18, c.2525A>T (p.D842V)

DIAGNOSIS

Inflammatory fibroid polyp with

degenerative changes

Benign neoplasia (formerly reactive) (Vanek tumor)

Located in the whole GI tract

(Stomach, Small and large intestine, esophagus)

6th – 7th decade; size: 5-20cm

Rare familial cumulation

Clinical symptoms: Abdominal pain, obstruction

Therapy: Endoscopic or surgical excision

Prognosis: Favorable

INFLAMMATORY FIBROID POLYP Clinical aspects

INFLAMMATORY FIBROID POLYP Pathologic aspects

Tumour of the tunica submucosa

May infilitrate the mucosa and/or the muscularis propria (i.e. ileal)

Regular spindled and stellate mesenchymal cells

Onion skin pattern, edema, collagenous stroma, eosinophils, vascular

proliferation

Immunhistochemistry: PDGFRα and CD34 positive

PDGFRα mutation: 50-60% (exon 18 in the stomach, exon 12 in the small

intestine, rarely exon 14)

INFLAMMATORY FIBROID POLYP Differential diagnoses

GIST

- Origin: Muscularis mucosae

- Positiv: CD117, CD34 und DOG1

- KIT and PDGFRα mutation

Inflammatory myofibroblastic tumour

- Origin: Mesenterium

- Cellular myofibroblastic lesion

- ALK positive with ALK gene rearrangements

- Actin, calponin, desmin and caldesmon positive

INFLAMMATORY FIBROID POLYP Differential diagnoses

Leiomyom

- Origin: Submucosa

- Desmin, actin, calponin and

Caldesmon positive

- CD34 and S100 negative

- Hypocellular pattern

Perineuroma

- Origin: Lamina propria

- No inflammation

- EMA, GLUT1 and Claudin-1

positive

- No specific genetic

alterations

Schwannoma

- Origin: Muscularis propria

- Peritumoral, lymphoid

infiltration, few blood vessels

- S100 positive

- No specific genetic alterations

SELECTED LITERATURE

1: Liu TC, Lin MT, Montgomery EA, Singhi AD. Inflammatory fibroid polyps of the gastrointestinal tract:

spectrum of clinical, morphologic, and immunohistochemistry features. Am J Surg Pathol. 2013

Apr;37(4):586-92.

2: Huss S, Wardelmann E, Goltz D, Binot E, Hartmann W, Merkelbach-Bruse S,Büttner R, Schildhaus HU.

Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14 and 18 and are

associated with tumour localization. Histopathology. 2012 Jul;61(1):59-68.

3: Daum O, Hatlova J, Mandys V, Grossmann P, Mukensnabl P, Benes Z, Michal M. Comparison of

morphological, immunohistochemical, and molecular genetic features of inflammatory fibroid polyps

(Vanek's tumors). Virchows Arch. 2010 May;456(5):491-7.

4: Ozolek JA, Sasatomi E, Swalsky PA, Rao U, Krasinskas A, Finkelstein SD. Inflammatory fibroid polyps

of the gastrointestinal tract: clinical, pathologic, and molecular characteristics. Appl Immunohistochem Mol

Morphol. 2004 Mar;12(1):59-66.

5: Lasota J, Wang ZF, Sobin LH, Miettinen M. Gain-of-function PDGFRA mutations, earlier reported in

gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60

cases. Mod Pathol. 2009 Aug;22(8):1049-56.

6: Pantanowitz L, Antonioli DA, Pinkus GS, Shahsafaei A, Odze RD. Inflammatory fibroid polyps of the

gastrointestinal tract: evidence for a dendritic cell origin. Am J Surg Pathol. 2004 Jan;28(1):107-14.

71 year old woman

Screening for colorectal cancer

No gastrointestinal symptoms

Four small polyps in the left colon

Slight diverticulosis

CASE 3 Clinical information

HISTOLOGY Overview

HISTOLOGY Diffuse mast cell infiltration

MC: >100 / HPF

HISTOLOGY Immunohistochemistry: c-kit expression

HISTOLOGY Immunohistochemistry: mast cell tryptase expression

HISTOLOGY Immunohistochemistry: CD25 expression

HISTOLOGIC AND MOLECULAR DIAGNOSIS

Systemic mastocytosis

KIT p.D816V mutation

SYSTEMIC MASTOCYTOSIS Clinical aspects

GI Trakt involved in approximately 70%

Skin lesions may be absent in 50% of cases; abdominal pain and diarrhoea

Clinical variants:

Indolent systemic mastocytosis

Systemic mastocytosis with associated clonal hematologic

Non-mast cell linear disease

Aggressive systemic mastocytosis

Mast cell leukemia

Diagnosis is based on one major and one minor or three minor criteria

Therapy:

Indolent variant: H1 and H2 histamine anatgonists

Severe variant: Interferon-α-2b, Imatinib, corticosteroids

Prognosis: No curative therapy available; variant dependent

Macroscopy

Erythema, teleangiectasis, nodular lesions or multiple polyps

Histology

Subepithelial linear mast cell infiltration

Nodular and polypoid lesions: diffuse and confluent mast cell infiltration

Cytologically spindle-like and round nuclei with clear cytoplasm

Co-expression of C-kit and CD25 in mast cells is diagnostic

for a systemic mastocytosis

KITD816V mutation

SYSTEMIC MASTOCYTOSIS Pathologic aspects

Major criteria

Multifocal dense mast cell infiltration within the tissue (≥15 cells)

Minor criteria

>25% spindle cel-like, immature or atypic mast cells

KITD816V mutation

CD25 and/or CD2 expression in mast cells

Serum tryptase continuously increased (>20 ng/mL) in absence of a

clonal myleoid disease

Diagnosis is based on one major and one minor or three minor criteria !

SYSTEMIC MASTOCYTOSIS Diagnosic criteria

Mastocytic enterocolitis

Not associated with systemic mastocytosis

Increased mast cell number (>20 / HPF) as in chronic diarrhoea

Mantle cell lymphoma

Expression of CD20, CD5 and cyclin D1

MALT lymphoma

Lympho-epithelial lesions and CD20 expression

Inflammatory bowel disease (IBD)

Crypt distorsion

Cryptitis and crypt abscess

Basal plasmocytosise

SYSTEMIC MASTOCYTOSIS Differential diagnoses

SELECTED LITERATURE

1: Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A clinicopathologic study

of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of

mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg

Pathol. 2014 Jun;38(6):832-43.

2: Chiu A, Orazi A. Mastocytosis and related disorders. Semin Diagn Pathol. 2012 Feb;29(1):19-

30. Review.

3: Hollmann TJ, Brenn T, Hornick JL. CD25 expression on cutaneous mast cells from adult

patients presenting with urticaria pigmentosa is predictive of systemic mastocytosis. Am J Surg

Pathol. 2008 Jan;32(1):139-45.

4: Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is

specific for systemic mastocytosis. Am J Surg Pathol. 2007 Nov;31(11):1669-76.

5: Jakate S, Demeo M, John R, Tobin M, Keshavarzian A. Mastocytic enterocolitis: increased

mucosal mast cells in chronic intractable diarrhea. Arch Pathol Lab Med. 2006 Mar;130(3):362-7.

6: Siegert SI, Diebold J, Ludolph-Hauser D, Löhrs U. Are gastrointestinal mucosal mast cells

increased in patients with systemic mastocytosis? Am J Clin Pathol. 2004 Oct;122(4):560-5.

THANK YOU FOR YOUR ATTENTION !