Colorectal tumors: The histology report

Digestive and Liver Disease 43S (2011) S344–S355
Colorectal tumors: The histology report
Giovanni Lanza a, *, Luca Messerini b , Roberta Gafà c , Mauro Risio d
On behalf of the “Gruppo Italiano Patologi Apparato Digerente (GIPAD)” and of the “Società Italiana
di Anatomia Patologica e Citopatologia Diagnostica”/International Academy of Pathology,
Italian division (SIAPEC/IAP)
a Department
of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara, Italy
of Medical and Surgical Critical Care, Section of Pathological Anatomy, University of Florence, Italy
c Department of Imaging Diagnostics and Laboratory Medicine, Anatomic Pathology, Azienda Ospedaliero-Universitaria of Ferrara, Italy
d Unit of Pathology, Institute for Cancer Research and Treatment, Candiolo-Torino, Italy
b Department
Abstract
Epithelial colorectal tumors are common pathologic entities. Their histology report should be comprehensive of a series of pathologic
parameters essential for the correct clinical management of the patients. Diagnostic histologic criteria of adenomatous, serrated, inflammatory,
and hamartomatous polyps and of polyposis syndromes are discussed. In addition, the pathologic features of early and advanced colorectal
cancer are described and a checklist is given. Finally, molecular prognostic and predictive factors currently employed in the treatment of
colorectal cancer are discussed.
© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Keywords: Adenocarcinoma; Adenoma; Colorectal; GIPAD report; KRAS; Microsatellite instability; Polyposis syndromes; Serrated polyps
1. Introduction
2. Polypoid and nonpolypoid colorectal adenomas [1–3]
Epithelial tumors of the colon and rectum are frequent
pathologic entities and deserve to be histologically reported
with accuracy and completeness. Colorectal cancer is one of
the commonest malignant tumors worldwide and represents
in Italy the second cause of cancer-related death. Epithelial
polyps of the large intestine are often sampled or removed endoscopically. Adenomas are the precursors of most colorectal
cancers, whereas about 15% of colorectal carcinomas develop
through an alternative morphogenetic pathway from serrated
polyps.
Polypoid adenoma is a circumscribed lesion projecting into
the bowel lumen composed of mucosal neoplasia, encompassing categories 3–4 of the revised Vienna classification (i.e.:
low and high grade dysplasia/intraepithelial neoplasia, non invasive carcinoma/carcinoma in situ, intramucosal carcinoma)
[2] (Table 1).
Polypoid adenoma consists of the peduncolated and sessile
(broad base) morphology, whereas nonpolypoid adenomas
include flat and depressed adenomas, that are histologically
defined as those in which the thickness of the lesion is less
than twice that of the height of the adjacent normal colonic
mucosa, or even thinner than the surrounding mucosa. The
histological identification of nonpolypoid lesions needs the
complete endoscopical removal and the well-oriented paraffin
embedding of tissue samples. The endoscopy-based Paris
classification compares the height of the lesion to that of
closed cups of a biopsy forceps (2.5 mm) and allows to
Correspondence to: Prof. Giovanni Lanza, Department of Experimental and
Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara,
Via Fossato di Mortara 64/b, 44100 Ferrara, Italy.
1590-8658/$ – see front matter © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
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Table 1
Grading of superficial colorectal neoplasia
WHO 1989
WHO 2000
Revised Vienna Classification
Category 1: Negative for neoplasia
Category 2: Indefinite for neoplasia
Low grade dysplasia (mild and moderate
dysplasia)
Low grade intraepithelial neoplasia (mild and
moderate dysplasia)
Category 3: Mucosal low grade neoplasia
Low grade adenoma
Low grade dysplasia
High grade dysplasia (severe dysplasia)
High grade intraepithelial neoplasia
(severe dysplasia, adenocarcinoma in situ)
Carcinoma in situ (carcinoma in situ,
intramucosal carcinoma)
Intramucosal neoplasia
(intramucosal adenocarcinoma)
Category 4: Mucosal high grade neoplasia
4.1. High grade adenoma/dysplasia
4.2. Non-invasive carcinoma (carcinoma in situ)
4.3. Suspicious for invasive carcinoma
4.4. Intramucosal carcinoma
Invasive carcinoma (spreading into the
submucosa)
Invasive carcinoma (invasion into the
submucosa)
distinguish sessile polypoid lesions (Type 0-Is, protruding
above 2.5 mm) from the nonpolypoid ones (Type 0-IIa
protruding below 2.5 mm), the distinction being crucial given
the highly significative differences in cancerization rates
between nonpolypoid and sessile polypoid (adenomatous and
serrated) lesions [4]. The histological report for nonpolypoid
lesions should therefore confirm the adenomatous nature of
the lesion, determine the degree of neoplasia, exclude invasion
and, when possible, state the likelihood of consistency with
the endoscopical typing according to the Paris classification.
Category 5: Submucosal invasion by carcinoma
2.4. Villous histology [Diagnostic strength: Level 3]
Villous structures form at least 80% of villous adenomas,
and more than 20% of tubulovillous adenomas. Villi can
assume different morphologies, all of them equally contributing to villous histology of an adenoma: classical villi (long,
slender, finger-like processes), palmate villi (leaf-like, broad,
branched processes), foreshortened villi (isolated, slender outgrowths). The presence of at least one identifiable villus
in polyp biopsies or fragments deserves to be reported as
“predominantly tubular histology”.
2.1. Gross specimens and handling
2.5. Grade of neoplasia [Diagnostic strength: Level 3]
Size should be carefully measured identifying the maximum diameter of the adenomatous component, length and
diameter of the stalk, if present. The resection margin should
be identified, described, and sliced in a way that allows
complete assessment. Polyps need to be sliced and totally
embedded. At least three levels should be cut and H&E
stained through each block.
2.2. Pathology report
Since size, villous histology, and grade of neoplasia represent the most important determinants for the malignant
progression of colorectal adenomas, as well as for the risk of
development of synchronous and/or metachronous large bowel
neoplasia, histological report should focus on all of them.
2.3. Size [Diagnostic strength: Level 2]
The size of adenomas influences surveillance intervals, and
an accurate measurement by the pathologist to the nearest
millimeter is required. Grossly, measurement of the size can
be done from the formalin-fixed specimen, excluding the stalk,
if present. Microscopy allows the precise measurement of the
adenomatous sectors of polyps, excluding non neoplastic
tissues. When the two measurements significantly differ,
microscopic size should be made explicit in the report and
auditable.
Severity of both architectural (crypt branching and budding, complex glandular crowding, intraluminal papillary
tufting) and cytological features (loss of cell polarity and
differentiation, nuclear stratification, enlarged and rounded
nuclei with nucleoli) distinguish mucosal low grade neoplasia
(Category 3, equating low grade dysplasia) from mucosal high
grade neoplasia (Category 4.1, equating high grade dysplasia
in older systems) (Table 1). Only one or two glands with
high grade dysplasia and identifiable at low power examination are needed to classify an adenoma as high grade.
Trauma, erosion, prolapse and bleeding, mainly occurring in
the superficial portions of polyps, elicit reparative changes
in the adenomatous epithelium (loss of polarity and nuclear
stratification), mimicking high grade neoplasia, but these are
not to be overinterpreted as such. Cribriform or solid pattern of epithelial growth consistent with carcinoma in situ
and invasion by the neoplastic epithelium into the lamina
propria or muscularis mucosae consistent with intramucosal
carcinoma are included (categories 4.2 and 4.4, respectively)
within the spectrum of mucosal high grade neoplasia and as
such reported.
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G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
3. Cancerized adenoma, malignant polyp (pT1 colorectal
cancer) [3]
Neoplastic invasion into the submucosa through the muscularis mucosae (Category 5 in accordance with the revised
Vienna Classification) is diagnostic of cancerized adenoma
[Diagnostic strength: Level 3]. Colonic intramucosal carcinoma behaves like a benign adenoma and for this reason
polyps harbouring “in situ” or “intramucosal” cancer (Categories 4.2 and 4.4, respectively) are not generally regarded
as “malignant” polyps and classified as high grade dysplasia, high grade intraepithelial neoplasia or mucosal high
grade neoplasia (Table 1). Cancerized adenomas represent
the earliest form of clinically relevant colon cancer in most
patients. Invasion of the submucosa, in fact, opens the way to
metastasis via the haematogenous and lymphatic routes, and
the choice between surveillance and major surgery when an
endoscopically removed polyp is found to be an ACIC will
hinge on its metastatic potential, taking into account that post
operative mortality (within 30 days) ranges from 0.6 to 4.4%
in T1 cancers. At present, histopathologic parameters alone
determine whether a high (35%) or low (7%) risk of nodal
metastases exists [5–8]. Histologic risk factors – namely positive resection margin, poor differentiation of cancer, vascular
invasion and tumor budding – do not only predict lymph node
disease rate but also distant metastasis and mortality rates.
3.3. Margin involvement [Diagnostic strength: Level 3]
A negative deep (basal) margin is reported in the absence
of cancer within the diathermy and one high-power field
from diathermy, or more than 1 mm from the actual margin
of resection The presence of adenomatous tissue in the
lateral mucosal resection margin should also be independently
reported as an indication for further endoscopic treatment.
3.4. Tumor budding [Diagnostic strength: Level 2]
An isolated single cancer cell and a cluster composed
of fewer than 5 cancer cells are defined as “budding” foci.
Although several studies have shown that tumor budding
is independently associated with lymph node and distant
metastasis as well as shorter disease free and overall survival
in colorectal cancer, there is no consensus with regard to the
assessment methods and cut-off values.
Due to the usually small dimension of the submucosal invasive front in cancerized adenomas, tumor budding should be
assessed in the area where the highest activity is identified on
H&E, reserving immunohistochemistry for the better assessment of this feature. Awaiting the results from reproducibility
studies, a quantitative, two-grade system (low vs. high grade)
is advisable, counting tumor buds (< or ≥10) within a 0.385
mm2 area using a ×25 lens.
3.1. Carcinoma grading [Diagnostic strength: Level 3]
3.5. Microstaging [Diagnostic strength: Level 2]
Histologic grade should be in accordance with the system
used in advanced colorectal cancer and distinguish well/
moderately (low grade) from poorly differentiated (high
grade) tumors. It is based on the worst area, independently
from its extension. An anaplastic component (even in the form
of small, single or scattered foci) should be identified, as its
occurrence strongly correlates with the risk of lymph node
metastases. Signet ring cell carcinoma should be graded as
poorly differentiated. Tumor budding at the front of invasion
should not influence carcinoma grading and should be scored
separately (see below).
The level of submucosal invasion, assessed as Haggitt levels I–IV in peduncolated polyps and as sm1–3 Kikuchi levels
in sessile polyps, is important in predicting the outcome of
cancerized adenomas. On the other hand, cancerized adenomas with slight submucosal invasion to the depth of 200–300
micrometers are very unlikely to have metastatic lymph nodes
and the quantitative measurements of both depth (< or >2000
micrometers) and width (< or >4000 micrometers) of the
cancerous submucosal invasion are strongly indicative of the
nodal involvement and worthy reporting. In this setting the
rough estimate of the ratio of adenomatous to carcinomatous
tissue is meaningful, indicating the prevalence of the potentially metastatic cancerous tissue within the polyp, the risk of
lymph node metastasis being likely high (even in the absence
of other risk parameters) in pT1 polypoid adenocarcinoma,
consisting entirely of cancer without adenoma.
3.2. Vascular invasion [Diagnostic strength: Level 2]
Lymphatic invasion requires the presence of cancer cells
within endothelial-lined channels or spaces, distinguishing
such features from retraction artefacts. Venous invasion is
defined as tumor emboli within endothelial-lined channels
surrounded by a smooth muscle wall. Uncertainty in the
assessment (presence vs absence) of neoplastic vascular
invasion, even after the examination of serial and deeper
routinely H&E stained sections, should be reported. Evidence
is lacking for the additional use of immunohistochemistry in
detecting vascular invasion.
4. Serrated polyps [3,9,10]
Epithelial serration, namely the saw-toothed outline derived from infolded epithelial tufts in the crypt and in
the luminal surface can be found in several histotypes of
colorectal polyps. Transient serration associated with hyperproliferation can be seen in inflammatory polyps, above all
of myoglandular type. Steady serration is displayed in the
common hyperplastic polyps of the large bowel and, coupled
with focal or diffuse epithelial neoplastic changes, in serrated
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
adenomas and mixed polyps. Furthermore, cell maturation
and differentiation are altered in serrated epithelium, particularly in the mucus-producing process, so that abnormal goblet
cell, microvesicular, and mucus-poor cell components can be
found allowing the identification of different cytotypes of
serrated polyps: these, however, seem unrelated to different
risks of tumor progression.
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4.4. Mixed polyps [Diagnostic strength: Level 2]
In these polyps one or more serrated components (hyperplastic, SSA, TSA) are associated and/or intermingled with
classical adenomatous tissue (tubular, tubulovillous and villous). Extension and grading of neoplastic sectors should be
exhaustively described in the diagnosis, in order to support
clinical decision making.
4.1. Hyperplastic (metaplastic) polyps [Diagnostic strength:
Level 3]
5. Inflammatory polyps [13]
Epithelial serration together with minimal architectural
changes, and without cytological atypia are the diagnostic
features of hyperplastic polyps of the large bowel. They are
small-sized (0.2–0.5 cm) mucosal bumps of the sigmoid colon
and rectum, consisting of straight, parallel, slightly elongated
crypts lined by serrated epithelium in the intermediate and
upper third, and by undifferentiated cells in the lower third.
The nuclei are round or oval and located at the base with little
or no stratification.
4.2. Sessile serrated adenomas (SSA) /sessile serrated polyps
[Diagnostic strength: Level 2]
SSA are mainly right-sited, large-sized (>1 cm) sessile
serrated lesions displaying patchy or diffuse distorsions of
tissue organization: branching of crypts, serration of foveolar
cell phenotype at the base of the crypt, dilatation at the base
of the crypt, horizontal crypt growth [11]. Most findings are
only suggestive for SSA, and are localized in the deeper
sectors of the mucosa and require well-oriented samples for
identification. Subtle nuclear changes, when present, are focal
and include small prominent nucleoli, open chromatin, and
irregular contours. Frankly dysplastic nuclear abnormalities,
indicative of the initial transition toward traditional serrated
adenomas should be reported, in terms of extension and
neoplasia grade, in order to manage patient surveillance.
Intermingling and/or intermediate features of SSA and hyperplastic polyps can often be seen in the same histolgical
section, impairing diagnostic reproducibility. The term “sessile serrated polyp” has therefore been suggested for equivocal
lesions and even as a synonym of SSA, considering the improper use of “adenoma” for lesions lacking true neoplastic
changes.
Inflammatory polyps are defined as mucosal elevations
resulting from an inflammatory process. They may occur in
patients with inflammatory bowel disease (IBD), as well as in
patients with other forms of colitis, such as infectious colitis,
ischemic colitis, or diverticulitis. They may be also induced
by a mucosal trauma due to an inappropriate peristalsis and
in such cases are defined as mucosal prolapse-related inflammatory polyps. Different entities such as inflammatory cap
polyp, colitis cistica profunda and inflammatory myoglandular polyp are considered to belong to the mucosal prolapse
syndrome. Inflammatory polyps do not show an increased risk
of neoplastic transformation.
Inflammatory polyps may be sessile or pedunculated, and
their gross appearance varies from rounded lesions to fingerlike projections (filiform polyps, usually associated with IBD).
They may be single or multiple and their size generally ranges
from few mm to 2 cm; sometimes, they may be extremely
large (“giant” inflammatory polyps) and can cause intestinal
obstruction.
5.1. Histological features [Diagnostic strength: Level 3]
The lamina propria shows an intense inflammatory cell
infiltrate and contains dilated and branched colonic crypts;
neutrophilic cryptitis and crypt abscess may be prominent.
The colonic surface epithelium and the colonic crypts may
show both epithelial damage and regeneration. Intense vascular congestion and hemorrhage may also be present. Mucosal
prolapse-related inflammatory polyps show additional histological features such as thickening and vertical extension of
the muscularis mucosae toward the lamina propria.
5.2. Differential diagnosis [Diagnostic strength: Level 2]
4.3. Traditional serrated adenomas (TSA) [Diagnostic
strength: Level 2]
Nuclear (elongated, hyperchromatic, stratified nuclei) and
cytological frankly dysplastic features are seen within the
serrated epithelium, besides architectural changes and are diagnostic for TSA [12]. Rapid and protuberant growth parallels
nuclear dysplasia and, grossly, TSA can be indistinguishable
from villous or tubulovillous colorectal adenomas.
The differential diagnosis between reactive epithelial
changes and epithelial dysplasia or neoplasia is the main
potential pitfall that can occur in evaluating inflammatory
polyps. The regenerating epithelium usually shows maturation
toward the surface while dysplastic or neoplastic epithelium
do not show surface maturation. Moreover, the presence of an
inflammatory background should be carefully considered to
avoid an overdiagnosis of dysplasia or neoplasia, particularly
in patients with IBD.
Inflammatory polyps may contain bizarre stromal cells,
that may be mistaken for a sarcoma (“pseudosarcomatous”
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change). The location of these cells underneath areas of
ulceration, the presence of an inflammatory infiltrate together
with the absence of atypical mitoses can help in the differential diagnosis. Inflammatory polyps may also mimic juvenile
polyps, since the histological features of both are very similar;
the clinical data can help in the distinction between these two
types of polyps.
6. Hamartomatous polyps and polyposes
Hamartomatous polyps are characterized by a disorganized
overgrowth of tissues native to the anatomic area in which
they arise. They may occur as solitary polyps or in the context
of polyposis syndromes, and are defined by their histology.
6.1. Solitary juvenile polyp (JP)
Most JPs are located in the distal large intestine and their
size is generally less than 1–2 cm; their surface is smooth and
lobulated and they are usually pedunculated. Rectal bleeding
is the most frequent symptom; sometimes autoamputation of
the polyp can occur. Solitary JPs have no increased risk of
malignancy.
JP is composed of an expanded lamina propria with irregular glands that are often cistically dilated. The lamina propria
contains a variable amount of inflammatory cells but there is
no proliferation of smooth muscle. JP is the most frequent
hamartomatous colorectal polyp, and is especially common
before 10 years of age; however, it may occur also in adults.
6.2. Juvenile polyposis [14]
The polyps are histologically similar to solitary JPs.
Juvenile polyposis should be suspected when three or more
JPs are found; however the diagnostic criteria for Juvenile
polyposis are the following: five or more juvenile polyps
of the colorectum and/or juvenile polyps throughout the
gastrointestinal tract and/or any number of juvenile polyps
with a family history of Juvenile polyposis.
There are three types of Juvenile polyposis: (1) Juvenile
polyposis of infancy, that is usually fatal from non-neoplastic
conditions; (2) Juvenile polyposis coli, that shows an increased risk of colorectal cancer; (3) Generalized Juvenile
polyposis, which shows an increased risk of development of
gastrointestinal carcinomas.
Most patients with Juvenile polyposis show mutations of
the SMAD4/DPC4 gene. Polyps closely resembling juvenile
polyps are found in other conditions such as Cowden disease,
Bannayan-Riley-Ruvalcaba syndrome and Cronkhite-Canada
syndrome. The first two syndromes are related to inherited mutation of the PTEN gene, whereas Cronkhite-Canada
syndrome is a non-hereditary gastrointestinal polyposis of
unknown etiology. Patients with these syndromes show gastrointestinal multiple polyps, but they may also have extragastrointestinal clinical manifestations as well as an increased
risk of malignancy.
6.3. Peutz-Jeghers syndrome [15]
Peutz-Jeghers polyps mainly occur in the small bowel,
and less frequently in the large bowel and the stomach.
They are variable in size, being sessile or pedunculated.
They are generally multiple, but solitary Peutz-Jeghers type
polyps have been described. Mucocutaneous hyperpigmentation around the mouth, eyes, perianal area, and on the fingers
often precede gastrointestinal manifestations. The diagnosis
of Peutz-Jeghers syndrome is based upon clinical findings
and the histological appearance of the polyps [Diagnostic
strength: Level 3]. The incidence of gastrointestinal cancer
as well as extra-gastrointestinal neoplasms in Peutz-Jeghers
syndrome is greater than in the normal population [16]. Mutations of the LKB1/STK11 gene have been found in nearly
60% of affected patients.
The main histological feature is the presence of arborizing
bands of smooth muscle, derived from muscularis mucosae,
that are covered by normal or hyperplastic glandular epithelium. Epithelial misplacement into the intestinal wall may be
present and may mimic invasive adenocarcinoma. It can be
recognized by normal differentiation of the epithelium, lack
of stromal reaction and haemosiderin deposition.
7. Adenomatous polyposis [17]
Familial adenomatous polyposis (FAP) and its variant syndromes (Gardner syndrome and Turcot syndrome) are different phenotypic manifestations caused by germline mutations
of the adenomatous polyposis coli gene. FAP is characterized
by hundreds of adenomatous polyps in the large bowel, that
generally begin to emerge in the second decade of life. If
adenomas are not removed, colorectal cancer is inevitable,
since the penetrance of the disease is very high, reaching
nearly 100%. [Diagnostic strength: Level 3]
Extracolonic manifestations associated with FAP are: upper gastrointestinal adenomas and adenocarcinomas, adenocarcinoma of the ampulla of Vater, gastric fundic glands
polyposis, desmoid tumors, central nervous system tumors,
cancer of the thyroid, hepatoblastoma, hypertrophy of the
retinal pigment epithelium, osteomas, epidermoid cysts, and
dental abnormalities.
Duodenal cancer and desmoid tumors are the main causes
of death in FAP patients treated with prophylactic colectomy.
Attenuated familial adenomatous polyposis (AFAP) [18] is
characterized by multiple adenomas of the colon. In this
syndrome the number of adenomas is lower than in classical
FAP and it ranges from 2 to 100, averaging around 20–30
adenomas, with prominent variations among family members.
[Diagnostic strength: Level 3]
AFAP is associated with germline mutations of the APC
gene in only a small proportion of cases (approximately 10%).
Furthermore, adenomas are frequently flat and often localized
in the proximal colon. Extra-colonic manifestations may or
not be present, but upper gastrointestinal lesions are generally
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
present. AFAP patients have a high risk of colorectal cancer.
These patients develop colorectal cancer 10 years earlier than
individuals with sporadic colorectal cancer, but 15–20 years
later than patients with classical FAP.
MUTYH-associated adenomatous polyposis (MAP) [19]. Multiple adenomas can also occur in a subset of APC mutationnegative patients. These patients harbor germline mutations
in the repair gene MUTYH (MYH). The number of adenomas ranges from 15 to more than 100. These patients
present a very high risk of developing colorectal cancer.
Furthermore, the incidence of extra-colonic tumors, especially
duodenal cancer, is higher than that of the general population.
[Diagnostic strength: Level 3]
8. Hyperplastic polyposis (HP) [20]
The following criteria have been proposed to diagnose HP:
1) at least five histologically diagnosed hyperplastic polyps
proximal to the sigmoid colon of which two are greater than
10 mm in diameter, or 2) any number of hyperplastic polyps
occurring proximal to the sigmoid colon in an individual
who has a first degree relative with HP, or 3) more than 30
hyperplastic polyps of any size, but distributed throughout the
colon. [Diagnostic strength: Level 2]
Individuals with HP develop colorectal cancer on a background of multiple polyps that are mainly hyperplastic polyps.
However, SSAs, TSAs and mixed polyps can also be found
in these patients; therefore it the suggestion is to consider all
types of serrated polyps in diagnosing HP.
9. Surgically resected colorectal cancer
Careful pathologic reporting of colorectal cancer resection
specimens is of paramount importance to determine the
prognosis and to plan the treatment of individual patients.
In addition, pathologists have an increasing role in the
identification of hereditary tumors and in prediction of
tumor response to specific type of therapy. There is clear
evidence that the use of checklists improves the standard of
colorectal cancer reporting and therefore their use is strongly
recommended (Table 2). Pathologic parameters that need
to be absolutely reported on the basis of their prognostic
value or that are required for therapy will be discussed. In
addition, molecular prognostic and predictive factors recently
introduced in the clinical setting will be examined.
9.1. Histologic type [1,21] [Diagnostic strength: Level 2]
Histologic type should be evaluated according to the WHO
classification as follows [1].
• Adenocarcinoma
• Mucinous adenocarcinoma
• Signet-ring cell carcinoma
• Small cell carcinoma
•
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Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
• Undifferentiated carcinoma
Most colorectal carcinomas (nearly 85%) are usual adenocarcinomas, and 10 to 15% are classified as mucinous
adenocarcinomas (mucinous component >50%). The other
tumor types are rare. Tumor typing does not have major
prognostic relevance, but signet-ring cell carcinoma and small
cell carcinoma have been demonstrated to have adverse prognostic significance independent of stage. Notwithstanding,
the various subtypes of colorectal cancer are characterized
by different genetic alterations and probably more detailed
prognostic information will be obtained in the future by an
integrated histologic and molecular classification [22].
With respect to usual adenocarcinomas, mucinous tumors
have a greater tendency to develop peritoneal metastases, to
invade adjacent organs and to show extensive lymph node
involvement [21]. Mucinous carcinomas are evenly distributed
in the right and left colon and more frequently than common
adenocarcinomas harbour defects in the DNA mismatch repair
(MMR) system [23]. Mucinous adenocarcinomas differ from
common adenocarcinomas also on the basis of other molecular features, such as higher frequency of CIMP phenotype
and rare p53 mutations, suggesting that these tumors really
represent a distinct pathologic entity [22]. A less favourable
clinical outcome for patients with mucinous cancers has been
demonstrated in many studies but not in others and the
prognostic significance of the mucinous phenotype remains at
present undetermined. In addition, the prognosis of mucinous
carcinomas with microsatellite instability (MSI) has been reported to be better than that of microsatellite stable mucinous
carcinomas.
Signet-ring cell carcinoma is composed of at least 50%
signet-ring cells. It represents less than 1% of all colorectal
carcinomas and occurs more frequently in individuals younger
than 50 years of age and in patients with ulcerative colitis.
Histologically, colorectal signet-ring cell carcinomas differ
from gastric ones for the common presence of abundant
extracellular mucin and infrequent diffuse tissue infiltration.
Signet-ring cell carcinomas are often at an advanced stage
at diagnosis and are associated with a worse outcome
than common adenocarcinomas. Peritoneal carcinomatosis
develops in the majority of patients who die of the disease.
About 30% of signet-ring cell carcinomas display defect of
MMR function; however, MSI status does not appear to be a
significant predictor of survival in this tumor type.
Small cell carcinomas are histologically identical to those
arising in the lungs. They often appear to develop within an
adenoma and usually express neuroendocrine markers. Part
of the cases show a distinct adenocarcinomatous component.
Most patients have distant metastases at diagnosis and the
prognosis is very poor. Large cell poorly differentiated
neuroendocrine carcinomas may also occur in the colorectum
and their clinical behaviour is similar to that of small cell
carcinomas.
Medullary carcinomas are generally described as tumors
•
•
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G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
Table 2
Surgically resected specimens of colorectal cancer – Checklist
Table 2 (continued)
Extramural venous invasion
Not identified
Present
Tumor site
Cecum
Ascending colon
Hepatic flexure
Transverse colon
Splenic flexure
Descending colon
Sigmoid colon
Rectosigmoid junction
Rectum
Tumor size
Maximum tumor diameter:
cm
Histologic type
Adenocarcinoma
Mucinous adenocarcinoma
Signet-ring cell carcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Medullary carcinoma
Undifferentiated carcinoma
Other (specify):
Grade of differentiation
Low grade (well or moderately differentiated)
High grade (poorly differentiated or undifferentiated)
High grade component (%):
Depth of tumor invasion
No evidence of primary tumor
Tumor invades submucosa (pT1)
Tumor invades muscularis propria (pT2)
Tumor invades through the muscularis propria into the subserosal adipose
tissue or the nonperitonealized pericolic or perirectal soft tissues (pT3)
Tumor penetrates to the surface of the visceral peritoneum (serosa)
(pT4a)
Tumor directly invades other organs or structures
) (pT4b)
(specify:
Tumor penetrates to the surface of the visceral peritoneum (serosa) and
directly invades other organs or structures
) (pT4b)
(specify:
Margins of resection
Proximal/distal margin
Cannot be assessed
Invasive carcinoma present
Invasive carcinoma absent
mm
Distance of invasive carcinoma from closest margin:
Circumferential (radial) margin
Not applicable
Cannot be assessed
Invasive carcinoma present
Invasive carcinoma absent
Distance of invasive carcinoma from non-peritonealised margin:
Regional lymph nodes
Number examined:
Number involved:
Tumor deposits
Not identified
Present (number:
)
Response to neoadjuvant therapy
Not applicable (no prior treatment)
Complete regression
Minimal residual tumor
No marked regression
Pathologic staging (pTNM)
TNM descriptors (required only if applicable)
m (multiple primary tumors)
r (recurrent)
y (posttreatment)
Primary tumor (pT)
pTX: Cannot be assessed
pT0: No evidence of primary tumor
pTis: Carcinoma in situ, intraepithelial or invasion of lamina propria
pT1: Tumor invades submucosa
pT2: Tumor invades muscularis propria
pT3: Tumor invades through the muscularis propria into pericolorectal
tissues
pT4a: Tumor penetrates the visceral peritoneum
pT4b: Tumor directly invades other organs or structures
Regional lymph nodes (pN)
pNX: Cannot be assessed
pN0: No regional lymph node metastasis
pN1a: Metastasis in 1 regional lymph node
pN1b: Metastasis in 2 to 3 regional lymph nodes
pN1c: Tumor deposit(s) in the subserosa, or nonperitonealized pericolic
or perirectal tissues without regional lymph node metastasis
pN2a: Metastasis in 4 to 6 regional lymph nodes
pN2b: Metastasis in 7 or more regional lymph nodes
Distant metastasis (pM)
Not applicable
pM1: Distant metastasis
Specify site(s):
pM1a: Metastasis to single organ or site (e.g., liver, lung, ovary,
nonregional lymph node)
pM1b: Metastasis to more than one organ/site or to the peritoneum
Additional pathologic findings
None identified
Diverticular disease, ulcerative colitis, Crohn’s disease, familial
adenomatous polyposis, other forms of polyposis, synchronous
carcinoma(s) (complete a separate form for each cancer), etc.
Specify:
Polyps present (specify type and number):
Comment(s):
mm
characterized by solid growth pattern and marked intratumoral
and peritumoral lymphocytic infiltration, and composed by
cells with vesicular nuclei, prominent nucleoli, and abundant
eosinophilic cytoplasm [1,24]. Tumor cells form sheets or
may have an organoid or trabecular architecture; focal mucin
production or glandular differentiation are often present.
In our experience, medullary carcinomas often display a
clearly evident glandular and/or mucinous component and
are generally formed by quite uniform cells with mild or
moderate nuclear atypia and variable amount of cytoplasm
[25]. Moreover, intense intratumoral and peritumoral lymphocytic infiltration is not always present. At the molecular
level, the great majority of medullary carcinomas show MSI,
which probably explains their better prognosis with respect to
common poorly differentiated adenocarcinomas [25].
Undifferentiated carcinomas are tumors lacking morphological evidence of differentiation beyond that of an epithelial
tumor [1]. Some authors include in this category tumors
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
showing a minimal component of gland formation (<5%).
Undifferentiated carcinomas may form sheets of cells, cords,
or trabecular structures. Grade of anaplasia is variable, some
tumors displaying marked nuclear atypia and pleomorphism,
and others having relatively uniform and less atypical cytologic features. The clinical outcome of undifferentiated
carcinomas is quite unpredictable and seems to be mainly
related to the MMR status of the tumor.
Other subtypes of large bowel carcinoma (such as sarcomatoid carcinoma, choriocarcinoma, and clear cell carcinoma)
are extremely rare. Furthermore, in the recent years new
subtypes of large bowel adenocarcinoma – named serrated,
micropapillary, and villous adenocarcinoma – have been described, but their clinico-pathologic and molecular features
need to be more precisely defined.
9.2. Grade of differentiation [1,24,26] [Diagnostic strength:
Level 2]
Diverse grading systems for colorectal cancer are currently
employed. We recommend the use of a 2-tiered grading
system based on the WHO classification:
• Low grade: well differentiated and moderately differentiated
• High grade: poorly differentiated and undifferentiated
A 2-tiered stratification demonstrated greater reproducibility and prognostic relevance than stratification into 3 or 4
categories. Specifically, high grade tumors have repeatedly
been shown to behave more aggressively than low grade
carcinomas in multivariate analysis. According to the WHO
criteria, grading should be based on the evaluation of the
worst area, excluding areas of focal dedifferentiation present
at the invasive margin of the tumor. However, the grading
systems proposed by the College of American Pathologists
[26] and the Royal College of Pathologists [27] are both based
on the assessment of the predominant grade of differentiation.
We suggest that, using the WHO system, the percentage of
high grade tumor area when present should be also reported.
9.3. Depth of tumor invasion [28,29] [Diagnostic strength:
Level 3]
This is evaluated as the pT component of the TNM
classification [28,29]:
• Tumor invades submucosa (pT1)
• Tumor invades muscularis propria (pT2)
• Tumor invades through the muscularis propria into pericolorectal tissues (pT3)
• Tumor penetrates to the surface of the visceral peritoneum
(pT4a)
• Tumor directly invades other organs or structures (pT4b)
The TNM classification includes a pTis “carcinoma in
situ” level comprising intraepithelial carcinoma (confined
within the glandular basement membrane) and carcinoma
showing invasion of the lamina propria (intramucosal). As
colorectal neoplasia does not have metastatic potential until it
has invaded the submucosa, it is preferable to avoid the term
S351
pTis and use the term high grade dysplasia to indicate these
lesions.
The outer edge of the muscolaris propria represents the line
of demarcation between pT2 and pT3. pT3 indicates spread in
continuity beyond the bowel wall and does not apply to lymphatic or venous invasion. At variance with the sixth edition,
according to the new TNM and AJCC classifications tumor
deposits in the mesenteric fat are no longer classified in the pT
category as discontinuous extramural extensions. If a tumor
spreads to the outer edge of the muscolaris propria but not
beyond and no muscle separates cancer cells from the perivisceral tissues, then the tumor should be classified as pT3.
Tumors that have penetrated the visceral peritoneum as a
result of direct extension through the wall and subserosa are
assigned to the pT4 category, as tumors that directly invade
other organs or structures, whether or not they penetrate the
serosal surface. Identification of visceral peritoneal involvement needs adequate tumor sampling and eventually multiple
levels sectioning and microscopic examination. The histologic findings considered to represent carcinomatous serosal
involvement are [26,30].
• Tumor present at the serosal surface with inflammatory
reaction, mesothelial hyperplasia, and/or erosion or ulceration
• Free tumor cells on the serosal surface with underlying
ulceration of the visceral peritoneum
Previous studies indicated that serosal involvement was
associated with worse outcome than invasion of adjacent
organs. However, recent data obtained from a very large
cohort of colorectal cancer patients indicate that penetration
of the visceral peritoneum carries a 10% to 20% better
5-year survival rate than invasion of adjacent organs for
each category of N [31,32]. Therefore, designation of the
T4 subsets was changed in the seventh edition of the TNM
classification.
9.4. Margins of resection [24,26,27] [Diagnostic strength:
Level 3]
Proximal, distal, circumferential, and mesocolic margins
of resection need to be evaluated in colorectal cancer surgical
specimens. It is very useful to mark the margin(s) closest to
the tumor with ink after careful examination of the serosal
surface.
Proximal and distal resection margins are rarely involved
unless close (<2 cm) to the tumor or the tumor shows
histologically poor differentiation or a diffusely infiltrating
pattern of growth. Sections to assess proximal and distal
margins can be obtained either by longitudinal sections
perpendicular to the margin or by en face sections parallel to
the margin. The distance from the tumor edge to the distal
resection margin is very important for low anterior resection
and a clearance of 2 cm (1 cm for T1 and T2 tumors) is
considered adequate.
The circumferential (radial) margin represents the adventitial soft tissue margin closest to the deepest penetration
of tumor and is created surgically. Tumor involvement of
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G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
the radial margin is the most critical factor in predicting
local recurrence in rectal cancer and is also associated with
an increased risk of death from the disease [33]. The circumferential margin is considered positive if the tumor is
located 1 mm or less from the nonperitonealized surface.
This assessment includes tumor within veins, lymphatics or
lymph nodes and tumor deposits, as well as direct tumor
extension. However, if circumferential margin involvement
is based only on intranodal tumor, this should be stated. In
rectal cancer, the distance of the tumor from the radial margin
should be always reported. The circumferential margin should
be also assessed in colonic segments incompletely encased
by peritoneum (e.g., cecum, ascending colon, and descending
colon). The clinical relevance of pathologic examination of
the surgical mesocolic plane of dissection has been recently
recognized [34].
9.5. Regional lymph nodes [28,29] [Diagnostic strength:
Level 3]
The number of metastatic lymph nodes and the total
number of lymph nodes examined must always be reported.
Regional lymph node status should be assessed according to
the new TNM classification [28,29], as follows.
pN0 No regional lymph node metastasis
pN1 Metastasis in 1–3 regional lymph nodes
pN1a Metastasis in 1 regional lymph node
pN1b Metastasis in 2–3 regional lymph nodes
pN1c Tumor deposit(s), i.e., satellites, in the subserosa, or in non-peritonealized pericolic or
perirectal soft tissue without regional lymph
node metastasis
pN2 Metastasis in 4 or more regional lymph nodes
pN2a Metastasis in 4–6 regional lymph nodes
pN2b Metastasis in 7 or more regional lymph nodes
With respect to the previous edition a subdivision of pN1
and pN2 categories has been introduced, reflecting differences
in clinical outcome observed within each category on the
basis of the number of affected lymph nodes [31,32].
Histological examination of a regional lymphadenectomy
specimen ordinarily includes 12 or more lymph nodes. If
the lymph nodes are negative, but the number ordinarily
examined is not met, the tumor will be classified as pN0. All
macroscopically evident lymph nodes in the surgical specimen
should be dissected and examined histologically. Many factors
influence lymph node recovery and evaluation, such as extent
of surgical resection, quality of pathologic examination,
patient factors, and tumor characteristics [35,36]. The mean
number of nodes detected in a series of dissections is now
considered to be indicative of colon cancer quality care [37]
and should be comprised between 12 and 15 [24]. As nodal
metastases in colorectal cancer are often found in small lymph
nodes (<5 mm in diameter), meticulous search is required on
gross examination by the pathologist. If less than 12 lymph
nodes are retrieved, re-examining the specimen could be
useful. Use of visual enhancement techniques and inclusion of
pericolic fat are not generally recommended. In rectal cancer
specimens from patients treated with neoadjuvant therapy the
number of recovered lymph nodes is often lower than 12
despite accurate search.
Several studies reported that the total number of lymph
nodes evaluated after surgical resection is an important
prognostic factor in colorectal cancer. In particular, most
studies showed that increased survival of patients with stage
II colon cancer is associated with increased number of lymph
nodes examined [35]. A similar positive association was also
demonstrated among patients with stage III colon cancer [35].
In addition, recent investigations indicated that the ratio of
metastatic to examined lymph nodes is related to clinical
outcome in patients with colon and rectal cancer [38]. The
biologic bases of these findings are not fully understood and
factors other than staging accuracy are probably involved.
Some studies suggested that identification of micrometastases in lymph nodes of patients with colorectal cancer staged
as pT3N0 by conventional pathologic examination could be of
prognostic value [39]. However, at present data are insufficient
to recommend use of special measures to detect micrometastases or isolated tumor cells in the routine assessment of
regional lymph node status [26].
Peritumoral deposits (satellite nodules) are macroscopic
or microscopic carcinomatous nests or nodules in the pericolorectal adipose tissue lymph drainage area of a primary
carcinoma without histologic evidence of residual lymph node
tissue [28,29]. They may represent discontinuous spread of
the tumor, venous invasion with extravascular spread or totally replaced lymph nodes. According to the latest edition
of the TNM classification, if a nodule is considered by the
pathologist to be a totally replaced lymph node (generally
having a smooth contour), it should be recorded as a positive
lymph node and not as a satellite. In addition, pT1–2 lesions
that lack regional lymph node metastasis but have tumor
deposit(s) will be classified as pN1c whereas the pT category
is unchanged. There is no general agreement on the classification of pericolic tumor nodules [24,40] and probably these
new statements of the TNM classification will not be accepted
by part of the pathologists [41]. Tumor deposits are associated
with unfavourable disease outcome [40] and therefore their
presence and number should be separately recorded [29].
[Diagnostic strength: Level 2]
9.6. Response to neoadjuvant therapy [27,42] [Diagnostic
strength: Level 2]
Preoperative (neoadjuvant) chemo- and radiotherapy for
rectal cancer induces several secondary changes including
tumor regression and downstaging [42,43]. In the case of
rectal cancers treated with neoadjuvant therapy pathologic
staging should be performed according to the ypTNM system
and based on evaluation of viable cancer cells. Marked tumor
regression and especially complete tumor eradication are
associated with better clinical outcome. Therefore, specimens
from patients treated with neoadjuvant therapy should be
carefully examined and extensively sampled in particular
to demonstrate complete tumor regression. Several systems
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
for grading tumor regression have been proposed and there
is no general consensus on the histological classification
of this parameter. However, 3-tiered grading systems have
been generally recommended by National and International
Associations [24,26,27,29]. We suggest the use of the grading
system proposed by the Royal College of Pathologists, which
includes the following categories:
• No residual tumor cells and/or mucus lakes only (complete
regression)
• Minimal residual tumor, i.e. only occasional microscopic
tumor foci are identified with difficulty
• No marked regression
According to the TNM classification, cases with complete
regression are recorded as ypT0.
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10.1. KRAS mutation [48,49] [Diagnostic strength: Level 3]
Presence of KRAS gene mutations (codons 12 and 13)
is associated with lack of clinical response to therapy with
monoclonal antibodies (cetuximab and panitumumab) directed against the epidermal growth factor receptor (EGFR)
in metastatic colorectal cancer. Actually, tumors of patients
with metastatic disease who are candidates for anti-EGFR
antibody therapy have to be tested for KRAS mutations and
only patients whose tumors show absence of KRAS mutations
at codon 12 or 13 can be treated with anti-EGFR antibodies.
However, only a fraction of patients with KRAS wild type
carcinomas will respond to anti-EGFR antibody treatment and
further predictive molecular markers are actively investigated
nowadays [49].
9.7. Vascular invasion [26,27] [Diagnostic strength: Level 2]
Venous invasion has been shown in several studies to be an
independent negative prognostic factor in colorectal cancer.
In particular, invasion of large extramural veins has been
repeatedly associated with increased risk of cancer-related
death. The prognostic value of intramural venous invasion and
of invasion of lymphatics or thin-walled vessels is less clear.
We believe that extramural vein invasion should be always
reported, whereas reporting of intramural and thin-walled
structures is optional.
Elastic fiber stains could help in the recognition of venous
invasion, when suspected, on haematoxylin and eosin stained
sections; however routine use of elastic stains, as recently
suggested, is not at present recommended.
9.8. Additional histologic prognostic factors
Several other histopathologic variables, including perineural invasion, pattern of growth, lymphocytic infiltration at
the tumor margin, tumor infiltrating lymphocytes (TILs),
Crohn-like reaction, and tumor budding have been proposed
as prognostic factors in colorectal cancer. These parameters
are not commonly employed in the clinical setting and their
reporting is optional. Nowadays, tumor budding [44] and
grade of intratumoral lymphocytic infiltration [45] represent
the most promising prognostic factors to be introduced in
the pathologic evaluation of these tumors, provided that their
assessment will be standardized and their prognostic value
clearly defined.
10. Molecular prognostic and predictive factors [46,47]
Much effort has been produced to identify immunohistochemical, biologic and molecular prognostic and predictive
factors to be utilized in the management of patients with
colorectal cancer [46,47]. Actually, only KRAS mutational
status analysis and evaluation of proficiency of the DNA
mismatch repair (MMR) system by immunohistochemistry
and microsatellite instability (MSI) analysis are employed in
clinical practice.
10.2. DNA mismatch repair status [50] [Diagnostic strength:
Level 2]
About 15% of colorectal cancers are characterized by MSI
(or MSI-H, high frequency MSI), which is determined by impaired function of the MMR system. Most MSI-H carcinomas
(about 70%) are sporadic and produced by somatic biallelic
promoter methylation of the MLH1 gene. It is believed that
sporadic MSI colorectal carcinomas develop through the CpG
island methylator pathway. The other MSI-H tumors are
hereditary and caused by germline mutation of a MMR gene
(MLH1, MSH2, and less frequently MSH6 and PMS2) with
somatic inactivation of the remaining wild type allele (Lynch
syndrome). Genetic or epigenetic inactivation of MMR genes
is nearly always associated with immunohistochemical loss
of expression of the corresponding protein. Furthermore,
as MMR proteins work as heterodimers (MSH2 dimerizes
with MSH6, and MLH1 with PMS2) abnormalities of the
obligatory partners (MSH2 and MLH1) will result in proteolytic degradation of their dimer and concurrent loss of both
the obligatory and secondary partner proteins (MSH2/MSH6
and MLH1/PMS2). Conversely, mutations in genes of the
secondary partner proteins (MSH6 and PMS2) will be characterized by selective loss of MSH6 and PMS2 expression
respectively, as their function may be compensated by other
proteins [51]. Therefore, immunohistochemical pattern of
MMR protein expression allows the identification of the gene
that is most likely inactivated. Several studies demonstrated
an excellent correlation of the results obtained by immunohistochemistry and MSI analysis and both methods can be used
confidently for the identification of MMR-deficient colorectal
carcinomas. However, a small fraction of hereditary cases
having a missense mutation (generally of MLH1) that lead to
a nonfunctional protein with intact antigenicity might result in
MSI-H with intact expression of MMR proteins.
Lynch syndrome accounts for 2–3% of the total burden
of large bowel carcinomas. MSI testing and immunohistochemical analysis of MMR proteins expression are worldwide
employed for the identification of colorectal cancer patients
with presumptive Lynch syndrome, to be tested for MMR
genes germline mutations after appropriate genetic coun-
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G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355
selling. It is recommended that MSI testing should be carried
out on tumors from patients clinically at high risk or selected
on the basis of the revised Bethesda guidelines [52]. However,
molecular screening investigations performed by MSI and/or
immunohistochemical analysis on large series of unselected
surgically removed colorectal cancers followed by MMR
genes mutation analysis have indicated that a large fraction of
Lynch syndrome cases would go unrecognized using common
criteria of selection, and some Authors suggest screening all
colorectal carcinomas for MSI or abnormal MMR protein
expression.
Recent studies have shown that sporadic MSI-H MLH1negative tumors frequently harbour BRAF V600E gene mutation. Conversely, BRAF mutations have not been detected
in MSI-H MLH1-negative tumors from patients with Lynch
syndrome. Therefore, BRAF gene mutation analysis could
be employed as an aid for discriminating hereditary from
sporadic MLH1-negative MMR-deficient carcinomas [53].
MMR status has been demonstrated to be an independent
prognostic factor in colorectal cancer. In fact, several studies
displayed higher survival rates for patients with stage II and III
MSI carcinomas with respect to patients with non-MSI tumors
[54,55]. In addition, emerging data suggest that patients with
MSI tumors do not have significant benefit from adjuvant 5fluorouracil-based chemotherapy [54,56]. However, the use of
MMR status assessment as a prognostic and predictive test has
not yet been validated and incorporated into clinical practice.
Conflict of interest
The authors declare no conflict of interest.
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