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Chapter 1 Introduction to Pathophysiology; Cellular Responses to Stress, Injury, and Aging

Section 4 Cellular Change in Disease

Zoë Soon

Biopsies allow for the microscopic analysis of cells and tissues – known as cell morphology or the study of structure, shape, and arrangement of cells.  This is essential for detecting signs of disease and determining the cause and extent of disease progression.  Each of the 200+ human cell types has a typical diameter, shape, and set of organelles within the normal, healthy range.

Atrophy

Atrophy is the shrinkage of cells below their normal size.  The prefix a- means ‘without’ and tropy means ‘growth’.  At least seven causes of skeletal muscle atrophy have been identified:

  • Bed rest:  Muscles not used due to prolong immobility begin to shrink – a ‘use it or lose it’ phenomenon.
  • Casting:  Restraint of a limb (e.g., when a bone is broken) prevents muscle use, leading to atrophy visible when the cast is removed.
  • Low-gravity environments: Astronauts experience muscle atrophy because their muscles are nor required to generate as much force in microgravity.
  • Reduced neural input:  Nerve damage such as in spinal cord injuries (e.g., paraplegia or quadriplegia) severs the neural connections to muscles, which then atrophy without stimulation.
  • Poor nutrition / starvation: Without adequate dietary nutrients, cells lack the building blocks for growth and maintenance.
  • Ischemia:  Poor blood flow (from the Greek ischein ‘hold back’ + haima ‘blood’) means reduced nutrient and oxygen delivery, coupled with lowered waste removal, impairs cell function and maintenance.
  • Reduced hormones:  With aging, the body produces less estrogen, testosterone, and growth hormone, leading to reduced cellular stimulation and noticeable atrophy of muscle, bone, and other tissues.

Hypertrophy:  Physiologic vs. Pathologic

Hypertrophy is the opposite of atrophy – it refers to an increase in cell size.  The prefix hyper- means ‘more’.

Physiologic Hypertrophy Normal, healthy cell growth in response to increased demand.  Example:  skeletal muscle hypertrophy during exercise training, as cells produce more contractile proteins (myosin, actin) and increase in diameter and strength.
Pathologic Hypertrophy Cell enlargement caused by disease.  Example:  in heart disease and hypertension, the heart’s ventricular muscle must work harder to pump blood through damaged or narrowed vessels, leading to ventricular wall hypertrophy.  Unlike physiologic hypertrophy, this change is detrimental – the heart’s shape becomes less efficient at pumping blood, signalling deterioration.

 

 

Figure: Skeletal muscle physiologic hypertrophy
Difference between a normal muscle and an atrophied muscle

Athlete’s Heart:  Exercise-Induced Cardiac Remodeling

Both resistance and cardiovascular training cause beneficial cardiac remodeling, but in distinct ways:

Resistance training:  Ventricular wall thickness increases (without major increase in fill volume), helping the heart generate more pressure to pump blood through compressed vessels during weightlifting.

Cardiovascular (aerobic training):  Both wall thickness and fill volume increase, allowing the heart to send larger volumes of blood per beat – reducing the need for a rapid heart rate during long-duration events like marathons.

In both forms of training, progenitor cells are activated, meaning hyperplasia (increased cell number through cell division) in addition to the cellular hypertrophy is contributing to heart enlargement (physiologic cardiac hypertrophy).  Importantly, both adaptions are reversible – if training stops, the cellular changes reverse.

 

Figure: Exercise-induced cardiac growth. Aerobic and resistance exercise elicit different forms of physiological cardiac remodeling. Hypertrophic responses are primarily eccentric in nature for aerobic exercise and concentric in nature for resistance exercise.  Heart remodeling is beneficial in athletes in that it helps to deliver more blood to the working tissues of the body per minute during exercise.  Blood delivery of oxygen and nutrients supports increased ATP production required during muscle activity. LA, left atrium; LV, left ventricle; LVWT, left ventricular wall thickness; RA, right atrium; RV, right ventricle.
Figure: Pathologic hypertrophy of the heart due to cardiomyopathy (a disease that affects the myocardium).

 

 

 

 

 

 

 

 

 

 

Hyperplasia

Hyperplasia refers to an increase in cell number due to mitosis (cell division).  The suffix -plasis, comes from the Greek word meaning ‘formation’.  As with hypertrophy, hyperplasia can be physiologic or pathologic.

Physiologic Hyperplasia Normal growth occurring, for example, during childhood development (from embryo through to adulthood), or during pregnancy (growth of the uterus, breasts, and other supportive tissues).
Pathologic Hyperplasia Usually caused by a disease creating a hormonal imbalance that drives excess cell division.  It can also lead to the formation of a benign tumor, which may be surgically removed if it causes clinical manifestations.

Metaplasia

Metaplasia (from Greek: ‘change form’) occurs when one cell type replaces another in response to chronic irritation, producing a more resilient but less functional tissue.

Examples: Smoker’s Trachea

Under normal conditions, the trachea (windpipe) is lined with simple pseudostratified columnar ciliated epithelial cells and mucus-secreting Goblet cells.  Cilia sweep mucus and trapped pathogens upward to be swallowed and eliminated.

In a long-term smoker, this tissue is perpetually damaged by smoke and remodels itself into stratified squamous epithelium with no cilia and fewer Goblet cells.  This new tissue is more resistant to smoke, but far less functional:  mucus production decreases and cilia are absent, requiring the smoker to rely on coughing to clear the airway – the well-known ‘smoker’s cough’.  Metaplasia is thought to be reversible if the irritant is removed.

 

In the figure, the artist has illustrated some of the non-cancerous (non-neoplastic) cell morphology and growth pattern changes that can occur.  So let’s go through them one at a time. First of all, you will notice that the normal cells have been drawn to resemble stratified (many layer) cuboidal epithelial cells.  Each of these cells contains one purple nucleus. Okay, notice this is our starting point. Each human cell type has a typical diameter, shape, and set of organelles which would be considered to fall in the normal, healthy range. If a biopsy was taken and the cells examined were much smaller than expected, we would conclude that these cells had shrunk, and would say that there has been some atrophy.

Dysplasia, Anaplasia, and Neoplasia

Dysplasia Literally ‘bad growth’ (dys- = bad).  Cell shapes change and cells become less functional and de-differentiated (more immature).  Dysplastic cells are considered pre-cancerous.  If the irritant is removed and normal gene expression resumes, dysplastic cells may revert to normal.
Anaplasia Completely de-differentiated, non-functional cells that have entered a state of uncontrollable, continuous cell division.  Anaplastic cells are often immortal.
Neoplasia A ‘new growth’ or tumor produced by the accumulation of anaplastic cells  Can be benign (non-cancerous, confined within the basement membrane) or malignant (cancerous, capable of breaching the basement membrane, spreading through blood or lymph vessels and infiltrating other tissues.
Carcinoma in situ A pre-malignant state in which the basement membrane remains intact.  Most carcinomas in situ eventually progress to become malignant.

The typical sequence of changes is:  Normal → Dysplasia (reversible if the irritant is removed) → Anaplasia → Neoplasm (benign or malignant).  If malignant cancerous cells breach the basement membrane, they can enter blood or lymph vessels, spread to distant sites, form secondary cancers, and if untreated, cause multi-organ failure.  

 

Figure: Cell morphology changes during the development of a tumor, which may be benign (noncancerous and non-spreading) or malignant (cancerous).
Figure: Benign Tumour consists of dysplastic cells contained within a capsule, with cells not breaching through the basement membrane. Malignant Tumour consists of anaplastic cells that have breached the basement membrane and are spreading into neighbouring tissues.

 

Figure: Cell morphology and cell number changes during the development of cancer.

 

 

 

Figure: Cancer invasion is the first step of the metastatic cascade. Tumour cells penetrate the basement membrane and invade the surrounding tissues using two modes of movement—individual and collective invasion. Invading tumour cells reach the blood vessel, enter the blood flow and disseminate, eventually giving rise to secondary tumours.

Causes of Dysplasia and Cancer:  Three Examples

1. Smoking and Lung Cancer

Smoking causes persistent irritation to cells within the respiratory tract and is the leading cause of lung cancer.  It is also a risk factor for several other cancers.

 

2. UV Light and Skin Cancer

Ultraviolet (UV) light causes DNA mutations in skin cells and is the leading risk facto for the most common forms of skin cancer, including basal cell carcinoma, squamous cell carcinoma and melanoma

 

3. Human Papilloma Virus (HPV) and Cervical Cancer

Several strains of Human Papilloma Virus (HPV) are known oncoviruses (viruses that can cause cancer).  Some HPV strains are risk factors for cervical cancer, penile cancer and cancers of the mouth, throat, anus, and vagina; other stains cause genital or skin warts.  HPV is transmitted skin-to-skin contact, including sexually.

Figure 1. Stages of morphological cellular adaptations and molecular changes leading to lung cancer. Representative illustration highlighting morphological alterations of the epithelial cells during the gradual transition towards lung cancer and key molecular alterations contributing to this process.
Figure 1. Stages of morphological cellular adaptations and molecular changes leading to lung cancer. Representative illustration highlighting morphological alterations of the epithelial cells during the gradual transition towards lung cancer and key molecular alterations contributing to this process.

 

Figure: The skin is comprised of 3 main layers: the epidermis, dermis and subcutaneous fat. UV light from the sun can penetrate the skin and damage DNA in the nucleus of skin cells. If the cells are not able to repair this damage, or repair it improperly, it can lead to uncontrolled cell growth and formation of a tumor. A tumor is considered cancerous when it is able to metastasize, or grow outside of its normal tissue. Developing skin cancer is more likely to happen with more or more frequent sun exposure, sunburns, or with age, as the cells lose their ability to repair DNA because there is too much or too repeated damage. Wearing sunscreen can help shield your skin cells from UV light and can help prevent skin cancer

HPV Vaccination and Cervical Screening in Canada

In Canada, the HPV vaccine is available for youth and is ideally given prior to sexual activity – when the risk of viral exposure is lowest.  Early detection of cervical cancer is critical for a better prognosis and the following screening protocol is recommended:

Pap smear (Papanicolaou test): Cervical cells are scraped and examined under a microscope for abnormal morphology.  Recommended every 2-3 years after an individual becomes sexually active (as per physician recommendation).  Named after Dr. Georgios Papanikolaou, who developed this test in 1923.

HPV testing:  An emerging approach adds Primary HPV testing (a highly sensitive DNA test for high-risk HPV stains) as a first step, followed by the Pap smear (cytology), and then colposcopy (a specificity test) when abnormal cells are detected.  Colposcopy utilizes a lighted magnifying instrument, allowing the physician to examine the cervix, vagina and vulva for abnormal areas which can be biopsied and sent to the lab for testing.

 

Figure 1. Classification of normal squamous epithelial cells and human papillomavirus (HPV) infections in normal precancerous lesions (cervical intraepithelial neoplasia grades 1, 2, and 3 “CIN 1, CIN 2, and CIN 3”) and cervical cancer.

  

Anatomy of the uterus, including the lower end of the uterus termed the cervix which connects the uterus to the vagina via the opening called the external orifice (or external os).
Pap (Papanicolaou) Test or Pap Smear:  Cervical cells are collected from the outer opening of the cervix and examined under a microscope to look for abnormalities. The Bethesda system classifies cells into multiple diagnostic categories ranging from: normal, dysplastic/pre-cancerous, to anaplastic/cancerous.  The categories specifically include (but are not limited to) Negative for Intraepithelial Malignancy (NILM, normal, no abnormal cells), Low Grade Squamous Intraepithelial Lesion (LSIL, mild dysplasia), High Grade Squamous Intraepithelial Lesion (HSIL, indicating moderate or severe dysplasia, that doesn’t necessarily progress to cancer), and Squamous Cell Carcinoma (SCC, cancer).

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