Pathogenesis of Hirschprung Disease?

Hirschprung disease is a congenital absence of neurons in a portion of the

intestinal tract, usually the distal colon, due to a disruption of normal neural crest cell
migration, proliferation, differentiation, survival and/or apoptosis.

The ability of the GI tract to respond to the state of the lumen and gut wall by
activating peristalsis, controlling blood flow and secretions and thus maintain proper
physiological balance depends on the enteric nervous system (ENS). ENS neurons and
glia are organized into ganglia. The enteric ganglia are interconnected to form two plexi
that extend along the length of the bowel: an outer myenteric (Auerbach) plexus running
the full length of the gut, and an inner submucosal (Meissner) plexus, found only in the
small and large intestine. The myenteric plexus develops first and is situated between the
longitudinal and circular smooth muscle layers, and is involved in motility, while the
submucosal plexus, which forms later in gestation, regulates motility, blood flow, and the
transport of ions across the intestinal epithelium.

The absence of enteric ganglion cells of the myenteric and submucosal plexi
along variable portions of the GI tract results in Hirschsprung disease , which is
characterized by sustained contraction of the aganglionic bowel segment, leading to
intestinal obstruction and distension of proximal segments (megacolon). The ENS is
derived from a multipotent, migratory cell population called the neural crest, and the
formation of a functional ENS requires coordination of the survival, migration,
proliferation, and differentiation of these progenitor cells within the GI tract.

Proper neural crest cell migration, proliferation, differentiation, survival, and

apoptosis all contribute to a functional ENS. Perturbation in any of these processes can
lead to a Hirschsprung disease phenotype. Many genes which play a critical functional
role in neural crest cell development have been implicated in Hirschsprung, including the
proto-oncogene RET, endothelin signaling genes, and transcription factors . Although
over a dozen genes have been identified that contribute to the etiology of Hirschsprung,
these pathways only account for about half of the known cases
Source:

The Developmental Etiology and Pathogenesis of Hirschsprung disease Transl Res. 2013
July ; 162(1): 1–15 Availabe on : http://www.ncbi.nlm.nih.gov/pubmed/23528997

Carcinogenesis Fearon and Vogelstein’s Model of Colorectal Cancer?

The pathogenesis of CRC varies according to genetic or epigenetic changes,

which are related to each other in varying degrees. They follow the multiple stages
pattern theorized by Fearon and Vogelstein . Such genetic and epigenetic alterations are
directly responsible for a specific event within the sequence that leads to CRC, by
contributing to the “initiation” of neoplastic transformation of healthy epithelium and/or
determining the “progression” towards more malignant stages of the illness. The different
pathways are characterized by distinctive models of genetic instability, subsequent
clinical manifestations, and pathological behavior characteristics. Most CRC follows the
chromosomal instability (CIN) pathway, characterized by widespread loss of
heterozygosis (LOH) and gross chromosomal abnormalities.

- Chromosomal Instability (CIN) pathway

is also known as the adenoma-carcinoma sequence, and it follows a predictable
progression of genetic and corresponding histologic changes. The genomic
changes include activation of proto-oncogenes (K-Ras) and inactivation of at least
three tumor suppression genes, namely, loss of APC (chromosome region 5q21),
loss of p53 (chromosome region 17p13), and loss of heterozygosity for the long
arm of chromosome 18 (18q LOH).

- Adenomatous Polyposis Coli (APC) Gene and Wnt Signaling Pathway


The APC tumor suppressor gene normally blocks transition from G1 to S phase of
the cell cycle. The Wnt signaling pathway maintains native stem cells in their
undifferentiated state in the base of the colonic crypts, which contributes not only
to the survival of normal stem cells but also to the survival of cancer cell stem
 cells. Beta-Catenin is a major player in the Wnt signaling pathway. Unmutated
APC induces degradation of Beta-catenin and therefore functions as a negative
regulator of the Wnt signaling pathway. Sustained levels of intracellular Beta-
catenin result in prolonged activation of the Wnt pathway in APC mutated colo
rectal cancer cells.

- TP53 Mutation
The TP53 gene is significantly involved in the control of the cell cycle and
apoptosis and is commonly mutated in CRC. The p53 protein induces G1 cell-
cycle arrest and facilitates DNA repair prior to a cell committing to the process of
DNA replication. If DNA repair is unsuccessful, p53 induces cell death
(apoptosis). TP53 mutation is generally believed to occur at the time of transition
from adenoma to cancer.

- 18q Loss of Heterozygosity (LOH)

LOH is defined as loss of one of the two copies or alleles of a gene. Often the
remaining allele is affected by a mutation. The DCC (Deleted in Colorectal
Carcinoma) gene is located on the long arm of chromosome 18 (18q21.3). It
encodes the transmembrane protein DCC. DCC is a “conditional tumor
suppressor gene.”

Source: Genetic
Alterations in colorectal
cancer. Gastrointest
Cancer Res 5:19–27. ©
2012 by International
Society of
Gastrointestinal
Oncology
About micrometastasis?
Metastasis is the process of cancer cell dissemination and colonization to
distant sites in the body. It is responsible for as much as 90% of cancer related
deaths. Tumors of a given type appear to preferentially metastasize to certain
organs, implying that successful colonization requires some compatibility between
the circulating tumor cell and the receiving organ microenvironment. It was based
on these observations that Paget proposed the ‘seed and soil’ hypothesis and
challenged the idea that the site of tumor dissemination was solely determined by
the cell’s entrapment in the vasculature. Experimental models have since shown
that tumor cell extravasation (80% of injected cells, see previous section) of itself is
much more efficient than the rates of actual successful tumor formation (0.02%) (3).
These results may be explained primarily in two ways: certain subsets of cells are
especially proficient at initiating secondary tumor growth and disseminating tumor cells
require a specialized environment, or niche, for successful colonization.
The term micrometastasis refers to the development of tumors in new locations
in which they are too small in size to be clinically detectable by conventional tumor
staging methods. Early experiments separated micrometastatic tumors from
macrometastatic ones on a basis of size dimension, in which 2 mm or larger constituted a
macrometastatic tumor. With the development of sensitive techniques, capable of
detecting individual tumor cells hidden within millions of normal background
hematopoietic cells, micrometastasis came to be used to also refer to the presence of any
individual disseminated tumor cells (DTCs) in a new region. According to the stem-cell
hypothesis, only the disseminated tumor cells with stem-cell properties, and
micrometastases established by these cells, can escape from dormancy and give rise to an
overt metastasis. DTCs and micrometastases lacking stem-cell properties are unable to
undergo this important transition. At each stage of the metastatic cascade, tumor cells can
recirculate via the bloodstream into other distant organs. it can even be speculated that
tumor cells might recirculate to the primary tumor site and contribute to local relapse as
indicated by the correlation between DTCs detected in the bone marrow and local
relapse.
 There are several methods used to locate and study DTCs. Ficoll-Hypaque density
centrifugation combined with ICC (immunocytochemistry) or RT PCR is a widely used
method which allows separation of DTCs from blood and mononuclear cells on a basis of
bouyancy. Magnetic affinity cell sorting (MACS) and fluorescence-activated cell sorting
(FACS) are another techniques used for DTCs detection .

Source: Cancer Micrometastases. Pantel, K. et al. Nat. Rev. Clin. Oncol. 6, 339–351
(2009); advance online publication 28 April 2009; doi:10.1038/nrclinonc.2009.44

Esophageal Atresia Classifications?

There are 5 variants of esophageal atresia determined by the location of the atresia and
the presence of any associated fistula to the trachea.

A Esophageal atresia (EA) without tracheoesophageal fistula (TEF)

B Proximal TEF with distal EA

C Distal TEF with proximal EA

D Proximal and distal TEF

E TEF without EA or “H”-type TEF

Source : Current Knowledge of Esophageal Atresia. World J Gastroenterol 2012 July 28;
18(28): 3662-3672
Why is the most common location of the colorectal carcinoma is in the rectosigmoid ?

- Because the shape of the sigmoid is narrow that fecal stagnation is common in this area
that cause constipation.

- Because the inflammatory polyp which is have the potential to become maligna (in IBD
/ colitis ulcerative) happened mostly in distal colon.

Source: Syamsuhidajat R, Jong Wim D,(eds). 2011. buku ajar Ilmu Bedah 3rd ed. EGC:
jakarta.