Clinical and Pathological Overview of Colorectal Carcinoma

Anatomy and Physiology of the Colon and Rectum

The anatomy of the colorectal region is defined by its complex vascular and structural organization. The blood supply involves the transverse, middle hemorrhoidal, and inferior hemorrhoidal arteries. Venous drainage is conducted through the portal vein, superior rectal vein, superior mesenteric vein, inferior mesenteric vein, left colic vein, and sigmoidal veins. Specific anatomical structures include the peritoneal cavity, the peritoneal reflection, and the mesorectal fascia. The rectum is divided into three distinct zones: the low rectum, mid rectum, and high rectum.

The mesorectum (mesoretto) is defined as the cellulo-adipose tissue located between the muscular tunica of the rectum and the visceral layer of the pelvic fascia (fascia recti). This structure is present in the extraperitoneal rectum. Lymphatic drainage within the mesorectum occurs in an upward direction. The lymphatic system is categorized into zones: the upper zone (associated with superior rectal vessels and the inferior mesenteric vessels), the middle zone (associated with internal iliac and middle rectal vessels), and the lower zone (draining toward the inguinal nodes via inferior rectal vessels).

The physiological functions of the colon and rectum are centered on the progression of fecal content, with a transit time ranging from $12$ to $36\,\text{hours}$. Additionally, the colon is responsible for the absorption of water and electrolytes. Its secretory activity includes the production of mucus and immunoglobulins.

Epidemiology of Colorectal Cancer

Colorectal cancer (CRC) represents $99\%$ of all malignant tumors of the colon and rectum. In terms of frequency, it holds the second position following lung cancer in men and breast cancer in women. Regarding mortality, it also ranks second after lung cancer for both sexes. There is a high incidence of CRC in Western countries and urban areas, while low incidence rates are observed in Africa, Asia, and South America. In Italy, the mortality rate is recorded at $15\,\text{deaths}/100,000/\text{year}$. The age group most affected by the disease is between $60$ and $70\,\text{years}$.

Data from the United States indicates a correlation between the increase in screening percentages and the reduction of colorectal cancer rates in adults aged $50$ and over. According to The Economist and the National Cancer Institute (SEER), screening rates rose significantly between $1980$ and $2020$, while cancer rates per $100,000$ population declined from approximately $240$ to below $60$. Recent PubMed trends also highlight a growing research focus on colorectal cancer in young adults from $1964$ to $2024$.

Risk Factors and Heredity

Family history is a significant risk factor; first-degree relatives of individuals with colon cancer have a risk level that is $5$ times higher than the general population. Hereditary syndromes such as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (HNPCC) also significantly increase risk. Dietary factors play a critical role, specifically diets low in fiber and high in animal fats and proteins. These diets lead to prolonged contact between potentially cancerous substances and the mucosa, increased secretion of bile acids (which damage the colonic mucosa), and bacterial proliferation that transforms nitrates into nitrites and nitrosamines. Previous history of colon or breast cancer also increases the likelihood of developing the disease.

Precancerous Lesions and the Adenoma-Carcinoma Sequence

The development of colorectal cancer typically follows the adenoma-carcinoma sequence, a process that generally takes about $10\,\text{years}$. The sequence progresses from normal mucosa to a small adenoma, then to an at-risk adenoma, and finally to cancerized or advanced carcinoma over a period of $7$ to $15\,\text{years}$. This sequence involves various stages: hyperplasia, mild dysplasia, moderate dysplasia, severe polypoid dysplasia, and finally ulcerated adenocarcinoma. Adenomatous polyps may be tubular or villous. Endoscopic polypectomy acts as a primary intervention to interrupt this sequence.

Another major precancerous condition is long-standing Ulcerative Colitis (RCU). The risk of cancer increases with the duration of the disease as follows:

• $10\,\text{years}$: $5\%$ risk
• $20\,\text{years}$: $15\%$ risk
• $30\,\text{years}$: $30\%$ risk
• $35\,\text{years}$: $40\%$ risk

Morbid Anatomy and Histology

Topographically, the most frequent sites for CRC are the rectum and the sigma. However, recent years have shown an increase in localizations within the right colon. Morphologically, the tumors are classified as follows:

• Polypoid or Vegetative ("cauliflower" appearance): Common in the right colon.
• Ulcerated: Common in the rectum.
• Infiltrating or Scirrhous: Common in the left colon and transverse colon.

Histologically, the tumors may be classified as Adenocarcinoma, Mucinous Adenocarcinoma, Adenocarcinoma with Signet Ring Cells (cellule ad anello con castone), Squamos Carcinoma, Adenosquamous Carcinoma, or Undifferentiated Carcinoma.

Pathways of Dissemination

Colorectal cancer spreads through several routes:

• Continuity: Extension through the thickness and along the bowel wall.
• Contiguity: Involvement of adjacent organs, depending on the tumor's location.
• Intraperitoneal Route: Resulting in peritoneal carcinomatosis.
• Lymphatic Route: This is related to the parietal extension of the tumor. It involves epicoloc, paracolic, intermediate, and principal lymph nodes. For low rectal cancer, it involves the mesorectum, hypogastric nodes, and inguinal nodes.
• Hematogenous Route: Metastases are already present in $25\%$ of cases at the time of diagnosis. The most frequent sites for metastasis are the liver and the lungs.

Clinical Presentation and Symptoms

Symptoms of CRC depend on the site, morphology, and stage of the tumor.

In the Right Colon (Non-stenosing), obstructive symptoms appear late. Most common symptoms include diarrhea characterized by mucus and hyperperistalsis, anemia due to chronic occult bleeding (stillicidio), and inflammatory phenomena such as low-grade fever (febbricola), pain, and a palpable mass.

In the Transverse and Left Colon (Stenosing), symptoms appear earlier and include worsening constipation (stipsi ingravescente), "false diarrhea" (due to putrefactive phenomena), and pain on the right side caused by distension of the cecum. Patients may experience painful crises alleviated by the emission of gas. Stools may contain mixed blood and mucus, and a palpable mass (sigma or fecaloma) may sometimes be present.

In the Rectum, symptoms include tenesmus (a frequent urge to defecate), "heavy" pain (dolore gravativo), bright red rectal bleeding (rettorragia), and mucorrhea. For ampullary cancer, there is rapid evolution into stenosis. For sub-ampullary cancer, patients experience perianal pain accentuated by defecation and goat-like or ribbon-like stools (feci caprine o nastriformi) mixed with blood and mucus.

Diagnostic Procedures and Staging

Diagnosis involves a combination of clinical examination and imaging. Initial steps include clinical history (anamnesis) focused on family history, bowel habit alterations, rectal bleeding, mucorrhea, asthenia, and pain. Physical examination includes abdominal palpation (searching for masses, signs of obstruction, or peritonitis) and digital rectal exam (DRE), which can detect vegetative/stenosing neoformations or blood on the glove.

Modern diagnostic tools include:

• Fecal Occult Blood Test (FOBT).
• Double-contrast barium enema (Rx clisma opaco DC), which often shows the classic "apple core" (torsolo di mela) image.
• Virtual Colonoscopy and traditional Colonoscopy with biopsy (the gold standard for diagnosis).
• Abdominal Ultrasound (ETG) and CT scan (TC) with contrast to identify liver metastases.
• For rectal tumors: Pelvic MRI (RM) for local diffusion (T) and lymph node involvement (N), and Transrectal Ultrasound (EUS) for assessing tumor (T) invasion depth.

Complications and Therapeutic Interventions

Colorectal cancer may present initially with complications such as intestinal obstruction, perforation (either at the tumor site or diastasic), hemorrhage, or fistula formation (connecting to the small intestine or bladder).

Radical therapy is surgical and involves colectomies such as:

• Right Hemicolectomy: Includes removal of lymph nodes along the ileo-colic and right colic arteries, followed by ileo-colic anastomosis.
• Transverse Resection.
• Left Hemicolectomy: Includes removal of lymph nodes along the inferior mesenteric artery, followed by colo-rectal anastomosis.
• Anterior Recto-colic Resection.
• Abdominoperineal Resection (Miles procedure): Used for tumors less than $2\,\text{cm}$ from the anal margin or those infiltrating the sphincter apparatus, resulting in a permanent terminal colostomy.

Rectal cancer treatment is stratified by stage:

• T1N0M0 (Submucosa only): Local treatment like Transanal Endoscopic Microsurgery (TEM), which provides full-thickness excision for tumors $<12\,\text{cm}$ from the anal margin.
• T2N0M0 (Invasion of muscularis): Resective surgery.
• T3 or N+ (Invasion of subserosa or node involvement): Neoadjuvant therapy (Chemotherapy + Radiotherapy), followed by restaging and then resective surgery.

Palliative treatments include segmental resection, colostomy, by-pass, and the endoscopic placement of rectal stents.

Prognosis

The 5-year survival rate for colorectal cancer is heavily dependent on the stage at diagnosis:

• $N0, M0$ (No node or distant metastasis): $65-90\%$
• $N1, 2, 3, M0$ (Node involvement, no distant metastasis): $30\%$
• $M1$ (Distant metastasis present): $5\%$