Lower Gastrointestinal Pathology

Professor Neil A Shepherd

Gloucester and Cheltenham, UK

Sheffield Diagnostic Histopathology Course

16 June 2010
 The lower gastrointestinal tract

• where does it begin and end?

• 15 cases

• no picking on people but can we be a bit interactive?

• hand-out with full discussion and references

• you will get a full copy of this lecture with all of its marvellous
additional data……
Morson and Dawson’s
Gastrointestinal
Pathology
________________

Fourth Edition

Published in January 2003

704 pages,
559 illustrations (with 402 in full colour)
ISBN: 0 632 04204 4
Hardback £175.00
 CONTEXT

CONTEXT
CONTEXT
 Case 1

76M. Loose stool and weight loss. Duodenal biopsies.

 Duodenal biopsy:
indications, interpretation and implications
• commonest indication in the UK for duodenal biopsy is iron
deficiency or iron deficiency anaemia

• it is most often undertaken with a potential diagnosis of coeliac

disease in mind

• for the diagnosis of coeliac disease, duodenal biopsy remains the

gold standard

• serological methods (anti-endomysial antibody (EMA) and tissue

transglutaminase (TTG)) show only 90-95% sensitivity and
specificity

• TTG has improved things, is a good initial screen for CD but there
is still intra-laboratory variation
 BSG guidelines:
Management of iron
deficiency anaemia;
2000 (rev 2005)

see www.bsg.org.uk
 Duodenal biopsies for ‘malabsorption’

960 duodenal biopsies

802 normal/minimal abnormality

62 (6.5%) coeliac disease
20 (2%) raised IELs but normal villous architecture
6 giardiasis

38 non-specific duodenitis
32 miscellaneous

Gloucestershire audits 2005-6 & 2006-7

 Duodenal biopsy for ‘malabsorption’

coeliac disease/gluten enteropathy/gluten sensitivity

giardiasis
other infections +/- immunodeficiency
Whipple’s disease
other rare causes of malabsorption (especially in children)

food allergy
bacterial overgrowth
‘mechanical’ causes of villous atrophy and inflammation
 Duodenal biopsies for coeliac disease

• patchiness

• national and international recommendations require a

minimum of four 3mm biopsies from D2 or beyond
 Italian multicentre coeliac study

• 665 children & adolescents with proven coeliac disease

• multiple duodenal biopsies (1 D1, 3-4 more distally)
• ALL patients had CD-type changes in D1
• 16 had normal biopsies more distally
• 20 had patchy lesions more distally

• no D1 lesions in 348 non-CD subjects

• recommend 2 biopsies from bulb and 2 more distally

Bonamico M et al. J Ped Gastro Nutr 2008; 47: 618-22.

 Case 1

Endoscopy showed white plaques & yellow irregular

mucosa with oedema
Case 1
Case 1
Duodenal biopsies – occasionally one sees an unusual
disease!!

Whipple’s disease – Tropheryma whippelii

 Case 1 - learning points

• Whipple’s disease is rare and mainly affects older men (M:F = 8:1)

• it is a multisystemic bacterial infection

• it may require a host abnormality of histiocytic function

• you’ll only see it in DHC courses and in the MRCPath exam!!

 Case 1

DIAGNOSIS:
WHIPPLE’S DISEASE
 Case 2

26M. Loose stool and low B12. Nodular appearance to

duodenum. Duodenal biopsies.
 Nodular appearance to duodenum

Usually first part of the duodenum

Diagnoses to consider:

1. Gastric heterotopia
2. Brunner’s gland hyperplasia
3. Lymphoid follicular hyperplasia
Case 2
Case 2
Case 2
Case 2
 Giardiasis in duodenal biopsies

• varying degrees of villous atrophy, chronic inflammation in the lamina

propria and modest intra-epithelial lymphocytic infiltrate may be seen

• BUT, in most cases of giardiasis (96% in one series), the duodenal

mucosa appears normal (apart from the bugs)

• a search for the parasite should be undertaken in all duodenal

biopsies, in patients presenting with diarrhoea and malabsorption,
whether the biopsies are morphologically normal or not

• the protozoan may be detected in gastric, jejunal, ileal and colonic

mucosa: these mucosae are also usually ‘normal’ in giardia infection

Oberhuber et al, 1997

Giardiasis in duodenal biopsies
Giardiasis ?
Massive infestation with giardiasis
 Case 2
Massive infestation by giardiasis and lymphoid follicular hyperplasia
– should trigger a thought....
 Case 2 - learning points

• duodenal nodulation has three common(ish) causes

• most duodenal biopsies with giardiasis are normal (apart

from the parasites!)

• if you see heavy giardia infestation, think immunoparesis

• in the exam, don’t relax (too much) when you spot an easy
case, especially if it’s an infection. There may be
two/multiple pathologies – especially in HIV/AIDS……
 Case 2

DIAGNOSIS:
NODULAR LYMPHOID HYPERPLASIA DUE TO
AGAMMAGLOBULINAEMIA WITH
MASSIVE INFESTATION BY GIARDIASIS
 Case 3

56F. Small bowel obstruction and intussusception. Polypoid

tumour mass 36 mm in diameter. Right hemicolectomy.
 Case 3
56F. Small bowel obstruction and intussusception.
Polypoid tumour mass 36 mm in diameter. Right
hemicolectomy.
Case 3
Case 3
Case 3
 Case 3

DIAGNOSIS: INFLAMMATORY FIBROID POLYP

 DIFFERENTIAL DIAGNOSIS OF
GASTRO-INTESTINAL EOSINOPHILIA
• drugs

• infections – especially parasites, worms, etc

• CIBD – Crohn’s and UC

• inflammatory fibroid polyp

• eosinophilic gastro-enteritis

• vasculitis, including PAN and Churg-Strauss syndrome

• malignant lymphoma
 Case 3 - learning points

• antrum – IFPs are small, submucosal and well circumscribed

• ileum – IFPs are larger and more diffuse, with deep

involvement

• IFPs of oesophagus, proximal stomach, colon, rectum, pelvic

pouch all described but rare

• CD34, CD21, CD23, CD35, ASMA, fascin and cyclin-D1

positive (? dendritic cell origin)

• CD117, desmin, S100, synaptophysin, nestin, h-caldesmon,

bcl-2, ALK-1 and nuclear beta-catenin negative
 Case 3 - learning points

• often mistaken for GIST……….

• ? reactive myofibroblastic proliferation

• ? dendritic cell origin

• excisional surgery is usually curative – rare cases

locally recur
 Case 3 - learning points

• ? reactive ? neoplastic

• 23 IFPs: consistently expressed PDGFRA

immunohistochemically

• 70% harboured activating mutations in exons 12 and 18

of the PDGFRA gene

• ? neoplastic process

Schildhaus HU et al. Inflammatory fibroid polyps

harbour mutations in the platelet-derived growth factor
receptor alpha (PDGFRA) gene. J Pathol 2008; 216: 176-82.
 Case 3

DIAGNOSIS: INFLAMMATORY FIBROID POLYP

 Case 4

43M. Perforated small bowel. Ill-defined mass lesion

in jejunum. Jejunal resection.
Case 4
Case 4
 DIFFERENTIAL DIAGNOSIS OF
GASTRO-INTESTINAL EOSINOPHILIA
• drugs

• infections – especially parasites, worms, etc

• CIBD – Crohn’s and UC

• inflammatory fibroid polyp

• eosinophilic gastro-enteritis

• vasculitis, including PAN and Churg-Strauss syndrome

• malignant lymphoma
Case 4
Immuno for CD3 and UCHL1
Case 4
Case 4
 Case 4 - learning points

• know the differential diagnosis of eosinophilic infiltrates

• eosinophils can obscure the true pathology

• if there is a destructive infiltrate, think ML – especially this

type and ulcerative jejunitis – often T-cell phenotype

• immunohistochemistry may be difficult to interpret because

of the admixture of ‘reactive’ cells

• molecular biology may be very useful

 Case 4

DIAGNOSIS:
T-CELL LYMPHOMA: ‘MALIGNANT LYMPHOMA
WITH EOSINOPHILIA’
 Case 5

62F. 87mm tumour of jejunum resected.

Case 5
Case 5
Case 5
Case 5
Case 5
 Case 5 – immuno results

• all areas positive for CD 117, bcl-2, DOG 1 & CD 34

• some areas showed dot positivity for

synaptophysin and chromogranin – typical GANT

• negative for ASMA, desmin and S100

Case 5
Thanks to Professor Marco Novelli
 Site

• stomach 50-60%

• small bowel 20-30%

• large bowel 10%

• oesophagus 2-5%

• other intra-abdominal sites 5%

(appendix, gallbladder, pancreas,
mesentery, omentum, retroperitoneum,
gynaecological tract (so-called e-GISTs))
 Site specificity of GISTs
Oesophagus:
true smooth muscle tumours relatively much more common

Stomach:
commonest site
epithelioid types common
small subserosal nodules (spindle cell) common

Small intestine:
skeinoid fibres
GANT phenotype
poorer prognosis size for size
true smooth muscle tumours slightly more common relatively

Large intestine:
true smooth muscle tumours of muscularis mucosae more common
superficial v deep
GISTs vs smooth muscle tumours in the GIST era

Site Cases % GIST Reference

Oesophagus 68 25% Miettinen et al,

2000

Stomach 1869 94% Miettinen et al,

2005

Duodenum 167 93% Miettinen et al,

2003

Jejunum & ileum 1091 83% Miettinen et al,

2006

Colon 164 23% * Miettinen et al,

2000

Rectum & anus 144 92% Miettinen et al,

(? mm SMT) 2001
 Imatinib (ST1571; Glivec)

• tyrosine kinase inhibitor

initially developed as inhibitor
of PDGF receptor

• powerful inhibitor of ABL

tyrosine kinases
– effective treatment for
chronic myeloid leukaemia
– dramatic response of
malignant GISTs with mild
toxicity

Joenssu et al, 2001

 Imatinib (ST1571; Glivec)

• complete response very unusual

• partial response rates - 48% to 85% according to mutation site

• “escape” with time in some cases - may be associated with novel

KIT mutation

• mean survival time now 4.5 years (cf 18 months untreated)

• not the whole answer but a very useful treatment option

• newer drugs (esp sunitinib) are now available and others are on
the way!
Imatinib (ST1571; Glivec)
 NICE recommendations for imatinib

• 400mg/day for kit-positive unresectable or metastatic

disease

• continue only if response is achieved within 12 weeks

• for responders continue until development of progressive

disease

• increased dose not recommended in non-responders

• £19,000 per year

• trials of sunitinib and of prophylaxis/adjuvant treatment

European Society of Medical Oncology
Blay et al. Ann Oncol 2005; 16: 566.
• three CD117 antibodies (inc. Dako A4502
polyclonal)
• 32 GISTs and 139 neoplasms (comprising
24 neoplasm types)
• with and without antigen retrieval
Dako -AR Dako +AR
• antigen retrieval does not cause false
positive CD117 immunostaining

• omitting antigen retrieval may cause

equivocal or false negative results
 Discovered on GIST 1 (DOG1)

• Stanford group: polyclonal (2004) and

then two monoclonals, DOG1.1 and DOG1.3
(2008)

• K9 monoclonal antibody from

Novocastra/Leica (2008)
• AJSP 2009; 33: 1401, K9 antibody

• amongst 1168 GISTS, sensitivity for KIT

(94.7%) and DOG1 (94.4%)
 Discovered on GIST 1 (DOG1)

• compared with CD117, DOG1 is equally sensitive

and more specific a marker for GISTs

• three GIST mimics may coexpress CD117 and

DOG1: melanoma, synovial sarcoma and Ewing’s
sarcoma

• only GISTs show diffuse expression of both CD117

and DOG1
Prognostication for GIST - update

‘NIH consensus
classification’
 Prognostication for GISTs

• NIH and Miettinen classifications apply well to most

adult GISTs but care with paediatric/wild type GISTs

• if reporting ‘risk’, state which classification used

• summarise with: location, size and mitotic count (per

50 hpfs)
 Case 5 - learning points

• site specificity of GISTs

• SISTSFs (small intestinal stromal tumour with skeinoid fibres) – just

means it’s likely to be a small intestinal tumour!

• GANTs – worse prognosis if pure? Usually small intestinal

• differential diagnosis includes true smooth muscle tumours, neural

tumours (especially schwannoma), IFP, solitary fibrous tumour,
inflammatory myofibroblastic polyp and mesenteric fibromatosis

• they can look like carcinoma, melanoma and plasmacytoma!

• pathology (and MDTMs) have a very important role in the management

of spindle cell tumours of the gut

• suddenly pathologists are sexy with drug companies because they are
crucial to the management of GISTs
 Case 5

DIAGNOSIS:
GIST WITH GANT DIFFERENTATION
AND AREAS WITH SKEINOID FIBRES
 Case 6

82F. Small bowel obstruction. At laparotomy gross

distension of the small bowel with a strictured
length of ileum. Right hemicolectomy.
Case 6
Case 6
Case 6
Case 6
 Case 6

82F. Small bowel obstruction. At laparotomy gross

distension of the small bowel with a strictured
length of ileum. Right hemicolectomy.

30 years ago she had radiotherapy for

carcinoma of the endometrium

she had been entirely well since…….

until………
 Case 6 – learning points

• radiation enteritis and colitis may present up to 40 years

after previous radiotherapy (cervix, endometrium,
bladder, prostate, etc)

• in chronic radiation pathology of the gut, the submucosa

bears the brunt

• vessels, hyaline fibrosis, stellate/atypical fibroblasts

• mucosa may be relatively normal – watch this in biopsies!!

 Case 6

DIAGNOSIS:
RADIATION ENTERITIS WITH STRICTURE
 Case 7

55M. Acute appendicitis.

Case 7
Case 7
Case 7
Case 7
Case 7
Case 7 – chromogranin immuno
 Goblet cell carcinoid – the (old) literature

• females > males

• incidental or associated with

appendicitis

• propensity for transcoelomic

spread, especially to ovary

• lymph node and liver

metastases relatively unusual

• 80% 5 year survival

 Goblet cell carcinoid/crypt cell carcinoma

RCPath dataset (May 2009) on GI ‘neuro-endocrine tumours’ has now

reclassified all of these as ‘endocrine tumours’

carcinoid strictly does not exist any more in the gut

Isaacson P. Crypt cell carcinoma of the appendix (so-called

adenocarcinoid tumor). Am J Surg Pathol 1981; 5: 213-24.

van Eeden S, Offerhaus GJ, Hart AA, Boerrigter L, Nederlof PM, Porter
E, van Velthuysen ML. Goblet cell carcinoid of the appendix: a specific
type of carcinoma. Histopathology 2007; 51: 763-73.
 Goblet cell ‘carcinoid’/crypt cell carcinoma

• a continuum through to
mucinous adenocarcinoma
with neuroendocrine
differentiation

• the latter are more

aggressive tumours with
a behaviour more like
that of mucinous
carcinoma of the
appendix/colon
Prognostic factors in goblet cell ‘carcinoid’/
crypt cell carcinoma

• cytological atypia

• mitotic rate (> 2/10 HPF)

• carcinomatous growth:
– single file structures
– diffusely infiltrating signet ring cells
– cribriform glands
– solid sheets
 Management of goblet cell ‘carcinoid’/crypt cell
carcinoma

• tumour confined to appendix with minimal invasion of

meso-appendix
• minority component “carcinomatous”
Appendicectomy only (usually done already!!)

• extensive invasion of meso-appendix

• involvement of resection line, invasion of caecum and/or
lymph node involvement
• majority component “carcinomatous”
Right hemicolectomy
 Case 7 – learning points
• carcinoids are now all called GI ‘endocrine tumours’

• don’t forget to look for ETs in acute appendicitis!

• GCC/crypt cell carcinoma can be subtle!

• immunohistochemistry can be misleading – synaptophysin

generally better than chromogranin

• controversial management…… needs MDTM discussion

• more to come in the literature on this difficult topic

 Case 7

DIAGNOSIS:
ACUTE APPENDICITIS WITH
GOBLET CELL CARCINOID (sic)/CRYPT CELL CARCINOMA
 Case 8

62F. Diarrhoea. Mildly inflamed-appearing ascending

colon. Colonic biopsies.
Case 8
Case 8
Case 8
Microscopic colitis – one more recently recognised
pattern

• pseudomembranous collagenous colitis

Yuan et al, 2003

• 10 cases – only one associated with C diff toxin. Little

evidence of a drug association.
Yuan et al 2003

• ? pseudomembranous changes are part of the spectrum

of CC. ?? toxin-mediated, ?? ischaemia-mediated
 Microscopic colitis as a concept

• normal colonoscopy
• chronic watery diarrhoea without blood
• significant, usually chronic, inflammation on biopsy

• varied histological patterns

• does it require colonoscopic normality?

• strong association with drugs

• diarrhoea is the commonest recorded complication of drug therapy
• how many cases are due to microscopic colitis?

• used to be considered rare – a disease of private practice!!

• now increasingly recognised throughout Europe & N Am
• we see 50 cases + a year
 Collagenous colitis

• there may be endoscopic abnormality

• mucosal tears
Cruz-Correa et al, 2002

• submucosal dissection with gas evident on

barium enema
Mitchell et al, 2004

• modest pseudo-membrane material

• ESPECIALLY in the right and transverse

colon
Case 8: pseudomembranous collagenous colitis

some resolution with metronidazole (empirical

treatment). Then steroid therapy helped but not
complete resolution.

6 months later: colonoscopy showed erythematous

mucosa but no fibrinous exudate.

next 6 months: gradual resolution with steroid

withdrawal.

2 years after presentation: colonoscopy normal and no

symptoms.
 Case 8 – learning points

• microscopic colitis is an important concept

• there are ‘new’ variants including this one, giant cell

MC and granulomatous MC

• drugs are important causes

• increasingly the colonoscopy may not be entirely

normal….
 Case 8

DIAGNOSIS:
PSEUDOMEMBRANOUS COLLAGENOUS COLITIS
 Case 9

40M. Previous total colectomy. Now resection of

rectum.
 CONTEXT

CONTEXT
CONTEXT
Case 9
Case 9
Case 9
Case 9
 Case 9

• 40M. Previous total colectomy. Now resection of rectum.

• colectomy was for ulcerative colitis

• underwent three stage pouch procedure with subsequent

pouch construction at the time of proctectomy

• don’t call it Crohn’s disease after all that – surgeon and

patient will not be pleased!
 Case 9 – learning points

• surgery causes mimicry of Crohn’s disease – especially in the

defunctioned rectum and in the ileal pouch….

• always review virginal pathology (untouched by surgical

hand)

• diversion causes inflammation, granulomas, PMC-like changes

• it also causes nodules – lymphoid follicular hyperplasia

 Case 9

DIAGNOSIS:
MIMICRY OF PSEUDOMEMBRANOUS COLITIS AND
CROHN’S DISEASE IN DIVERTED RECTUM WITH
ULCERATIVE COLITIS
 Case 10

73M. Ulcerative colitis failing to respond to

medical therapy. Polyp in ascending colon.
Total colectomy.
Case 10
Case 10: ascending colonic lesion
Case 10
Flat mucosa
Case 10
 Case 10

• 73 M with 2 year history of chronic ulcerative colitis

• Answers:

No doubt it’s ulcerative colitis but is it dysplasia

and/or DALM?
 Dysplasia associated lesion of mass (DALM) in
ulcerative colitis

• An indication for colectomy

Riddell et al, 1983, etc

 Dysplasia in UC

• no dysplasia
• indefinite for dysplasia
• low grade dysplasia
• high grade dysplasia
• intramucosal carcinoma
• invasive adenocarcinoma

Riddell et al, 1983

 DALM v SALM
(sporadic adenomatous lesion or mass – Talbot, 2001)

LGD DALM HGD Adenoma

• this can be difficult: adenomas occur in older UC patients

• critical management issue – colectomy v local excision

Case 10: ascending colonic lesion
 Favouring adenoma

• lesion in bowel unaffected by UC

• no other foci of dysplasia
• regular architecture: tubular, tubulovillous, villous
• pedunculated
• adenoma age group

Stolte, M et al
 DALM or adenoma
Immunohistochemistry

DALM sporadic
adenoma

p53 + -

bcl-2 - +

nuclear - +
ß catenin
 DALM v sporadic adenoma
DALM sporadic adenoma

CK7 71% 16%

MUC6 34% 2%
MUC5AC 80% 43%

MUC2 90% 76%

CK20 88% 92%

• relative specificity of DALMs for gastric-type markers

• gastric differentiation of importance in UC-associated
neoplasia?
Tatsumi et al, 2006
 Case 10

• lesion in ascending colon is (probably) a sporadic

adenoma (SALM)

• but what about the remaining mucosa?

 Case 10: flat mucosa

• if it’s dysplasia, it’s very diffuse

• BUT intravenous cyclosporin therapy for severe UC

• villous change and mimicry of dysplasia

• clues are diffuseness of change, low N/C ratio toward

surface despite nuclear enlargement

Hyde, Jewell & Warren, 2002

• but biggest clue is the history – only 2 years of UC

 Case 10: Diagnosis

• extensive chronic active ulcerative colitis

• sporadic adenoma (SALM) in ascending colon

• diffuse mimicry of dysplasia due to IV cyclosporin

therapy

• no evidence of viral infection, radiotherapy, etc (other

mimics of diffuse dysplasia)

• CONTEXT, CONTEXT AND CONTEXT

 Factors in the development of UC neoplasia
• extent of disease
• longevity of disease
• primary sclerosing cholangitis
• family history of CRC

• age of onset
• number and severity of relapses

• backwash ileitis
• inflammatory polyps

• long term effective treatment & chemo-prevention

Rubio et al, 2001; Eaden, 2004

 Cumulative risk of cancer in extensive UC
18
16
14 0 years
12 5 years
10 10 years
15 years
8
20 years
6 25 years
4 30 years

2
0
Eaden et al, 2001

Rutter et al, 2006: constant cancer risk with time

How is the management of dysplasia in UC changing?

• chromo-endoscopy can detect most lesions in UC,

whether flat or otherwise
Kiesslich et al, 2003; Rutter et al, 2004;
Hurlstone et al, 2004

• dysplastic lesions, invisible to endoscopy, including

dye-spray, are very unusual
Rutter, 2006
Chromo-endoscopy in ulcerative colitis
 How is it all changing?

• most dysplasia can be detected by expert endoscopy

• pathology is more reliable with double reporting, expert

reporting, subspecialisation, etc

• special pathological techniques add little

• then, correctly diagnosed, most polypoid dysplastic

lesions can be treated by local excision at endoscopy

• there may be a lot less surgery…..

Narrow band imaging at endoscopy in the diagnosis of
dysplasia in UC

• low-magnification and high-

magnification NBI capable of
distinguishing neoplastic from
non-neoplastic colorectal lesions

• diagnostic accuracy of NBI

better than conventional
colonoscopy and equivalent to
chromo-endoscopy

• role of NBI in screening

colonoscopy needs further
evaluation

Chiu et al,
Gut 2007; 56: 373-379
 Endoscopic management of lesions confirmed as
dysplastic by biopsy

• MDTM discussion

• EMR/ESD/TEMS/NOTES

• histopathological assessment

LGD or HGD – completely excised – routine UC

surveillance

LGD/HGD incompletely excised – repeat EMR/

ablation therapy
ESDs of dysplastic lesions in UC
The management of dysplasia in UC now/soon

Rutter, 2007;
Revised BSG IBD Management Guidelines, in press
 Case 10 – learning points

• mimics of dysplasia – radiotherapy, IV cyclosporin, viral infection

• the clues are the diffuse dysplasia (dysplasia is pretty much never
diffuse {in the colon and rectum anyway….}) and the history

• there are great difficulties in differentiating adenomas from DALMs

in UC patients (but it matters less now)

• use commonsense and circumstantial evidence rather than relying too

heavily on subtleties of immunohistochemistry

• the management of dysplasia in UC is undergoing a massive sea

change – go to www.bsg.org.uk soon!
 Case 10

DIAGNOSIS:
SPORADIC ADENOMA WITH ‘PSEUDO-DYSPLASIA’
DUE TO IV CYCLOSPORIN(E) THERAPY
 Case 11

46F. Nodular area in sigmoid colon, sigmoidoscopically

malignant. Sigmoid colonic biopsies.
Case 11
Case 11
Case 11
 Case 11

This is polypoid endometriosis

 Case 11 - learning points

• endometriosis may mimic neoplasia clinically,

radiologically, endoscopically and histopathologically

• prove it by ER, CD10, etc

• especially may be misinterpreted as dysplasia or even

carcinoma

• can also produce mimicry of CIBD by inducing

inflammation and distortion in overlying mucosa

• rarely can be complicated by neoplasia

Petersen, Wells, Underwood & Shepherd, 2002

 Case 11

DIAGNOSIS:
POLYPOID ENDOMETRIOSIS OF THE SIGMOID COLON
 Case 12

73M. Pedunculated sigmoid colonic polyp snare resected.

Case 12
Case 12
Case 12
Case 12
 Case 12

• 73M. Pedunculated sigmoid colonic polyp

• adenocarcinoma arising in adenoma

• moderately differentiated

• no vascular invasion

• more than 1 mm from diathermy margin

The adenomatous polyp harbouring malignancy
What do we do with the adenomatous polyp
harbouring malignancy?
The big three criteria

• is it poorly differentiated?

• does it show vascular invasion?

• does it reach the margin? i.e. within 1

mm (or 2mms ?)

Cooper et al. Gastroenterology 1995;

108:1657-65.
Classification of early colorectal cancer in polyps:
Haggitt et al 1986
 Vascular invasion in malignant polyps

Significant predictor of metastasis

Muller et al. Gut 1989; 30: 1385-91

81 malignant polyps: 5 year follow up - no

prognostic significance

Geraghty, Williams & Talbot. Gut 1991; 32: 774-8

 When is polypectomy alone justified?

729 adenomas of which 39 had adenocarcinoma.

• 24 resection complete but colectomy.
• 6 were node positive. No features were helpful in
predicting node positivity.
• All should have resection!
Colacchio et al. Ann Surg 1981; 194: 704-7.

73 adenocarcinomas in adenomas, completely excised,

polypectomy alone.
• 5-139 months later: no luminal recurrence.
• 4 patients died of intra-abdominal malignancy:
presumed separate primary.
• Polypectomy alone is OK whatever the histology, as
long as excision is complete!
Chapman et al. Colorectal Dis 2000;2:8-12.
So what are the risks of lymph node metastasis?

• less doubt about the big three: margin, poor

differentiation and lymphovascular spread

• Haggitt 4 is a major risk factor

• it is not always easy to assess Haggitt level

• the literature has become biased by early reports

suggesting conservatism
Adenocarcinoma in colorectal adenomatous polyps

• conflicting views in the literature

• most papers favour conservatism if the three

criteria are fulfilled

• if not fulfilled (high risk cancer), 33% chance of

nodal metastasis

Coverlizza S et al. Cancer 1989; 64: 1937-47.

 Selecting patients for resection

• a careful balance between risks of metastatic

disease and risks of surgery

• age and co-morbidity are important

ACPGBI Colorectal Cancer Data
ACPGBI Colorectal Cancer Data
 Adenocarcinoma in colorectal adenomatous polyps
• if malignant polyp is suspected, the site needs tattooing

• if malignancy is diagnosed, if ever there was a reason for MDTM

discussion, this is it

• full discussion with gastroenterologist, surgeon, oncologist, pathologist

and the patient

• judge each case on its merits with full staging and knowledge of local
results of surgery

• if resection, do a full cancer operation: it’s the nodes we’re after!

(Astler-Coller C1)

• we all have those cases where we wished we had called the surgeons in
(and those where we wished we hadn’t!)
 Case 12

DIAGNOSIS:
ADENOCARCINOMA ARISING IN ADENOMATOUS POLYP.

MANAGEMENT ISSUES ARE PARAMOUNT……

 Case 13

40M. Multiple polyps in colon and rectum.

13A represents sigmoid polyps resected in 1999 and 13B

colorectal polyps resected in 2001.
Case 13
Case 13 – slide A from 1999
Case 13 – slide B from 2001
Case 13 – slide B from 2001
Case 13
 Case 13

• 40M. Multiple polyps in colon and rectum

• over many years

• funny looking papillary polyps with cystic dilatation,

some ulceration, etc

• definite focal dysplasia

Case 13
Case 13
 Juvenile polyposis

• 1 in 80,000

• genetics becoming clearer but polymorphic: SMAD4

implicated in 21%

• high rates of colorectal cancer: life time risk - ? up to 60%

• dysplasia in atypical juvenile polyps

• ? surveillance ? prophylactic colectomy

Jass et al 1988
 A quick question for you on molecular biology

SMAD 4 mutation is implicated in about a quarter of

cases of juvenile polyposis. What does SMAD stand
for? Is it:

1. small mothers against decapentaplegia

2. serine-methionine-arginine deletion

3. somatic mutation in Aleutian drosophila

 A quick question for you on molecular biology

SMAD 4 mutation is implicated in about a quarter of

cases of this condition. What does SMAD stand for?
Is it:

1. small mothers against decapentaplegia

2. serine-methionine-arginine deletion

3. somatic mutation in Aleutian drosophila

 Case 13 - learning points

• juvenile polyps are common – commonest polyp in the

under 20s – and have classic pathology

• juvenile polyposis causes strange-looking polyps which

are multiple although not of the number, usually, seen
in FAP

• significant cancer risk for JP and it may affect the

whole gut

• seen in FRCPath exams!!

• some genes have some seriously weird names…..

 Case 13

DIAGNOSIS:
JUVENILE POLYPOSIS
WITH ‘ATYPICAL JUVENILE POLYPS’ & FOCAL DYSPLASIA
 Case 14

58F. Sessile anal polyp 15 mm in diameter. Local excision.

Case 14
Case 14
Case 14
Case 14
 Case 14

• 58F. Sessile anal polyp 15 mm in diameter

• anorectal junction

• villous change of rectal mucosa

• epithelial hyperplasia but not dysplasia, fibromuscular

proliferation in the lamina propria, superficial erosions
& ulcers
 Case 14 - learning points

• there is the all embracing pathological entity of mucosal

prolapse – SU(MP)S, stomas, cap polyps, ICPs,
diverticular polyps, etc, etc

• here it can be called polypoid mucosal prolapse

• mimicry of rectal villous adenomas

• mimicry of carcinoma by epithelial misplacement,

proctitis cystica profunda and mucin lakes with spillage
Inflammatory cloacogenic polyp (polypoid
mucosal prolapse at the anorectal
junction) with florid proctitis cystica
profunda
Inflammatory cloacogenic polyp
 Mucosal prolapse and its mimicry of neoplasia

• BUT ………

• don’t get too hung about mimics because the occasional

‘mimic’ is the real thing……

• the changes of classical solitary ulcer (mucosal prolapse)

syndrome may occur as a complication of associated
carcinoma
Li & Hamilton, 1998
Polypoid mucosal prolapse at the anorectal junction

• a word of warning with inflammatory cloacogenic polyp

• four cases of adenomas of the lower rectum causing

secondary polypoid mucosal prolapse

Parfitt & Shepherd, 2008

Ki-67 p53
 Case 14

DIAGNOSIS:
POLYPOID MUCOSAL PROLAPSE OR ’INFLAMMATORY
CLOACOGENIC POLYP’
 Case 15

39M. Chronic anal sepsis with anorectal fistula. Anal

biopsies.
Case 15
Case 15
Case 15
Case 15
Case 15
 Case 15

• and when you fired immunos at it, those big cells

were positive for…..

• S 100, melan A and HMB 45 ?

• no: they were positive for CD 45, CD 20 and CD 79A

Case 15
 AIN terminology

(i) classic, usual, Bowenoid:

HPV-associated, p16 positive,
p53 negative

(ii) differentiated/simplex:
HPV negative, older, p16
negative, p53 positive, usually
seen at edge of SCC,
associated with LS
nuclear subtleties, less
dyskeratosis
 The diagnosis of AIN

Clinical features
– thickened skin (hyperkeratotic)
– changes in pigmentation
– plaque-like or filiform (rare)
– normal

Histology: the gold standard

 Risk factors for AIN and anal cancer
• HPV types 16 & 18 (and others)

• US data shows anal SCC increase in MSM and HIV cohorts

– homosexual men
Daling et al, 1987; Palefsky et al, 1998 & 2001

– immunosuppressed (HIV/AIDS & transplant recipients)

– AIN is an aggressive disease in HIV/AIDS with little effect by
HAART
Palefsky et al, 1991, Ogunbiyi et al, 1994;
Bonner et al, 2001

– women with VIN and CIN

Scholefield et al, 1989
 Importance of p16 and MIB1 in the diagnosis

(i) classic, usual, Bowenoid:

HPV-associated, p16 positive, p53 negative

(ii) differentiated/simplex:
HPV negative, older, p16 negative, p53 positive,
usually seen at edge of SCC
associated with LS
nuclear subtleties, less dyskeratosis

Bean et al, 2007

MIB1 in classic, usual, Bowenoid AIN

MIB1
MIB1 in AIN diagnosis

MIB1

MIB1

Bean et al, 2007

 Case 15 - learning points

• the old dual pathology story beloved of MRCPath

examiners…

• the multiple pathology story of HIV/AIDS

• of course, I have to accept that poor pathologists

have lost a whole raft of interesting pathology with
effective AIDS treatment with HAART

• but there’s still some around, especially in London

 Case 15

DIAGNOSIS:
DIFFUSE LARGE B-CELL LYMPHOMA
AND AIN 3 (AIDS-RELATED)
 And when you’ve passed the FRCPath exam,
you will feel just like the chap in the middle…..
 Gloucestershire GI Pathology Course

• Friday, 1 October 2010

• The Gold Cup Suite, Cheltenham Racecourse

• Novelli, Shepherd, Warren & Williams

• Dr Judy Wyatt and Professor Phil Quirke, Leeds, as

guest lecturers

• go to www.glospathology.com