GS II Presentation

A report by Block 6

General Information
This is the case of a 58 year old female, presenting with a chief complaint of epigastric pain

History of Present Illness

10 months PTC
Pt felt epigastric pain, VAS 3/10. Sought consult and was prescribed omeprazole which she took daily. (+) vomiting, anorexia

5 months PTC

Pt felt a hard fixed mass on R flank with pain upon movement (+) direct tenderness

Targeted Review of Systems

(+) increased bowel movements, hematochezia, mucus mixed with stool, stool more malodorous, watery stools, abdominal pain, anorexia, weight loss
(-) vomiting, fever, chills,

Past Medical History

(-) TB, BA, Hpn, DM, Blood dyscracias
Has had no previous operations

Family Medical History

(+) bukol sa bituka in the mother
(-) TB, BA, Hpn, DM, Blood dyscracias

Personal/Social History
(+) prior OCP use
(+) occasional alcoholic beverage drinker (-) smoking, illicit drug use

OB History
G4P4 (4004)
All 4 kids born full term, at home via a midwife and encountered no fetomaternal complications

Targeted Physical Examination Findings

HEENT: Pink conjunctivae, anicteric sclerae, pink oral mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD, trachea midline
Chest and lungs: ECE, CBS, (-) crackles, wheezes Cardiac: AP, DHS, NRRR, (-) murmurs

Targeted Physical Examination Findings

HEENT: Pink conjunctivae, anicteric sclerae, pink oral mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD, trachea midline
Chest and lungs: ECE, CBS, (-) crackles, wheezes Cardiac: AP, DHS, NRRR, (-) murmurs

Targeted Physical Examination Findings

Abdomen: Flat, soft, HABS, (+) direct tenderness on R waist, (+) firm, tender mass on R waist.
GU: IE deferred

Targeted Physical Examination Findings

HEENT: Pink conjunctivae, anicteric sclerae, pink oral mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD, trachea midline
Chest and lungs: ECE, CBS, (-) crackles, wheezes Cardiac: AP, DHS, NRRR, (-) murmurs

Targeted Physical Examination Findings

Abdomen: Flat, soft, HABS, (+) direct tenderness on R waist, (+) firm, tender mass on R waist.
GU: IE deferred

Targeted Physical Examination Findings

HEENT: Pink conjunctivae, anicteric sclerae, pink oral mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD, trachea midline
Chest and lungs: ECE, CBS, (-) crackles, wheezes Cardiac: AP, DHS, NRRR, (-) murmurs

Targeted Physical Examination Findings

Abdomen: Flat, soft, HABS, (+) direct tenderness on R waist, (+) firm, tender mass on R waist.
GU: IE deferred

Targeted Physical Examination Findings

HEENT: Pink conjunctivae, anicteric sclerae, pink oral mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD, trachea midline
Chest and lungs: ECE, CBS, (-) crackles, wheezes Cardiac: AP, DHS, NRRR, (-) murmurs

Targeted Physical Examination Findings

Abdomen: Flat, soft, HABS, (+) direct tenderness on R waist, (+) firm, tender mass on R waist.
GU: IE deferred

Targeted Physical Examination Findings

Abdomen: Flat, soft, HABS, (+) direct tenderness on R waist, (+) firm, tender mass on R waist.
GU: IE deferred

Differential Diagnoses

Colorectal Cancer
R/I
(+) change in bowel movements, hematochezia, watery stools, abdominal pain, anorexia, weight loss, FMH of abdominal tumor

R/o
Cannot be ruled out

Crohns Disease
R/I
(+) increased bowel movements, hematochezia, watery stools, abdominal pain, anorexia, weight loss

R/o
Cannot be entirely ruled out Diarrhea of patient is of acute onset

Ulcerative Colitis
R/I
(+) increased bowel movements, watery stools, abdominal pain, anorexia, weight loss

R/O
Incontinence, urgency No specific trigger for diarrhea

Colonic Diverticulitis
R/I
(+) increased bowel movements, watery stools, abdominal pain, anorexia, weight loss

R/o
(-) fever, chills, nausea, vomiting, constipation/diarrhea pattern, urinary symptoms

Colonic Polyps
R/I
(+) increased bowel movements, watery stools, decreased caliber of stools, abdominal pain, >50 yo,

R/o
(-) fever, chills, nausea, vomiting, constipation/diarrhea pattern, urinary symptoms

Colon Cancer
Pathophysiology

From adenoma to carcinoma

carcinomas evolve through a progression of benign polyps to invasive carcinoma
the larger the polyp, the higher the risk for cancer
tubular adenoma <1 cm tubular adenoma >2 cm < 5% 35%

villous adenomas carry a higher risk than tubular adenomas

villous adenoma >2 cm 50%

Hereditary
(+) family history young age at onset presence of other specific tumors and defects genetic mutation/s present in all cells of the affected individual.

Sporadic
(-)family history older population (6080 y.o.) usually presents as an isolated colon or rectal lesion genetic mutation/s limited to the tumor itself.

Familial
Higher risk for family members: index case is young (<50 years of age) first degree relation more family members with colorectal ca genetic polymorphisms, gene modifiers, and defects in tyrosine kinases

Mutation
Activation of oncogenes (K-RAS) Inactivation of tumorsuppressor genes (APC, DCC, p53)

APC gene
tumor suppressor gene located on chromosome 5q21 regulates the intracytoplasmic pool of -catenin
-catenin is a multifunctional protein which activates transcription of genes like c-myc and others that regulate cellular growth and proliferation.

APC gene
also influences cell cycle proliferation by regulating Wnt expression
As -catenin levels rise, Wnt is activated. Overexpression of Wnt leads to activation of Wnt target genes such as cyclin D1 and Myc, which drive cell proliferation and tumor formation.

K-ras gene
proto-oncogene mutation of only one allele will perturb the cell cycle The K-ras gene product is a G protein involved in intracellular signal transduction mutation G protein remains
in active formuncontrolled cell division

DCC gene
tumor suppressor gene loss of both alleles is required for malignant degeneration role is poorly understood may be involved in differentiation and cellular adhesion in colorectal cancer more than 70% of colorectal

p53 gene
most frequently mutated tumor suppressor gene occur rather late in the adenoma-carcinoma sequence induces apoptosis in response to cellular damage causes G1 cell-cycle arrest, allowing DNA repair mechanisms to occur 75% of colorectal cancers prognostic significance

MYH gene
Recently, a number of families were characterized with a phenotype resembling that of FAP or AFAP, but without a discoverable APC gene defect.
Autosomal recessive inheritance mutations in the gene responsible for base excisionrepair and used to repair oxidative DNA damage

Genetic Pathways
Loss of heterozygosity (LOH) pathway chromosomal deletions and tumor aneuploidy 80% of colon CA Replication error

(RER) pathway
errors in mismatch repair during DNA replication 20% of colon CA associated with microsatellite instability (MSI) tumors with MSI are more likely to be right sided, possess diploid DNA, and are associated with a better prognosis

microsatellite stable
tend to occur in the more distal colon, often have chromosomal aneuploidy, and are associated with a poorer prognosis

Mismatch repair genes

hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6/GTBP caretaker genes police the integrity of the genome and correct DNA replication errors mutations result in in the HNPCC syndrome microsatellite instability

Incidence & risk factors

Incidence
Most common malignancy of the GI tract
In 2003, the World Health Organization estimated that approximately 940,000 individuals were diagnosed with colorectal cancer worldwide and 492,000 died from it that year. Colorectal cancer is the third leading cause of cancer deaths in the Philippines. In 2005, there were 2,657 deaths due to colorectal cancer.

Risk Factors
Aging
dominant risk factor for colorectal cancer >90% of cases diagnosed in people older than 50 years

Hereditary Risk Factors

~ 80% sporadic ~ 20% with (+) family history

Risk Factors
Environmental and Dietary Factors
Saturated or polyunsaturated fats Oleic acid (olive oil, coconut oil, fish oil) Vegetable fiber Alcohol

Risk
Increase No increase Appears to be protective Increase

Calcium, selenium, vitamins A, C, and E, carotenoids, and plant phenols Obesity and sedentary lifestyle

May decrease

Increase dramatically

Risk Factors
Inflammatory bowel disease
increased risk for the development of colorectal cancer Other factors thought to increase risk include the presence of primary sclerosing cholangitis and family history of colorectal cancer.

Other Risk Factors

Cigarette smoking
increased risk especially after >35 years of use

Patients with ureterosigmoidostomy Acromegaly

increased human growth hormone and IGF-I

Pelvic irradiation Obesity

Factors With Decreased Risk of Colon Cancer

Physical activity
Relative reduction risk of 40-50% for people with high energy expenditure

NSAIDS

Postmenopausal female supplement

Diet Modification
Dietary fat and meat intake Dietary fiber, vegetables,fruit Vitamin E, Calcium Statins

Screening

Screening
Preferred CRC screening recommendations:
Cancer prevention tests should be offered rst. The preferred CRC prevention test is colonoscopy every 10 years, beginning at age 50. Screening should begin at age 45 years in African American Cancer detection test. This test should be offered to patients who decline colonoscopy or another cancer prevention test. The preferred cancer detection test is annual FIT for blood.

Screening
Alternative CRC prevention tests:
Flexible sigmoidoscopy every 5 10 years CT colonography every 5 years

Alternative cancer detection tests:

Annual Hemoccult Sensa Fecal DNA testing every 3 years

Screening
Recommendations for screening when family history is positive but evaluation for HNPCC considered not indicated
Single rst-degree relative with CRC or advanced adenoma diagnosed at age 60 years
Recommended screening: same as average risk (colonoscopy every 10 years beginning at age 50 years)

Single rst-degree with CRC or advanced adenoma diagnosed at age <60 years or two rst-degree relatives with CRC or advanced adenomas.
colonoscopy every 5 years beginning at age 40 years or 10 years younger than age at diagnosis of the youngest affected relative

Screening
FAP
Patients with classic FAP (>100 adenomas) should be advised to pursue genetic counseling and genetic testing, if they have siblings or children who could potentially benet from this testing Patients with known FAP or who are at risk of FAP based on family history (and genetic testing has not been performed)should undergo annual exible sigmoidoscopy or colonoscopy, as appropriate, until such time as colectomy is deemed by physician and patient as the best treatment

Screening
FAP
Patients with retained rectum after subtotal colectomy should undergo exible sigmoidoscopy every 6 12 months Patients with classic FAP, in whom genetic testing is negative, should undergo genetic testing for bi-allelic MYH mutations. Patients with 10 100 adenomas can be considered for genetic testing for attenuated FAP and if negative, MYH associated polyposis

Screening
HNPCC
Patients who meet the Bethesda criteria should undergo microsatellite instability testing of their tumor or a family members tumor and/or tumor immunohistochemical staining for mismatch repair proteins Patients with positive tests can be offered genetic testing. Those with positive genetic testing, or those at risk when genetic testing is unsuccessful in an affected proband, should undergo colonoscopy every 2 years beginning at age 20 25 years, until age 40 years, then annually thereafter

Work-up

Laboratory Studies
Goal of assessing patients organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures
Estimate tumor burden (carcinoembryonic antigen [CEA] level)

Laboratory Studies
Complete blood cell count
Chemistries and liver function tests Serum CEA

Imaging Studies
Adequate imaging of the chest and abdomen should be obtained for the purpose of staging.
Chest radiograph or chest CT scan Abdominal barium study Abdominal/pelvic computerized tomography (CT scan) Contrast ultrasound of the abdomen/liver Abdominal/pelvic MRI Positron emission tomography (PET) scans

Procedures
Rectal examination
Colonoscopy Sigmoidoscopy

Double contrast barium enema

Histologic Findings
Microscopic appearance of colon adenocarcinomas
well-differentiated or poorly differentiated glandular structures

Normal topological architecture of colonic epithelium in terms of a crypt-villous axis is lost.

Normal Histology

Poorly Differentiated

Colon cancer staging

TNM Staging
International standard for staging colorectal cancer
3 descriptors:
T for primary tumor N for lymph nodal involvement M for metastasis

Primary Tumor (T)

NCCN: Clinical Practice Guidelines in Oncology: Colon Cancer. 2011.

Regional Lymph Nodes (N)

NCCN: Clinical Practice Guidelines in Oncology: Colon Cancer. 2011.

Distant Metastasis (M)

NCCN: Clinical Practice Guidelines in Oncology: Colon Cancer. 2011.

Anatomic Stage/Prognostic Groups

NCCN: Clinical Practice Guidelines in Oncology: Colon Cancer. 2011.

Management of Colorectal Cancers

A report by Block 6
References: Sabiston, Textbook of Surgery 18th ed Schwartz, Principles of Surgery, 9th ed NCCN Guidelines for Colon Cancer

Principles of Resection
Tumor Removal Identify Field Defects
Lymphovascular supply Vessels, omentum, adjacent organs Strong family history of colonic neoplasms Subtotal versus Complete colectomies

Lymph Node Resections

Oncologic adequacy of resection 12-node minimum

Stage Specific Therapy

Stage 0 Stage 1 Malignant Polyp
No risk of lymph node metastasis Excision with assurance

Based upon the risk of local recurrence and the risk of lymph node metastasis. Depends primarily on depth of invasion

Stage 1 Localized Carcinoma

Cured with surgical resection Up to 46% of patients cured, die of colon cancer, hence neoadjuvant therapy is advised.

Stage Specific Therapy

Stage III Tany, N1, M0
Stage IV Tany, N1, M1
Neoadjuvant therapy based on 5-FU reduces recurrence. New chemotherapeutic agents, capecitabine, irinotecan, oxaliplatin, angiogenesis inhibitors, and immunotherapy are promising

All patients require neoadjuvant chemotherapy Survival is extremely limited, but highly selected patients with isolated, resectable metastases (usually in the liver or lungs) may benefit from metastectomy. In those who cannot be cured surgically, palliation is the focus of therapy.

Malignant Polyp
A malignant polyp is defined as one with cancer invading the submucosa
Classified as carcinoma in-situ, and therefore they have not penetrated the submucosa and do not metastasize. In patients with invasive cancer or adenoma (tubular, tubulovillous, or villous), no additional surgery is required if the polyp has been completely resected and has favorable histological features.
Favorable features: grade 1 or 2 lesion, no lymphovascular space invasion, negative resection margins

Malignant Polyp
Colectomy with en bloc removal of lymph nodes is recommended if:
The polyp is fragmented The margins cannot be assessed There is unfavorable histology

All patients who have resected polyps should undergo total colonoscopy to rule out other synchronous polyps, as well as appropriate follow-up surveillance endoscopy.

Non-metastatic Invasive Carcinoma

A complete staging workup is mandatory, including:
Pathologic tissue review Total colonoscopy CBC Blood chemistry profile Carcinoembryonic antigen (CEA) determination Baseline computed tomographic (CT) scans of the chest, abdomen, and pelvis.

Non-metastatic Invasive Carcinoma

Surgical procedure of choice (if resectable):
Colectomy with en bloc removal of the regional lymph nodes.

Extent should be based on the tumor location, resecting the portion of the bowel and arterial arcade containing the regional lymph nodes. Other nodes, such as those at the origin of the vessel feeding the tumor, as well as suspicious lymph nodes outside the field of resection, should also be biopsied or removed if possible.

Non-metastatic Invasive Carcinoma

For resectable colon cancer that is causing overt obstruction, resection with diversion, stent insertion followed by colectomy, or diversion followed by colectomy are options. If the cancer is locally unresectable or medically inoperable, chemotherapy is recommended with the goal of converting the lesion to a resectable state.

Chemotherapy in Colon Cancer

Choices for adjuvant therapy for patients with resected nonmetastatic colon cancer are dependent on the stage of disease:

Stage 1

No need for adjuvant therapy

Stage 2 (low risk)

5-FU capecitabine

Stage 2 (high risk) & Stage 3

6 mos. 5-FU/LV/oxaliplatin capecitabine

Endpoints of Chemotherapy in Colon Cancer

Relapses occur within 2 years following surgery
Relapse rates (<1.5%/year after 5 years & <0.5%/year after 8 years) More than 5 years follow up may be needed to adequately assess the adequacy of adjuvant chemotherapy.

Types of Chemotherapy
FOLFOX (infusional 5-fluorouracil (5-FU), leucovorin (LV), oxaliplatin)
Regimen of choice in both adjuvant and metastatic chemotherapy. Complication: grade 3 peripheral sensory neuropathy

FLOX (bolus 5-FU/LV/oxaliplatin)

No statistically significant difference in over survival. Grade 3 neurotoxicity, diarrhea, and dehydration were higher in FLOX than FOLFOX.

Capecitabine
Single agent, at least equivalent to bolus 5- FU/LV

Adjuvant Chemoradiation
Radiation therapy delivered concurrently with 5-FUbased chemotherapy may be considered for very select patients with disease characterized as T4 tumors penetrating to a fixed structure or for patients with recurrent disease.
Radiation therapy fields should include the tumor bed as defined by preoperative radiological imaging and/or surgical clips. Intraoperative radiotherapy (IORT), if available, should be considered for these patients as an additional boost.1

Invasive Metastatic Colon Cancer

50%-60% of patients diagnosed with colorectal cancer will develop colorectal metastases
80%-90% of these have unresectable metastatic liver disease over one-half of patients who die of colorectal cancer have liver metastases at autopsy and that metastatic liver disease is the cause of death in the majority of these patients.

The criteria for determining patient suitability for resection of metastatic disease are
the likelihood of achieving complete resection of all evident disease with negative surgical margins maintaining adequate liver reserve

Incomplete resection or debulking has not been shown to be beneficial.

 Chemotherapy is recommended in conjunction with liver resection in those patients who are chemotherapy naive.
Potential advantages of preoperative chemotherapy include:
earlier treatment of micrometastatic disease determination of responsiveness to chemotherapy (which can be prognostic and help in the planning of postoperative therapy) avoidance of local therapy for those patients with early disease progression.

Neoadjuvant Therapy in Invasive Metastatic Colon Cancer

 Potential disadvantages include:

Neoadjuvant Therapy in Invasive Metastatic Colon Cancer

chemotherapy-induced liver injury missing the window of opportunity for resection making it difficult to identify areas for resection. potential for development of liver steatohepatitis and sinusoidal liver injury when irinotecan- and oxaliplatin-based chemotherapeutic regimens are administered.

The current management of disseminated metastatic colon cancer uses various active drugs, either in combination or as single agents: 5-FU/ LV, capecitabine; irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab.

Nonresectable Invasive Metastatic Colon Cancer

Primary treatment of unresectable synchronous liver or lung metastases by palliative colon resection should be considered only if the patient has an unequivocal imminent risk of obstruction or acute significant bleeding.
Symptomatic improvement in the primary is often seen with systemic chemotherapy even within the first 1 to 2 weeks, and routine palliative resection of a synchronous primary lesion should not be routinely done in the absence of overt obstruction.

Post-treatment Surveillance
Evaluate:
possible therapeutic complications discover a recurrence that is potentially resectable for cure to identify new metachronous neoplasms at a preinvasive stage

Increased rates of resectability and survival in patients treated for local recurrence and distant metastases of colorectal cancer in more recent years, thereby providing support for more intensive post-treatment follow-up in these patients.

Post-treatment Surveillance
Colonoscopy is recommended at approximately 1 year following resection (or at approximately 3 to 6 months post resection if not performed preoperatively due to an obstructing lesion).
Repeat colonoscopy is typically recommended at 3 years, and then every 5 years thereafter, unless follow-up colonoscopy indicates advanced adenoma. CT scan is recommended to monitor for the presence of potentially resectable metastatic lesions, primarily in the lung and the liver. CT Scan and CEA monitoring should be done from the 1st to 5th years but are not recommended after 5 years.

Post-treatment Surveillance
Initial follow-up office visits at 3 month intervals for history and physical examination may be more useful for patients diagnosed with stage III disease, whereas patients with a diagnosis of stage I disease may not need to be seen as frequently.

Recommendation

First 3 years

Years 4 and 5

Physical Examination Serum CEA Chest and Abdominal CT Scan Follow-up Colonoscopy

q 3-6 months
q 3 months

q 6 months
q 6 months

Annually
3rd Year q 5 years

RECOMMENDATIONS
Patients should undergo regular surveillance for at least 5 years following resection.
American Society of Clinical Oncology (2005)