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Title: SBALO


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COLORECTAL CANCER - MORPHOLOGY

• SBALO Angel MILEV
• UMBAL St. ANN Stefan PETROV
• 07 11 - 2009

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History says In the beginning was Duke 1 and
2 Afther that was Astler Coller (Annals of
Surgery, June, 1 9 5 4)

• Astler Coller RESULTS

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GROSS MORPHOLOGYColorecal cancer / edited by Jim
Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

• Early carcinomas, i.e., tumors limited to the
  submucosa, are mostly
• polypoid
• pedunculated
• semipedunculated
• sessile
• flat lesions
• flat with slight elevation
• with light central depression
• Advanced carcinomas (invading beyond the
  submucosa) are four types, similar to the
  Borrmann categories of gastric carcinoma
• Polypoid (protuberant)
• Ulcerated, with sharply demarcated margins
• Ulcerated without definite borders
• Diffusely infiltrating
• In contrast to gastric carcinomas, the latter
  two types are uncommon.
• The most common type is the ulcerated type with
  sharply demarcated margins.

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GROSS MORPHOLOGYRosai and Ackermans
SurgicalPathology, Juan Rosaj Edt., Vol. I,
Mosby. (2004)
Advanced carcinomas (invading beyond the
submucosa) are four types, similar to the
Borrmann categories of gastric carcinoma
Polypoid (protuberant)
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GROSS MORPHOLOGYRosai and Ackermans
SurgicalPathology, Juan Rosaj Edt., Vol. I,
Mosby. (2004)
Advanced carcinomas (invading beyond the
submucosa) are four types, similar to the
Borrmann categories of gastric carcinoma
Ulcerated, with sharply demarcated margins
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GROSS MORPHOLOGYRosai and Ackermans
SurgicalPathology, Juan Rosaj Edt., Vol. I,
Mosby. (2004)
Advanced carcinomas (invading beyond the
submucosa) are four types, similar to the
Borrmann categories of gastric carcinoma
Ulcerated without definite borders
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GROSS MORPHOLOGYRosai and Ackermans
SurgicalPathology, Juan Rosaj Edt., Vol. I,
Mosby. (2004)
Advanced carcinomas (invading beyond the
submucosa) are four types, similar to the
Borrmann categories of gastric carcinoma
Diffusely infiltrating
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HISTOMORPHOLOGY - Histological TypingColorecal
cancer / edited by Jim Cassidy, Patrick Johnston,
Eric Van Cutsem. (2007)

• Extremely uncommon carcinomas not listed in
  theWHO classification,
• and reported in only a few cases, include
  microglandular goblet cell carcinoma,
• clear cell carcinoma, adenosquamous carcinoma,
  spindle cell and
• metaplastic carcinoma (carcinosarcoma), giant
  cell carcinoma, choriocarcinoma,
• carcinomas arising in endometriosis, melanotic
  adenocarcinoma, and
• Paneth cell rich papillary adenocarcinoma.

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
CRC - 1

• ADENOCARCINOMA GRADING 1 TO 3

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
CRC - 2

• MUCINOUS ADENOCARCINOMA

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
CRC - 3

• SIGNET RING-CELL CARCINOMA

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
CRC - 4

• PROGNOSTIC FACTORS IN CRC

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HISTOMORPHOLOGY - Histological GradingColorecal
cancer / edited by Jim Cassidy, Patrick Johnston,
Eric Van Cutsem. (2007)

• Histopathological grading of tumors is performed
  to provide some indication
• of their aggressiveness, which relates to
  prognosis and/or choice of
• treatment. The traditional system of grading also
  used by the International
• Union Against Cancer (UICC) tumor node metastasis
  (TNM) classification
• distinguishes four grades
• G1 well differentiated
• G2 moderately differentiated
• G3 poorly differentiated
• G4 undifferentiated
• The WHO provides and recommends a grading system
  with two
• classes
• Low-grade, encompassing G1 and G2
• High-grade, encompassing G3 and G4
• This latter grading system fulfills all clinical
  requirements, and can be
• performed with higher reproducibility. We prefer
  this grading with only
• two categories. When a carcinoma shows different
  grades of differentiation,
• the higher grade should determine the final
  categorization. Thus a carcinoma
• that shows both low- and high-grade areas should
  be classified as high-grade.
• However, the disorganized glands seen commonly at
  the advancing edge of

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HISTOMORPHOLOGY - Additional Histological
ParametersColorecal cancer / edited by Jim
Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

• The character of the invasive margin (pushing or
  expanding, or
• well-circumscribed vs. irregular diffusely
  infiltrating)
• Peritumoral inflammation
• The presence of peritumorous lymphoid aggregates
• Invasion of lymphatic vessels (L
  classification) L0, no lymphatic
• invasion, L1, lymphatic invasion LX, lymphatic
  invasion cannot be
• assessed
• Venous invasion (V classification) V0, no
  venous invasion V1,
• microscopic venous invasion V2, macroscopic
  venous invasion
• VX, venous invasion cannot be assessed. In case
  of microscopic
• venous invasion, it is important to distinguish
  between involvement
• of intramural veins (submucosa, muscularis
  propria) and that
• of extramural veins (beyond muscularis propria)
• Invasion of perineural spaces Pn (perineural)
  classification
• Pn0, no perineural invasion, Pn1, perineural
  invasion PnX,
• perineural invasion cannot be assessed.

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SPECIAL CLINICAL TYPES OF COLORECTAL CANCER
Colorecal cancer / edited by Jim Cassidy, Patrick
Johnston, Eric Van Cutsem. (2007)

• Hereditary Nonpolyposis Colon Cancer (HNPCC) -
  between 35 and 45 years), uncommon histological
  feature of medullary carcinoma (TILs), mucinous
  adenocarcinomas and high-grade tumors. An
  increased incidence of metachronous multiple
  primary tumors. HNPCC accounts for at least 4 to
  6 of all colorectal carcinomas.
• Carcinoma Arising in Familial Adenomatous
  Polyposis (FAP) (HFAS) -usually with fewer than
  100 adenomas, mostly of the flat type. The
  histological features are similar to those of
  sporadic cancers. High proportion of multiple
  synchronous primary tumors in symptomatic cases
  (up to a third of cases).
• Carcinoma Developing in Inflammatory Bowel
  Disease - predominantly in extensive ulcerous
  colitis with a history of 10 years or longer,
  involving most of the large bowel (right-sided
  colitis) and with high activity of inflammation.
  Often synchronous multiple carcinomas. High-grade
  tumors, mucinous adenocarcinomas, and signet-ring
  cell carcinomas. Less than 1 of all colorectal
  carcinomas arise in inflammatory bowel disease.

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TUMOR SPREAD IN COLORECTAL CARCINOMA Colorecal
cancer / edited by Jim Cassidy, Patrick Johnston,
Eric Van Cutsem. (2007)

• Cases of high-grade tumors, required a 2 cm
  distal resection margin.
• The bidirectional lymph drainage of tumors of the
• splenic flexure and the adjacent left third of
  the transverse colon and upper
• third of the descending colon requires an
  extended left hemicolectomy (left
• and transverse colectomy) for radical resection.

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Colon Cancer, Adenocarcinoma Differential
Diagnoses WorkupT Dragovich VL Tsikitis
Arizona Medical Center (2009)

• If he has already acquired - 1

If he has already acquired - 2
1 . pTNM STAGING
causal treatment
STAGING pTNM 5-year RELAPSE FREE SURVIVAL
(short)
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The UICCTNM/pTNM Classification of Tumors of the
Colon and Rectum Colorecal cancer / edited by
Jim Cassidy, Patrick Johnston, Eric Van Cutsem.
(2007)
Ramifications (i.e., optional subdivisions of
existing TNM/pTNM categories) pT3 pT3a Minimal
tumor invades through the muscularis propria into
the subserosa or into nonperitonealized pericolic
or perirectal tissues, not more than 1mm beyond
the outer border of the muscularis propria pT3b
Slight tumor invades through the
muscularis propria into the subserosa or
into nonperitonealized pericolic or
perirectal tissues, more than 1mm but not more
than 5mm beyond the outer border of
the muscularis propria pT3c Moderate tumor
invades through the muscularis propria into the
subserosa or into nonperitonealized pericolic or
perirectal tissues, more than 5mm but not more
than 15mm beyond the outer border of
the muscularis propria pT3d Extensive tumor
invades through the muscularis propria into the
subserosa or into nonperitonealized pericolic or
perirectal tissues, more than 15mm beyond
outer border of the muscularis propria pT4 pT4a
Invasion of adjacent organs or structures, without
perforation of the visceral peritoneum pT4b
Perforation of the visceral peritoneum (extended
edition)

• T/pTPrimary tumor
• TX/pTX Primary tumor cannot be assessed
• T0/pT0 No evidence of primary tumor
• Tis/pTis Carcinoma in situ intraepithelial or
  invasion of lamina propriaa
• T1/pT1 Tumor invades submucosa
• T2/pT2 Tumor invades muscularis propria
• T3/pT3 Tumor invades through muscularis propria
  into subserosa or into nonperitonealized
  pericolic or perirectal tissue
• T4/pT4 Tumor directly invades other organs or
• structuresb,c and/or perforates visceral
  peritoneum
• N/pNRegional lymph nodesd
• NX/pNX Regional lymph nodes cannot be assessed
• N0/pN0 No regional lymph node metastasis
• N1/pN1 Metastasis in 13 pericolic or perirectal
  lymph nodes
• N2/pN2 Metastasis in 4 or more pericolic or
  perirectal lymph nodes
• M/pMDistant metastasis
• MX/pMX Distant metastasis cannot be assessed
• M0/pM0 No distant metastasis
• M1/pM1 Distant metastasis
• Regional lymph nodes for each anatomical site or
  subsite the following are regional Appendix
  Ileocolic Cecum Ileocolic, right colic Ascending
  colon Ileocolic, right colic, middle colic
  Hepatic flexure Right colic, middle colic
  Transverse colon Right colic, middle colic, left
  colic, inferior mesenteric Splenic flexure Middle
  colic, left colic, inferior mesenteric Descending
  colon Left colic, inferior mesenteric Sigmoid
  colon Sigmoid, left colic, superior rectal
  (hemorrhoidal), inferior mesenteric, and
  rectosigmoid Rectum Superior, middle, and
  inferior rectal (hemorrhoidal), inferior
  mesenteric, internal iliac, mesorectal
  (paraproctal), lateral sacral, presacral, sacral
  promontory (Gerota)

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The UICCTNM/pTNM Classification of Tumors of the
Colon and Rectum Colorecal cancer / edited by
Jim Cassidy, Patrick Johnston, Eric Van Cutsem.
(2007) (continued)

• Note The definitions of the clinical
  classification (TNM) correspond to those of the
  pathological classification (pTNM).
• Stage grouping is shown in Figure 2.
• A This includes cancer cells confined within the
  glandular basement membrane (intraepithelial) or
  lamina propria (intramucosal) with no extension
  through the muscularis mucosae into the
  submucosa.
• B Direct invasion in T47pT4 includes invasion of
  other segments of the colorectum by way of the
  serosa, e.g., invasion of the sigmoid colon by a
  carcinoma of the cecum.
• C Tumor that is adherent to other organs or
  structures, macroscopically, is classified as T4.
  However, if no tumor is present in the adhesion,
  microscopically, the classification should be
  pT3.
• D A tumor nodule in the pericolic/perirectal
  adipose tissue without histological evidence of
  residual lymph node in the nodule is classified
  in the pN category as a regional lymph node
  metastasis if the nodule has the form and smooth
  contour of a lymph node. If the nodule has an
  irregular contour, it should be classifies in the
  T category and also coded as V1(microscopic
  venous invasion) or V2, if it was grossly
  evident, because there is a strong likelihood
  that it represents venous invasion.

Figure 2.
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MALIGNANT TUMORS OTHER THAN CARCINOMAS Colorecal
cancer / edited by Jim Cassidy, Patrick Johnston,
Eric Van Cutsem. (2007)

• Traditionally, neuroendocrine tumors have been
  separated from epithelial tumors and classified
  in a special way. They are classified as
• Well-differentiated neuroendocrine tumor
  (formerly carcinoid), ICD-O code 8240/1
• Well-differentiated neuroendocrine carcinoma
  (formerly malignant carcinoid), ICD-O code
  8240/3
• Poorly differentiated neuroendocrine carcinoma
  (small cell carcinoma), ICD-O code 8041/3
• GIST (1 of malignomas)
• Kaposi sarcoma (AIDS?)
• Primary malignant melanomas in the rectum
  (without involvement of the anal region)
• Primary colorectal malignant lymphomas
  (involving the ileocecal region and the rectum)
• The classification is not yet standardized
• (for further details in noncarcinomatous
• malignant tumors. ( ! )

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 1

• Anatomy of the anal canal

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 2

• WHO histological classification of tumours of the
  anal canal (2000)

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 3

• TNM classification of tumours of the anal canal
  (STAGING)

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 4

• SQUAMOUS CELL CARCINOMA - PURE

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 5

• SQUAMOUS CELL CARCINOMA COMBINED

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 6

• MUCINOUS ADENOCARCINOMA

gt
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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 7

• ADENOCARCINOMA

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 8

• MELANOMA MALIGNUM

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 9

• PRECANCEROSES HPV GENESIS

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 10

• PRECANCEROSES M. PAGET

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Pathology and Genetics of Tumours of the
Digestive System World Health Organization
Classification of Tumours 2000
AC - 11

• Anal tumours - immunoreactivity profile

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The results of our study cecum, colon
ascendens(1988 June 2008 June incl. )
?ucinous Ring-Cell ?deno-squamous Squamous Small cell Medullar Undifferentiated Other Carcinoid Mixed (carcinoid carcinoma) MPC
19.444 0,128 0,256 0,512 - - 0,128 0,384 0,256 1,024 0,128
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The results of our study MPC of colon ascendens
- 1

• Fig. 2. MPC with chondroid ( C ) and osseous ( O
  ) metaplasia. Hematoxylin and Eosin. x 200.

Fig. 3 High Power view of chondroid metaplasia
chondroid ( C ) with a close connection between
that foci and the border of carcinomas glandule
(BM basement membrane - arrow). Hematoxylin and
Eosin. x 400
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The results of our study MPC of colon ascendens
- 2

• Fig. 4 High Power view of osseous metaplasia ( O
  ) with a close connection between that foci and
  the border of carcinomas glandule (BM basement
  membrane - arrow). Hematoxylin and Eosin. x 400

Fig. 5. Metastases of adenocarcinoma only in
lymphatic nodule. Hematoxylin and Eosin. x 100
35
The results of our study MPC of colon ascendens
- 3

• Fig. 6. Diffuse ( 3 ) Cytokeratin. Anti-Human
  Cytokeratin Clones AE1/AE3 (Dako), x 150

Fig. 7. Focal staining for Vimentin. Monoclonal
Mouse Anti-Vimentin Clone VIM 3B4 (Dako), x 150
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The results of our study MPC of colon ascendens
- 4

• Fig. 8. S-100 immunoreactivity positive
  neuroendocrine cells and neuronal endings.
  Polyclonal Rabbit Anti-Cow S-100 (Dako), x 100

Fig. 9. VEGF (6p21,3) strongly positive in the
stroma and perivascular. Monoclonal Mouse
Anti-Human Vascular Endothelial Growth Factor
Clone VG1 (Dako), x 200
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The results of our study MPC of colon ascendens
- 5

• Fig. 10. a-SMA positive in perineoplastic smooth
  muscle. Monoclonal Mouse Anti-Human Alpha Smooth
  Muscle Actin Clone 1A4 (Dako), x 200

Fig. 11. HER2 focal positive ( 2 ). Polyclonal
Rabbit Anti-Human c-erbB-2 Oncoprotein (Dako), x
150
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The results of our study MPC of colon ascendens
- 6

• RESULTS
• Clinical Findings
• The Patients ranged in age from 39 to 84 years
  were with an average age of 68. The Proportion
  between the men and women are 44.68 / 55.32
  (all 77 patients) all white. The local
  distribution of the tumors are as follows 36
  colon ascendens 41 cecum. Matrix production of
  cartilaginous and osseous substance was found in
  only one case.
• In the current study were found MPC in a white
  man at the age of 78. The Patient had right-sided
  hemicolectomy. No metastases were found out
  intraoperatively or by CAT.
• Gross Pathology
• The MPC tumor was with diameter of 10 cm.
  Macroscopically this nodular protruded tumor had
  Invaded deep into the surrounding soft tissues.
  The Metastases were found in one of the two
  lymphonodules. No invasion was found in the
  resection borders and the omentum. Pathologically
  this case was
• estimated as pTNM 9 T3N1Mx.
• Histopathology
• Microscopically (on the base of the
  histological estimation) we found G2 G3.
• Intestinal adenocarcinoma, in which, the most
  of the matrix foci were of cartilaginous and
  osseous mature tissues. None of them reaches to
  the intestinal inner surface. In the high
  magnification ( x 40 ) we found out a close
  connection between that foci and the border of
  carcinomas glandule. These foci were located
  only in the carcinoma, and not in the metastase.

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The results of our study MPC of colon ascendens
- 7

• DISCUSSION
• This study describes a distinct subgroup of MPC
  of the human colon which hasnt been described up
  till now.
• In addition to the mayor criterion for a
  diagnosis of MPC, as follows
• the presence of overt carcinoma with direct
  transition to matrix-producing cells and
  cartilaginous / osseous matrix
• the matrix of MPC had to lack of intervening
  spindle cell or osteoclastic component (Wargotz,
  E.S, 1988), we propose to include the following
• 3. The foci of cartilage and osseous mature
  tissues in the matrix carcinoma must not reach
  the intestinal inner surface.
• 4. They must be MULTIPLE.
• 5. The MPC must be located only in the wall of
  the colon.
• Cartilaginous and osseous metaplasia is an
  uncommon feature of tumors, arising in the human
  overted glands mammary, salivary and others.
  They may occur in both benign and malignant
  neoplasms.
• In the colon they can be found in the so called
  benign metaplastic polypus, but their presence
  in malignant epithelial blastomas (carcinomas)
  was not recorded until now.

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Whats next?

• Classification of colorectal cancer based on
  correlation of clinical, morphological and
  molecular features.
• 1. The Vienna classification of
  gastrointestinal epithelial neoplasia Gut
  200047251-255, Dixon, P Sipponn, AN Price
  HWatanabe, T Hirota, Y Kato et all. 48
  pathologists from 15 countries reviewed a
  circulating slide set and attend this workshop on
  5 and 6 September 1998 - Vienna, Austria.

In summary, this new classification is
practical and should be useful for resolving many
of the discrepancies between Western and
Japanese pathologists in the diagnosis of
gastrointestinal epithelial neoplastic lesions.
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And the next?

• 1. Molecular Validation of the Modified Vienna
  Classification of Colorectal Tumors Journal of
  Molecular Diagnostics, Vol. 4, No. 4, November
  2002, T Sugai, W Habano, N Uesugi, Yu-Fei Jiao,
• Shin-ichi Nakamura, K Sato, T Chiba, and
  Motohiro Ishii. Iwate Medical University
  Morioka Japan.
• Based on Crypt Isolation Method and DNA
  Extraction, Analysis of DNA Ploidy Pattern,
  Analysis of Allelic Imbalances at Chromosomal
  Loci and Analysis of Microsatellite Instability,
  using Polymerase Chain Reaction-Single-Strand
  Conformation Polymorphism Analysis and
  Sequencing,

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COLORECTAL CANCER - MORPHOLOGY

• SBALO Angel MILEV
• UMBAL St. ANN Stefan PETROV

WELCOME TO bpa-pathology.com
The END