Medical School · Year 2 · Pathology · includes a quiz and discussion video

Lecture 07: Neoplasia - Clinical Aspects

Unit 2.11: Pathology

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe tumor staging systems and their clinical significance
2. Explain tumor markers and their uses
3. Describe paraneoplastic syndromes
4. Explain the epidemiology of cancer
5. Describe cancer screening principles
6. Explain the immune response to tumors

Lecture Outline

I. Tumor Staging

Tumor staging describes the anatomic extent of tumor spread at the time of diagnosis and is the most important prognostic factor for most solid malignancies. The purposes of staging are multifold: it provides prognostic information that helps patients and clinicians understand the expected disease course, it guides treatment decisions by determining whether surgery, systemic therapy, or both are appropriate, it enables standardized communication among healthcare providers, and it allows comparison of outcomes across institutions and clinical trials. Stage at diagnosis correlates strongly with survival, making accurate staging essential for appropriate management.

The TNM system, developed and maintained by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), is the most widely used staging system worldwide. The T category describes the primary tumor based on size and local extent, typically ranging from T1 (small, localized tumor) through T4 (large tumor or invasion of adjacent structures), with T0 indicating no evidence of primary tumor and Tis representing carcinoma in situ. The N category indicates regional lymph node involvement, with N0 indicating no nodal metastases and higher numbers indicating progressively greater nodal disease. The M category denotes distant metastases, with M0 indicating no distant spread and M1 indicating metastatic disease.

The methods used for staging include clinical staging based on physical examination and imaging studies, and pathologic staging based on examination of surgically resected specimens. Clinical staging, designated with the prefix "c," is performed before definitive treatment and guides initial therapy selection. Pathologic staging, designated with the prefix "p," provides more accurate information about tumor extent and is typically performed after surgical resection with histologic examination of the specimen and lymph nodes. Sentinel lymph node biopsy has become standard for many cancers, allowing accurate nodal staging with less morbidity than complete lymph node dissection.

The TNM categories are combined to assign an overall stage, typically expressed as Stage 0 through Stage IV. Stage 0 represents carcinoma in situ, a preinvasive lesion confined to the epithelium without penetration of the basement membrane. Stage I generally indicates a small, localized tumor without nodal or distant spread. Stages II and III represent progressively more advanced locoregional disease with varying combinations of T and N categories. Stage IV indicates distant metastatic disease regardless of T and N status and generally carries the poorest prognosis. The specific criteria for each stage vary by tumor type and are periodically updated as new prognostic information becomes available.

<image>Panel A: The TNM staging system illustrated with a primary tumor showing T categories from Tis through T4 based on size and depth of invasion, with corresponding diagrams for each stage. Panel B: Lymph node staging showing progression from N0 (no nodes) through increasing nodal involvement with regional nodes depicted. Panel C: Stage groupings chart showing how TNM combinations define overall stages I-IV with corresponding five-year survival curves for a representative cancer type. Panel D: Comparison of clinical versus pathologic staging showing how surgical resection and microscopic examination can upstage or downstage tumors.</image>

II. Tumor Grading

Tumor grading is a histopathologic assessment of the degree of differentiation and biologic aggressiveness of a malignancy, distinct from but complementary to staging. Grading is based on microscopic examination of tumor tissue and evaluates how closely the tumor resembles its tissue of origin. Well-differentiated tumors (Grade 1 or low grade) closely resemble normal tissue architecture and cell morphology, while poorly differentiated tumors (Grade 3 or high grade) show little resemblance to normal tissue. Grade 2 tumors represent an intermediate level of differentiation. Some systems include Grade 4 for completely undifferentiated or anaplastic tumors.

The criteria used for grading typically include assessment of tissue architecture, cytologic features, and proliferative activity. Architectural features evaluate how well the tumor maintains the organizational patterns of normal tissue, such as glandular formation in adenocarcinomas. Cytologic features include nuclear pleomorphism, nuclear-to-cytoplasmic ratio, chromatin pattern, nucleolar prominence, and mitotic activity. The mitotic count, often expressed as mitoses per high-power fields, provides a measure of proliferative rate. Necrosis is another factor in some grading systems, as it indicates rapid growth outpacing blood supply.

Specific grading systems have been developed for particular tumor types and may differ from generic grading schemes. The Gleason scoring system for prostate cancer assigns grades from 1 to 5 based on architectural pattern, with the Gleason score being the sum of the primary (most prevalent) and secondary patterns, yielding scores from 2 to 10 (now reported as grade groups 1-5). The Nottingham grading system for breast cancer evaluates tubule formation, nuclear pleomorphism, and mitotic count, each scored 1-3, with the sum determining the grade. The WHO grading system for central nervous system tumors uses grades I-IV, with Grade IV (glioblastoma) being the most aggressive. Soft tissue sarcomas use the FNCLCC grading system based on differentiation, necrosis, and mitotic count.

The distinction between grade and stage is important to understand. Grading reflects the histologic appearance and biologic behavior of the tumor cells themselves, while staging reflects the anatomic extent of disease spread. A tumor can be low grade (well-differentiated) but high stage (widely metastatic), or high grade (poorly differentiated) but low stage (localized). Both grade and stage provide independent prognostic information, and both are routinely reported in pathology reports to guide treatment and predict outcomes. For some tumors, grade may influence treatment selection independent of stage.

<image>Panel A: Tumor grading comparison showing Grade 1 (well-differentiated with recognizable glandular structures), Grade 2 (moderately differentiated), and Grade 3 (poorly differentiated with minimal tissue architecture) adenocarcinoma. Panel B: Gleason scoring system for prostate cancer showing architectural patterns 1-5 with examples of Gleason 6, 7, and 9 tumors. Panel C: Nottingham grading for breast cancer showing the three components - tubule formation, nuclear pleomorphism, and mitotic count - and how they combine into overall grade. Panel D: Comparison of grade versus stage showing that these are independent prognostic factors that together inform prognosis and treatment.</image>

III. Tumor Markers

Tumor markers are substances produced by tumor cells or by the host in response to tumors that can be measured in blood or other body fluids to provide information about cancer presence, prognosis, or response to treatment. The clinical uses of tumor markers include monitoring response to therapy (the most common and reliable application), detecting recurrence after treatment, supporting diagnosis in the appropriate clinical context, and providing prognostic information. Importantly, tumor markers are generally not recommended for population screening due to limited sensitivity and specificity, with a few notable exceptions.

Serum tumor markers include carcinoembryonic antigen (CEA), which is elevated in colorectal cancer and other adenocarcinomas and is most useful for monitoring response to treatment and detecting recurrence. Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma and germ cell tumors, particularly yolk sac tumors. Prostate-specific antigen (PSA) is organ-specific but not cancer-specific, elevated in prostate cancer but also in benign prostatic hyperplasia and prostatitis. CA-125 is elevated in ovarian cancer but also in various benign conditions including endometriosis. CA 19-9 is elevated in pancreatic and biliary cancers. Beta-human chorionic gonadotropin (beta-hCG) is elevated in germ cell tumors and choriocarcinoma.

The limitations of serum tumor markers must be understood for appropriate clinical use. Most tumor markers lack sufficient sensitivity and specificity for screening asymptomatic populations. Elevated levels may occur in benign conditions, leading to false-positive results and unnecessary invasive procedures. Normal levels do not exclude cancer, as early-stage tumors may not produce detectable marker elevations. Marker levels may be affected by factors unrelated to tumor burden, including renal function, liver function, and other medical conditions. Despite these limitations, tumor markers remain valuable for monitoring disease in patients with known cancer.

Molecular markers represent a newer category of tumor markers that provide information about specific genetic alterations with therapeutic implications. HER2 amplification in breast cancer predicts response to trastuzumab and other HER2-targeted therapies. EGFR mutations in lung adenocarcinoma predict response to EGFR tyrosine kinase inhibitors. BRCA1/2 mutations identify candidates for PARP inhibitor therapy. Microsatellite instability (MSI) or mismatch repair deficiency predicts response to immune checkpoint inhibitors. PD-L1 expression is used to select patients for checkpoint inhibitor therapy in several cancer types. These molecular markers have transformed cancer treatment by enabling precision medicine approaches.

<image>Panel A: Common serum tumor markers showing PSA (prostate), CEA (colorectal), AFP (liver, germ cell), CA-125 (ovarian), CA 19-9 (pancreatic), and beta-hCG (germ cell) with their associated cancers and monitoring applications. Panel B: Graph showing tumor marker kinetics during treatment with declining levels indicating response and rising levels indicating recurrence. Panel C: Molecular markers and their therapeutic implications including HER2, EGFR, BRCA, MSI, and PD-L1 with corresponding targeted therapies. Panel D: Algorithm showing appropriate versus inappropriate use of tumor markers in screening, diagnosis, and monitoring contexts.</image>

IV. Paraneoplastic Syndromes

Paraneoplastic syndromes are clinical manifestations of cancer that are not caused by direct tumor invasion or metastasis but rather by tumor production of hormones, cytokines, or immunologic cross-reactivity between tumor and host tissues. These syndromes affect approximately 10-15% of cancer patients and may be the first manifestation of an underlying malignancy, sometimes preceding diagnosis by months to years. Recognition of paraneoplastic syndromes is important because they may provide the first clue to an occult cancer, they can cause significant morbidity, and their severity often parallels tumor burden, improving with successful cancer treatment.

Endocrine paraneoplastic syndromes result from ectopic hormone production by tumor cells. Hypercalcemia of malignancy is the most common, caused by tumor production of parathyroid hormone-related peptide (PTHrP) in squamous cell carcinomas, breast cancer, and renal cell carcinoma. Cushing syndrome results from ectopic ACTH production, most commonly by small cell lung carcinoma. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion causes hyponatremia and is also associated with small cell lung cancer. Hypoglycemia can result from tumor production of insulin-like growth factors, particularly in fibrosarcoma and hepatocellular carcinoma.

Neurologic paraneoplastic syndromes are often antibody-mediated, with autoantibodies directed against neural antigens that are also expressed by the tumor. Lambert-Eaton myasthenic syndrome, caused by antibodies against voltage-gated calcium channels, is associated with small cell lung cancer and manifests as proximal muscle weakness that improves with repeated use (unlike myasthenia gravis). Paraneoplastic cerebellar degeneration, associated with anti-Yo antibodies, occurs with ovarian and breast cancers. Limbic encephalitis, associated with anti-Hu antibodies, causes memory loss, seizures, and psychiatric symptoms in patients with small cell lung cancer. Peripheral neuropathies can occur with various tumors through multiple antibody-mediated mechanisms.

Other paraneoplastic syndromes include Trousseau syndrome, a migratory superficial thrombophlebitis that classically occurs with mucin-secreting adenocarcinomas, particularly pancreatic cancer. Acanthosis nigricans, velvety hyperpigmented skin typically in flexural areas, is associated with gastric carcinoma when it develops in an adult without insulin resistance. Dermatomyositis, characterized by proximal muscle weakness and heliotrope rash around the eyes, is associated with various internal malignancies in adults. Hypertrophic osteoarthropathy, featuring clubbing and painful periosteal new bone formation, is associated with lung cancer. These syndromes demonstrate the diverse systemic effects that cancers can produce through non-metastatic mechanisms.

<image>Panel A: Endocrine paraneoplastic syndromes showing hypercalcemia from PTHrP, Cushing syndrome from ectopic ACTH, and SIADH from ADH production, with associated tumor types for each. Panel B: Neurologic paraneoplastic syndromes illustrating Lambert-Eaton syndrome (calcium channel antibodies), cerebellar degeneration (anti-Yo), and limbic encephalitis (anti-Hu) with their clinical features. Panel C: Mucocutaneous paraneoplastic syndromes showing acanthosis nigricans, dermatomyositis with heliotrope rash, and clubbing with hypertrophic osteoarthropathy. Panel D: Trousseau syndrome showing migratory thrombophlebitis associated with mucin-secreting adenocarcinoma and the underlying pathophysiology.</image>

V. Local and Systemic Effects of Cancer

The local effects of tumors result from mass effect, invasion of adjacent structures, and disruption of normal tissue function. Mass effect causes compression of surrounding tissues and obstruction of hollow structures, such as bowel obstruction from colorectal carcinoma or biliary obstruction from pancreatic cancer. Ulceration of tumor surfaces can cause bleeding, which may be occult (as in gastrointestinal cancers causing anemia) or clinically apparent. Pain results from invasion of sensory nerves, stretching of organ capsules, or involvement of bone. Organ dysfunction occurs when tumor replaces or destroys functional parenchyma, as in hepatic failure from extensive liver metastases.

Cancer cachexia is a complex metabolic syndrome characterized by progressive loss of skeletal muscle mass (with or without fat loss) that cannot be fully reversed by conventional nutritional support. Cachexia affects up to 80% of patients with advanced cancer and is associated with reduced treatment tolerance, decreased quality of life, and shortened survival. The pathophysiology involves tumor-derived factors and host inflammatory mediators including tumor necrosis factor (TNF-alpha, originally called cachectin), interleukin-1, and interleukin-6 that alter metabolism, promote muscle protein breakdown, and suppress appetite. Cachexia is notoriously difficult to treat, as simple nutritional supplementation is largely ineffective.

Anemia is common in cancer patients and can result from multiple mechanisms. Anemia of chronic disease develops through cytokine-mediated effects on iron metabolism, with hepcidin elevation causing iron sequestration in macrophages. Bone marrow infiltration by tumor cells (myelophthisic anemia) directly suppresses normal hematopoiesis. Blood loss, particularly from gastrointestinal tumors, causes iron deficiency anemia. Microangiopathic hemolytic anemia occurs when red blood cells are fragmented passing through abnormal tumor vasculature. Treatment-related anemia from chemotherapy-induced myelosuppression is also common.

Fever in cancer patients may result from tumor-related factors or intercurrent infections. Tumor-associated fever results from cytokine release, particularly IL-1 and IL-6, and is common in lymphomas, renal cell carcinoma, and hepatocellular carcinoma. However, fever in cancer patients must prompt evaluation for infection, as immunocompromise from the cancer itself or its treatment increases susceptibility to bacterial, viral, and fungal pathogens. Tumor necrosis can also cause fever as breakdown products stimulate inflammatory responses. The workup of fever in a cancer patient requires consideration of both infectious and non-infectious etiologies.

<image>Panel A: Local effects of tumors showing mass effect causing obstruction (bowel, biliary), invasion causing nerve compression and pain, ulceration causing hemorrhage, and organ replacement causing dysfunction. Panel B: Cancer cachexia pathophysiology showing tumor-derived factors and host cytokines (TNF, IL-1, IL-6) leading to muscle wasting, anorexia, and metabolic changes. Panel C: Mechanisms of cancer-associated anemia including anemia of chronic disease (hepcidin pathway), bone marrow infiltration, blood loss, and microangiopathic hemolysis. Panel D: Algorithm for evaluation of fever in cancer patient considering tumor-associated fever, infection, and drug reaction with appropriate diagnostic workup.</image>

VI. Cancer Epidemiology

Cancer incidence and mortality vary by cancer type, sex, age, and geographic region, reflecting the complex interplay of genetic susceptibility and environmental exposures. In the United States, prostate cancer is the most commonly diagnosed cancer in men, while breast cancer is most common in women. However, lung cancer remains the leading cause of cancer death in both sexes, reflecting its poor prognosis compared to prostate and breast cancers. Colorectal cancer is the third most common cancer in both men and women. Understanding these patterns informs public health priorities and resource allocation for prevention and early detection.

Age is the strongest risk factor for most cancers, with incidence increasing dramatically after age 50 for most solid tumors. This age-related increase reflects the accumulation of somatic mutations over time and the multistep nature of carcinogenesis. However, certain cancers have distinct age distributions. Childhood cancers are predominantly leukemias, brain tumors, and embryonal tumors such as neuroblastoma. Testicular cancer and Hodgkin lymphoma peak in young adults. Bone sarcomas have a bimodal distribution with peaks in adolescence and elderly patients. Most carcinomas increase progressively with age.

Geographic variation in cancer incidence provides important clues about environmental and lifestyle risk factors. Gastric cancer has historically been very common in Japan and Korea, likely related to dietary factors including high salt intake and infection with Helicobacter pylori. Hepatocellular carcinoma is common in Asia and sub-Saharan Africa due to high prevalence of hepatitis B and aflatoxin exposure. Cervical cancer remains common in developing countries where HPV vaccination and screening programs are less available. Colorectal cancer is more common in Western countries, associated with diet high in red meat and low in fiber. Migration studies demonstrate that cancer patterns change when populations move to new environments, supporting the importance of environmental factors.

The major modifiable risk factors for cancer include tobacco use, which accounts for approximately 30% of all cancer deaths and is causally linked to lung, bladder, pancreatic, head and neck, and many other cancers. Obesity is associated with increased risk of breast, colon, endometrial, and several other cancers. Alcohol consumption increases risk of liver, esophageal, and head and neck cancers, with synergistic effects when combined with tobacco. Diet, including high red meat consumption and low fruit and vegetable intake, influences colorectal and other cancer risks. Infectious agents including HPV, H. pylori, and hepatitis viruses cause approximately 15-20% of cancers worldwide. Understanding these risk factors enables prevention strategies.

<image>Panel A: Cancer incidence and mortality graphs for the United States showing most common cancers (prostate, breast, lung, colorectal) and leading causes of cancer death with lung cancer at top for both sexes. Panel B: Age-specific cancer incidence showing the dramatic rise after age 50 for most solid tumors, with specific cancers showing childhood or young adult peaks. Panel C: World map showing geographic variation in cancer incidence with high gastric cancer in Asia, high liver cancer in Africa and Asia, and high colorectal cancer in Western countries. Panel D: Pie chart of modifiable risk factors showing tobacco, obesity, alcohol, diet, and infections as major contributors to cancer burden with prevention strategies for each.</image>

VII. Cancer Screening

Cancer screening aims to detect cancer at an early, potentially curable stage in asymptomatic individuals before symptoms develop. Effective screening programs must satisfy several criteria: the target disease must be common and have a significant disease burden, there must be a recognizable preclinical phase during which the disease can be detected, the screening test must be acceptable, safe, and accurate, and early detection must improve outcomes compared to waiting for symptomatic presentation. Additionally, the benefits of screening must outweigh the harms, which include false-positive results, overdiagnosis, and complications of diagnostic procedures.

Current evidence-based screening recommendations include mammography for breast cancer, which is recommended every one to two years for women aged 50-74, with earlier initiation and more frequent screening considered for high-risk women. Cervical cancer screening with Pap smear and/or HPV testing is recommended for women aged 21-65, with screening intervals depending on age and test type. Colorectal cancer screening is recommended starting at age 45, with various options including colonoscopy, fecal immunochemical testing (FIT), and other modalities. Low-dose CT screening for lung cancer is recommended for adults aged 50-80 with significant smoking history. PSA-based prostate cancer screening is a shared decision-making process given the balance of potential benefits and harms.

The metrics used to evaluate screening tests include sensitivity (the proportion of people with disease who test positive), specificity (the proportion of people without disease who test negative), positive predictive value (the probability that a positive test result represents true disease), and negative predictive value (the probability that a negative test result correctly excludes disease). Positive predictive value is strongly influenced by disease prevalence in the screened population, which is why screening is most effective for relatively common cancers in appropriate risk groups.

Several biases can affect the apparent effectiveness of screening programs. Lead time bias creates the appearance of longer survival simply because disease is detected earlier, without actually extending life. Length time bias occurs because screening preferentially detects slower-growing tumors, which inherently have better prognosis. Overdiagnosis refers to the detection of cancers that would never have caused symptoms or death during the patient's lifetime, exposing patients to the harms of treatment without benefit. These biases underscore the importance of randomized controlled trials with mortality endpoints to establish screening effectiveness, rather than relying solely on observed survival improvements.

<image>Panel A: Criteria for effective cancer screening programs showing disease characteristics (common, detectable preclinical phase), test characteristics (safe, accurate, acceptable), and outcome requirement (early detection improves survival). Panel B: Current recommended cancer screening tests showing mammography (breast), Pap/HPV (cervical), colonoscopy/FIT (colorectal), and low-dose CT (lung) with target populations and intervals. Panel C: Sensitivity, specificity, PPV, and NPV definitions illustrated with 2x2 table and formulas, showing how prevalence affects PPV. Panel D: Screening biases illustrated showing lead time bias (earlier detection without survival benefit), length time bias (slow-growing tumors preferentially detected), and overdiagnosis (detecting inconsequential cancers).</image>

VIII. Cancer Immunology

The immune system plays a complex role in cancer, capable of both recognizing and eliminating tumor cells and inadvertently promoting tumor growth through inflammation. Tumor antigens are molecules that can be recognized by the immune system and potentially targeted for immune destruction. Tumor-specific antigens (neoantigens) are unique to tumor cells and arise from somatic mutations that create novel epitopes. Tumor-associated antigens are normal proteins that are overexpressed, aberrantly expressed, or differentially expressed on tumor cells, including oncofetal antigens like CEA and AFP, cancer-testis antigens, and differentiation antigens like tyrosinase in melanoma.

The immune cells capable of anti-tumor activity include CD8-positive cytotoxic T lymphocytes (CTLs), which recognize tumor antigens presented on MHC class I molecules and kill tumor cells through perforin-granzyme mechanisms and death receptor pathways. Natural killer (NK) cells kill tumor cells that have downregulated MHC class I expression, providing a backup mechanism when tumors evade CTL recognition. Macrophages can be polarized toward anti-tumor (M1) or pro-tumor (M2) phenotypes depending on the cytokine milieu. Helper T cells coordinate the anti-tumor response through cytokine production. Antibodies can contribute through antibody-dependent cellular cytotoxicity (ADCC) and complement activation.

Tumors evade immune destruction through multiple mechanisms. Antigen loss variants emerge under selective pressure from immune attack, as tumor cells lacking immunogenic antigens survive while those expressing them are eliminated. MHC class I downregulation prevents CTL recognition of tumor antigens. Tumors secrete immunosuppressive factors including TGF-beta and IL-10 that suppress anti-tumor immunity. Recruitment of immunosuppressive cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) creates an immunosuppressive tumor microenvironment. Upregulation of immune checkpoint molecules, particularly PD-L1, directly inhibits T cell function.

The theory of cancer immunosurveillance proposes that the immune system constantly identifies and eliminates nascent tumor cells, with clinical cancer developing only when tumors successfully evade immune control. Evidence supporting immunosurveillance includes the increased cancer incidence in immunosuppressed individuals (transplant recipients, HIV/AIDS patients) and the presence of tumor-infiltrating lymphocytes in many cancers, which often correlates with better prognosis. The three Es model describes cancer immunoediting as proceeding through Elimination (immune system destroys tumor cells), Equilibrium (balance between immune control and tumor growth), and Escape (tumor evades immune control and grows progressively).

<image>Panel A: Types of tumor antigens showing tumor-specific antigens (neoantigens from mutations), tumor-associated antigens (overexpressed or aberrantly expressed normal proteins), and oncofetal antigens (CEA, AFP) with examples. Panel B: Immune cells in anti-tumor immunity showing CD8+ CTLs, NK cells, M1 macrophages, and helper T cells with their mechanisms of tumor cell killing. Panel C: Tumor immune evasion mechanisms including antigen loss, MHC downregulation, immunosuppressive cytokines (TGF-beta, IL-10), checkpoint molecule expression (PD-L1), and recruitment of Tregs and MDSCs. Panel D: Cancer immunoediting diagram showing the three Es - Elimination, Equilibrium, and Escape - as sequential phases of tumor-immune interaction.</image>

IX. Cancer Immunotherapy

Immune checkpoint inhibitors have revolutionized cancer treatment by releasing the brakes on anti-tumor T cell responses. PD-1 (programmed cell death protein 1) is expressed on activated T cells and, when bound by its ligand PD-L1, delivers an inhibitory signal that suppresses T cell activity. Tumors exploit this pathway by expressing PD-L1, thereby evading immune attack. Antibodies blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab) prevent this inhibitory signal and restore anti-tumor T cell function. CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is another checkpoint molecule that inhibits T cell activation; ipilimumab blocks CTLA-4 to enhance T cell priming and activation.

The clinical efficacy of checkpoint inhibitors varies by tumor type, with the highest response rates in tumors with high mutation burden (and therefore more neoantigens), such as melanoma, non-small cell lung cancer, and microsatellite instability-high tumors. A distinctive feature of checkpoint inhibitor responses is their durability, with some patients achieving long-lasting remissions lasting years. However, not all patients respond, and predictive biomarkers are needed to identify those most likely to benefit. Current biomarkers include PD-L1 expression (though imperfect), tumor mutational burden, and microsatellite instability status. Immune-related adverse events, resulting from loss of normal immune tolerance, include colitis, hepatitis, pneumonitis, and endocrinopathies.

Chimeric antigen receptor T cell (CAR-T) therapy represents a highly personalized approach in which a patient's T cells are collected, genetically engineered to express a chimeric antigen receptor targeting a tumor antigen, expanded in culture, and reinfused. The most successful applications target CD19 in B-cell malignancies, with remarkable response rates in relapsed/refractory acute lymphoblastic leukemia and certain lymphomas. CAR-T therapy can cause cytokine release syndrome (CRS), a potentially severe systemic inflammatory response, and neurotoxicity. The therapy is currently limited by the need for identifiable target antigens, manufacturing complexity, and the immunosuppressive tumor microenvironment of solid tumors.

Cancer vaccines aim to stimulate or enhance anti-tumor immune responses. Preventive vaccines targeting oncogenic viruses (HPV vaccine, hepatitis B vaccine) prevent virus-associated cancers and represent one of the most successful applications of cancer immunology. Therapeutic vaccines aim to treat existing cancers by enhancing immunity against tumor antigens. Sipuleucel-T, a dendritic cell vaccine for prostate cancer, modestly improves survival but is complex and expensive. Personalized neoantigen vaccines, based on sequencing of individual tumors to identify unique mutations, are under active investigation and represent a promising frontier in precision immunotherapy.

<image>Panel A: Checkpoint inhibitor mechanism showing PD-1/PD-L1 interaction suppressing T cell activity, and antibody blockade restoring anti-tumor T cell function, with similar diagram for CTLA-4 pathway. Panel B: CAR-T cell therapy process showing T cell collection, genetic engineering to express chimeric antigen receptor, expansion, and reinfusion, with illustration of CAR structure. Panel C: Predictive biomarkers for checkpoint inhibitor response including PD-L1 expression, tumor mutational burden, and microsatellite instability, with corresponding patient selection algorithms. Panel D: Cancer vaccines showing preventive vaccines (HPV, HBV), therapeutic approaches (sipuleucel-T, neoantigen vaccines), and their mechanisms of action.</image>

X. Laboratory Diagnosis of Cancer

Histopathology remains the gold standard for cancer diagnosis, providing definitive classification of tumor type, grade, and other features essential for treatment planning. Standard hematoxylin and eosin (H&E) staining allows assessment of tissue architecture and cytologic features. Frozen section examination provides rapid intraoperative diagnosis to guide surgical decision-making, though with somewhat reduced quality compared to permanent sections. Special stains can highlight specific tissue components: mucin stains detect mucin-producing adenocarcinomas, and melanin stains identify melanoma. Pathologic examination of surgical resection specimens provides staging information and assesses completeness of excision.

Immunohistochemistry (IHC) uses antibodies to detect specific proteins in tissue sections, aiding in tumor classification and providing prognostic and predictive information. Cytokeratins identify epithelial tumors (carcinomas), while desmin and smooth muscle actin identify muscle tumors. S-100 protein is expressed in neural tumors and melanoma. CD markers help classify lymphomas and other hematopoietic malignancies. In breast cancer, IHC for estrogen receptor (ER), progesterone receptor (PR), and HER2 provides essential information for treatment selection. TTF-1 and napsin A help identify lung adenocarcinoma, while p40 identifies squamous cell carcinoma. These markers are indispensable for accurate tumor classification.

Molecular diagnostics have become integral to cancer diagnosis and treatment planning. Fluorescence in situ hybridization (FISH) detects chromosomal translocations, gene amplifications, and deletions, such as HER2 amplification in breast cancer and BCR-ABL fusion in chronic myeloid leukemia. Polymerase chain reaction (PCR) methods detect specific mutations, such as EGFR mutations in lung cancer. Next-generation sequencing (NGS) enables comprehensive profiling of tumor genomes, identifying multiple actionable mutations simultaneously. Liquid biopsy analyzes circulating tumor DNA (ctDNA) in blood, enabling non-invasive tumor profiling and monitoring.

Cytology provides a less invasive alternative to tissue biopsy in appropriate settings. Fine needle aspiration (FNA) is commonly used for thyroid nodules and accessible lymph nodes, providing rapid diagnosis with minimal morbidity. Exfoliative cytology, exemplified by the Pap smear, detects abnormal cells shed from epithelial surfaces. Body fluid cytology examines pleural, peritoneal, and cerebrospinal fluid for malignant cells. Cytologic specimens can also be used for ancillary studies including cell blocks for IHC and molecular testing. The main limitation of cytology is the smaller sample size, which may limit assessment of tissue architecture and adequacy for molecular testing.

<image>Panel A: Histopathologic workflow showing tissue processing, H&E staining, and microscopic examination with examples of adenocarcinoma, squamous cell carcinoma, and melanoma appearances. Panel B: Immunohistochemistry panel showing cytokeratins for carcinomas, CD markers for lymphomas, S-100 for melanoma, and ER/PR/HER2 for breast cancer with clinical implications. Panel C: Molecular diagnostic techniques including FISH for translocations and amplifications, PCR for mutations, and NGS for comprehensive profiling, with examples of actionable targets. Panel D: Cytology techniques showing fine needle aspiration procedure, Pap smear collection, and body fluid cytology with characteristic cellular features of malignancy.</image>

Summary

• Staging (TNM system) describes anatomic extent of disease and is the most important prognostic factor; combines T (primary tumor), N (nodes), and M (metastases) into stages I-IV
• Grading assesses histologic differentiation; distinct from but complementary to staging; specific systems exist for prostate (Gleason), breast (Nottingham), and CNS tumors
• Tumor markers are most useful for monitoring treatment response and detecting recurrence; PSA, CEA, AFP, CA-125, CA 19-9 have specific associations
• Molecular markers (HER2, EGFR, BRCA, MSI) guide targeted therapy selection
• Paraneoplastic syndromes result from ectopic hormone production (hypercalcemia, Cushing, SIADH) or antibody-mediated effects (Lambert-Eaton, cerebellar degeneration)
• Cachexia is cytokine-mediated wasting; cancer anemia results from chronic disease, marrow infiltration, or blood loss
• Cancer epidemiology shows lung cancer as leading cause of death; tobacco accounts for 30% of cancer deaths
• Screening benefits must outweigh harms; mammography, Pap/HPV, colonoscopy, and low-dose CT are evidence-based
• Tumor immunity involves CTLs, NK cells; tumors evade through antigen loss, MHC downregulation, PD-L1 expression
• Immunotherapy includes checkpoint inhibitors (anti-PD-1, anti-CTLA-4) and CAR-T cells; cancer diagnosis uses histology, IHC, and molecular testing

Key Terms

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