发信人: USMedEdu (US_CMGs), 信区: MedicalCareer [删除]
标 题: Re: YJZ： 医网情深：5-22-2017病理实习笔记
发信站: BBS 未名空间站 (Sun Feb 25 06:14:14 2018, 美东)
两周的病理实习中幸运见到几例典型的tubular adenoma, tubularvillous adenoma
and villous adenoma with high-grade dysplasia的病理切片。结合阅片系统地学习
的诊断，从而再次学习到如何在sign out report中给出严谨而准确的诊断描述。
另外何老师立即加做MSI-H testing, 结合之前面试辅导中何老师和我谈到分子诊断在
Colorectal cancer (CRC) is the third most common cancer in both men and
women in the U.S. and it is also the third cause of cancer death in the U.S.
The majority of CRCs are carcinomas, with more than 90% of which are
adenocarcinomas. Understanding the risk factors, progression, pathology and
molecular diagnostic markers are extremely important in guiding the
management and prognosis of colorectal cancer.
It is well accepted that most human CRCs undergo the adenoma-carcinoma
sequence and arise from dysplastic changes of the adenomas. This occurs when
the normal cell renewal pathways become dysregulated in the colon
epithelial cells. It is critical to recognize the cell growth patterns in
different types of adenomas and adenocarcinomas for accurate diagnosis and
Figure 1. The adenoma-carcinoma sequence
Histological features of Adenoma
An adenoma is a polyp with low-grade dysplasia. The key morphological change
includes the tall and dark cells lining the crypts, and the surface with
cigar-shaped or pseudostratified hyperchromatic nuclei.
Depending on the histology and architecture, Adenomas can be classified into
tubular adenoma, villous adenoma and tubularvillous adenoma.
Tubular adenomas consist of more than 80% of colonic adenomas. They present
with smooth surface and parallel crypts. The tubular adenomas typically have
at least 75% of tubular component. By definition, villous adenoma should
have at least 75% of the villous component. Morphologically, villous adenoma
is covered by the long finger-like projections; the glands extend straight
down from the surface to the center of the polyp. Tubularvillous adenomas
present the mixed features of both tubular and villous adenomas and they
account for approximately 5-15% of all colonic adenomas. An advanced adenoma
is defined as adenomas with the size larger than 10 mm, or with villous
components or high-grade dysplasia.
High-grade dysplasia can be considered as an intermediate step of
progression between low-grade dysplasia and cancer. Strictly speaking, it is
diagnosed based on architecture rather than cytology. Usually the term high
-grade dysplasia is used when the lesions are confined to the epithelial
layer and no invasion through the basement membrane can be proven. High-
grade dysplasia is often accompanied by ugly cytology, such as total loss of
nuclear polarity, significant pleomorphism, atypical mitoses figures and
Figure 2. Tubular adenoma
Figure 3. Normal colonic mucosa (left); tubular adenoma (right)
Figure 4. Villous adenoma
Figure 5. Tubularvillous adenoma
Histological features of Adenocarcinoma
To diagnose adenocarcinoma instead of high-grade dysplasia, one must prove
the invasion of the cancer cells across the muscularis mucosae (if can be
identified) into the submucosa. Cancer cells in submucosa rich in blood
vessels and lymphatic tissues poses the risk of progression and metastasis.
However, if the biopsy is superficial or poorly oriented, invasion can be
very difficult to identify. Another important feature of invasion is
desmoplasia or desmoplastic reaction with prominent fibrous proliferation,
instead of the loose connective tissue around the cancerous cells.
Molecular features of colorectal cancer
Clinical studies suggest that molecular features may be of crucial
prognostic value for CRCs, independent of cancer staging. However, more
comprehensive statistically valid clinical studies are still needed before
many molecular or genetic markers can be used in clinic. Of note, currently
only the mismatch repair proteins (MMR), BRAF and RAS mutations are proven
to be useful for clinical decision-making.
1. MSI-high (MSI-H)
Nowadays the MMR (mismatch repair) status testing in patients with CRC is
routinely ordered for prognostic stratification and/or for identifying
patients at high risk for Lynch syndrome. MSI is one of the clinically
important prognostic factors recommended in the newest 2017 TNM staging
criteria for CRC.
The term MSI refers to Microsatellite instability. An important feature of
the cells with mismatch repair defect is the accumulation of abnormalities
in short sequences of nucleotide bases, repeating dozens to hundreds of
times within the genome. These clusters of sequences are called
microsatellites. Genes critical for cell growth regulation may contain
microsatellites in the promoter region and they are susceptible to
A panel of several microsatellite loci were used for testing the MSI. A
proposed standard test is consisted of three dinucleotide repeats and two
mononucleotide repeats. In this case, a MSI-H (MSI-high) tumor is defined as
having at least two (40 percent) foci affected by instability. If less than
40 percent of foci is affected by instability, it is called MSI-L (MSI-low)
instead. However, most tumors show either high degree of instability or no
unstable markers. MSI-L tumors only represents a minor tumor population,
with no MMR defect.
The majority of Lynch syndrome and approximately 15% of sporadic tumors are
MSI-H. In particular, sporadic tumors with MSI-H have several characteristic
clinical and pathological features, including the tendency to occur in the
proximal colon, a greater mucinous component, lymphocytic infiltration, and
more likely to be poorly differentiated. Despite the tendency to be poorly
differentiated, interestingly, MSI-H localized CRCs are associated with
better prognosis and longer survival in both Lynch syndrome and sporadic
colorectal cancers. The biological basis for this finding is unknown. For
metastatic CRC, the prognostic value of MSI is less clear.
2. RAS and BRAF
On the other hand, RAS and BRAF mutations are useful for predicting
prognosis in metastatic CRC. KRAS mutations involving either codon 12 or 13
is associated with a worse prognosis in a majority of clinical studies.
Furthermore, KRAS and NRAS mutations suggest poor response to anti-EGFR
therapy. The molecular basis lies in the EGFR signaling pathway responsible
for colon tumorigenesis. RAS mutation downstream of EGFR results in the
constitutive activation of this pathway regardless of the blockade of EGFR.
Therefore, RAS mutation testing is ordered for CRC patients considering anti
BRAF V600E mutation also confer resistance to anti-EGFR therapy. In MMR
deficient tumors, BRAF V600E mutation is particularly useful for evaluation
of lynch syndrome risk. Lynch syndrome do not possess the BRAF V600E
mutation; and therefore, the presence of BRAF V600E strongly indicates a
sporadic CRC. It is also found to be prevalent in smokers.
In summary, the comprehensive molecular classification system is not yet
incorporated into the CRC staging system. However, the molecular tumor
classification has undergone a lot of progress and potentially contributes
to the development of the new molecular prognostic stratification system and
target specific therapies.
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