Pathology · Year 2 · from Pathology

Case 1: Colorectal Adenocarcinoma with Multi-Step Carcinogenesis

Patient Demographics

• Age: 58 years old
• Sex: Male
• Occupation: Office manager

Chief Complaint

"Blood in my stool and change in bowel habits for 3 months"

History of Present Illness

A 58-year-old male presents with a 3-month history of intermittent bright red blood mixed with stool. He has noticed a change in bowel habits with alternating constipation and diarrhea, narrower caliber stools, and a sensation of incomplete evacuation. He reports unintentional weight loss of 8 kg over the past 4 months and progressive fatigue. His father was diagnosed with colon cancer at age 62. The patient had never undergone colonoscopy screening.

Physical Examination

• Vital Signs: BP 128/78 mmHg, HR 88 bpm, RR 16/min, Temp 37.1C
• General: Thin male appearing fatigued, no acute distress
• Abdomen: Soft, mild tenderness in left lower quadrant, no palpable masses, no hepatomegaly
• Rectal: Palpable mass on digital rectal examination, guaiac-positive stool
• Lymph nodes: No palpable adenopathy

Diagnostic Workup

Laboratory Studies:

Colonoscopy:

• Large, ulcerated, circumferential mass in the sigmoid colon causing partial luminal obstruction
• Multiple polyps in ascending colon (biopsied)

CT Abdomen/Pelvis:

• 5 cm sigmoid colon mass with extramural extension
• Two hypodense liver lesions (2.1 cm and 1.4 cm) concerning for metastases
• Enlarged pericolonic lymph nodes

Biopsy Pathology:

• Sigmoid mass: Moderately differentiated adenocarcinoma with glandular architecture
• Ascending colon polyps: Tubular adenoma with high-grade dysplasia

Pathology Correlation

This case exemplifies the adenoma-carcinoma sequence of colorectal cancer:

Multi-Step Carcinogenesis:

1. APC gene inactivation (early event) - Loss of tumor suppressor leads to increased beta-catenin and cell proliferation
2. KRAS mutation - Oncogene activation drives adenoma growth
3. SMAD4 loss - Further tumor suppressor inactivation
4. TP53 mutation (late event) - "Guardian of the genome" loss enables genomic instability and invasion

Tumor Characteristics:

• Parenchyma: Neoplastic glandular cells forming irregular, infiltrating glands
• Stroma: Desmoplastic response with fibrosis surrounding tumor glands
• Grade: Moderately differentiated (Grade 2) - maintains some glandular architecture
• Metastasis: Liver metastases via portal venous drainage (common pathway)

Key Hallmarks Demonstrated:

• Sustaining proliferative signaling (KRAS activation)
• Evading growth suppressors (APC, TP53 loss)
• Activating invasion and metastasis
• Inducing angiogenesis

Clinical Image

Gross pathology of colorectal carcinoma showing an ulcerated, infiltrating mass in the colonic wall. The tumor demonstrates raised, rolled edges with central ulceration, consistent with an adenocarcinoma.

Image Source: Wikimedia Commons - "Colon cancer" License: CC BY-SA 3.0 URL: https://commons.wikimedia.org/wiki/File:Colon_cancer_2.jpg

Diagnosis

Stage IV Colorectal Adenocarcinoma (T3N1M1a - liver metastases)

Treatment

1. Molecular profiling (RAS/BRAF status, MSI testing)
2. Neoadjuvant chemotherapy (FOLFOX or FOLFIRI)
3. Consider targeted therapy based on molecular profile:

• Anti-VEGF (bevacizumab) if RAS mutant
• Anti-EGFR (cetuximab) if RAS wild-type

1. Surgical resection of primary tumor if good response
2. Liver-directed therapy for metastases

Teaching Points

1. Multi-step carcinogenesis requires accumulation of multiple genetic alterations over years
2. The adenoma-carcinoma sequence demonstrates progression from benign to malignant
3. Driver mutations (APC, KRAS, TP53) confer growth advantage; passenger mutations accumulate passively
4. Clonal evolution creates tumor heterogeneity and therapy resistance
5. Tumor markers (CEA) are useful for monitoring but not screening
6. Family history increases colorectal cancer risk - screening guidelines recommend colonoscopy at age 45

All cases for this lecture as Markdown