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Pathology - Systemic Lupus Erythematosus (SLE)
I. Definition & Epidemiology:
SLE's wide-ranging symptoms depend on the affected organs. Remember the diverse nature of its presentations:
Specific autoantibodies are key diagnostic indicators. Note the high prevalence of certain markers:
I. Definition & Epidemiology:
- Definition: SLE is a multisystem autoimmune disease characterized by the production of autoantibodies targeting nuclear and cytoplasmic antigens. This means the body's immune system mistakenly attacks its own cells.
- Epidemiology:
- Incidence: 4 per 100,000 people annually.
- Predominantly affects women of childbearing age.
- Higher prevalence in individuals of African and Asian descent.
- Etiology (Cause): Unknown. A leading hypothesis suggests defective phagocytosis (the process of engulfing and destroying pathogens) of apoptotic bodies (dying cells). This failure to properly clear apoptotic cells exposes intracellular self-antigens, potentially triggering an autoimmune response.
- Pathogenesis (Mechanism):
- Autoreactive B and T cells (immune cells) become activated.
- Immune complexes form: Autoantibodies bind to self-antigens.
- These circulating immune complexes deposit in various tissues (skin, joints, kidneys).
- Tissue inflammation and damage result from the immune complex deposition. (Visualize this process using Fig 18.1 if available).
SLE's wide-ranging symptoms depend on the affected organs. Remember the diverse nature of its presentations:
- Common Symptoms: Fatigue, weight loss, low-grade fever.
- Musculoskeletal: Arthralgia (joint pain).
- Skin: Scaly red lesions (often on sun-exposed areas).
- Pulmonary: Pleuritis (lung inflammation), pleural effusion (fluid buildup around lungs), pneumonitis (lung inflammation), potentially leading to pulmonary fibrosis (scarring).
- Renal: Glomerulonephritis (kidney inflammation), leading to chronic kidney disease. This is a serious complication.
- Hematological: Anemia (low red blood cell count), lymphopenia (low lymphocyte count), thrombocytopenia (low platelet count).
Specific autoantibodies are key diagnostic indicators. Note the high prevalence of certain markers:
- Anti-nuclear antibodies (ANA): >95% of SLE patients test positive. This is a common, but non-specific, finding.
- Anti-double-stranded DNA (dsDNA) antibodies: 60% of patients. More specific to SLE.
- Anti-Smith antigen antibodies: 20-30% of patients. Very specific to SLE.
- Anti-phospholipid antibodies: 20-30% of patients. These antibodies cause a hypercoagulable state (increased risk of blood clots).
- 15-year survival rate: Approximately 80% from the time of diagnosis.
- Causes of death: Often related to severe renal (kidney) and pulmonary (lung) complications.
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Oncology -Gender and Cancer Incidence
This section explores the relationship between gender and cancer occurrence. A key takeaway is that observed gender disparities in cancer rates are not always indicative of inherent biological differences.
Key Concept: While some cancers show a clear gender bias in incidence (e.g., stomach cancer is twice as common in men), attributing this solely to innate susceptibility is problematic.
Critical Point: Environmental factors and lifestyle choices significantly confound the interpretation of gender-based cancer statistics. The example of bladder carcinoma highlights this:
This section explores the relationship between gender and cancer occurrence. A key takeaway is that observed gender disparities in cancer rates are not always indicative of inherent biological differences.
Key Concept: While some cancers show a clear gender bias in incidence (e.g., stomach cancer is twice as common in men), attributing this solely to innate susceptibility is problematic.
Critical Point: Environmental factors and lifestyle choices significantly confound the interpretation of gender-based cancer statistics. The example of bladder carcinoma highlights this:
- Initial Observation: Bladder cancer was initially believed to be inherently more common in men.
- Revised Understanding: Studies revealed that when men and women are exposed to the same occupational carcinogens (e.g., certain chemicals in the workplace) and tobacco smoke, women exhibit similar, if not equal, susceptibility to bladder cancer.
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Pathology - Nervous System Malformations
This guide summarizes common nervous system malformations, focusing on understanding their causes, presentations, and associated complications.
I. Neural Tube Defects (NTDs)
This guide summarizes common nervous system malformations, focusing on understanding their causes, presentations, and associated complications.
I. Neural Tube Defects (NTDs)
- Definition: Failure of the neural tube to close properly during embryogenesis (weeks 3-4).
- Etiology: Multifactorial – both genetic predisposition and environmental factors contribute. Maternal folate deficiency during early gestation is a significant risk factor.
- Types:
- Anencephaly: Fatal malformation; absence of brain and cranial vault. Anterior neural tube defect.
- Encephalocele: Protrusion of malformed brain tissue through a skull defect (often occipital). Large encephaloceles are usually fatal.
- Spina Bifida: Group of malformations due to incomplete closure of the caudal neural tube. Lack of fusion of vertebral arches and skin. Severity varies:
- Meningocele: Outpouching of meninges only.
- Myelomeningocele: Outpouching of meninges and spinal cord. Can cause urinary incontinence, constipation, and motor/sensory impairment in legs.
- Definition: Failure of the glial bridge to form between cerebral hemispheres, preventing axon crossing. Can be complete or partial.
- Association: Frequently occurs with other malformations.
- Presentation: Variable degrees of psychomotor retardation.
- Definition: Narrowing of the cerebral aqueduct.
- Etiology: Developmental anomaly; can be inherited (autosomal recessive or X-linked).
- Presentation: Congenital hydrocephalus (build-up of cerebrospinal fluid in the brain).
- Definition: Downward displacement of cerebellar structures into the foramen magnum.
- Type II (Arnold-Chiari): Severe; small posterior fossa, downward displacement of cerebellar vermis and medulla. Usually associated with lumbar myelomeningocele.
- Type I: Milder; cerebellar tonsils extend into the spinal canal. May be asymptomatic.
- Definition: Absent or rudimentary cerebellar vermis; large cyst (dilated fourth ventricle) fills the posterior fossa.
- Association: Often associated with other malformations.
- Definition: Fluid-filled cavity (syrinx) within the spinal cord's central grey matter.
- Location: Usually cervical and upper thoracic segments; extension into the medulla is called syringobulbia.
- Effect: Syrinx expansion causes adjacent spinal cord atrophy.
- Presentation: Typically presents in early adulthood with isolated loss of pain and temperature sensation in the upper limbs (due to spinothalamic tract damage).
- Embryological timing: Understand the developmental windows during which these malformations occur.
- Etiological factors: Recognize the interplay of genetic and environmental influences, particularly folate's role in NTDs.
- Clinical presentations: Learn to differentiate between the various malformations based on their symptoms and associated findings (e.g., hydrocephalus, motor deficits).
- Associated anomalies: Many of these malformations occur together, highlighting the interconnectedness of neural development.
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Pathology - Pemphigus vulgaris
Definition: An immunobullous dermatosis resulting from autoantibodies targeting epidermal desmosomal proteins.
Epidemiology • Infrequent, occurring at a rate of 0.1–1 per 100,000 individuals annually. • Typically impacts middle-aged persons aged 40–60 years.
Aetiology: Production of autoantibodies targeting the epidermal desmosomal cadherin, desmoglein-3.
Pathogenesis • The autoantibody attaches to the extracellular domain of desmoglein-3, resulting in desmosomal impairment and acantholysis. • The conventional perspective posited that complement fixation resulted in acantholysis; however, other researchers have proposed that acantholysis may arise via cytoskeletal collapse independent of complement activity.
Exposition • The majority of cases commence with oral erosions and blisters, then followed weeks or months later by the emergence of cutaneous lesions. The cutaneous lesions are delicate vesicles arising on unremarkable or erythematous skin. The blisters readily burst, resulting in a painful eroded region. • The skin lesions generally manifest on the face, scalp, axillae, and groin.
Histopathology • Biopsies reveal a blister cavity within the epidermis populated by acantholytic keratinocytes. • Generally, the cleavage occurs at a suprabasal level, resulting in the blister floor being lined by a solitary layer of intact basal keratinocytes. • Acantholysis may also affect the epidermis of adnexal structures. • Typically, there exists a fundamental dermal inflammatory infiltrate characterized by a significant presence of eosinophils.
Immunofluorescence
Direct immunofluorescence on perilesional skin demonstrates the deposition of IgG and C3 in the intercellular space of the epidermis.
Prognosis: Mortality rates are minimal with suitable immunosuppressive therapies. • The majority of problems are associated with therapy.
Definition: An immunobullous dermatosis resulting from autoantibodies targeting epidermal desmosomal proteins.
Epidemiology • Infrequent, occurring at a rate of 0.1–1 per 100,000 individuals annually. • Typically impacts middle-aged persons aged 40–60 years.
Aetiology: Production of autoantibodies targeting the epidermal desmosomal cadherin, desmoglein-3.
Pathogenesis • The autoantibody attaches to the extracellular domain of desmoglein-3, resulting in desmosomal impairment and acantholysis. • The conventional perspective posited that complement fixation resulted in acantholysis; however, other researchers have proposed that acantholysis may arise via cytoskeletal collapse independent of complement activity.
Exposition • The majority of cases commence with oral erosions and blisters, then followed weeks or months later by the emergence of cutaneous lesions. The cutaneous lesions are delicate vesicles arising on unremarkable or erythematous skin. The blisters readily burst, resulting in a painful eroded region. • The skin lesions generally manifest on the face, scalp, axillae, and groin.
Histopathology • Biopsies reveal a blister cavity within the epidermis populated by acantholytic keratinocytes. • Generally, the cleavage occurs at a suprabasal level, resulting in the blister floor being lined by a solitary layer of intact basal keratinocytes. • Acantholysis may also affect the epidermis of adnexal structures. • Typically, there exists a fundamental dermal inflammatory infiltrate characterized by a significant presence of eosinophils.
Immunofluorescence
Direct immunofluorescence on perilesional skin demonstrates the deposition of IgG and C3 in the intercellular space of the epidermis.
Prognosis: Mortality rates are minimal with suitable immunosuppressive therapies. • The majority of problems are associated with therapy.
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Pathology - Dermatitis herpetiformis
Definition: An immunobullous skin disorder marked by severe pruritus, papules, and vesicles, granular IgA deposition in the papillary dermis, and a significant correlation with celiac disease.
Epidemiology • Uncommon. The condition can afflict individuals of any age, while the highest frequency occurs in young people aged 20 to 40 years. Males are impacted twice as frequently as females. This illness is very prevalent in Northern Europe and Ireland. Up to 90% of individuals exhibit indications of celiac disease, although this may be asymptomatic.
Aetiology mediator. • IgA transglutaminase antibodies generated in the gastrointestinal tract seem to be pivotal.
Pathogenesis • IgA transglutaminase antibodies interact with transglutaminase enzymes present in the skin. The fixation of complement induces chemotaxis of neutrophils into the papillary dermis. • Enzymes secreted by neutrophils induce blister development.
Presentation • The rash consists of clusters of papules and vesicles that are highly pruritic. • Preferred locations are the shoulders, back, buttocks, elbows, and knees.
Histopathology Biopsies from first lesions reveal aggregates of neutrophils within the papillary dermis (papillary dermal microabscesses). Biopsies from established lesions reveal a subepidermal blister abundant in neutrophils. Immunofluorescence Direct immunofluorescence of perilesional skin demonstrates granular deposition of IgA in the papillary dermis.
Prognosis: The condition is typically chronic and persistent; nevertheless, it exhibits a significant response to the medication dapsone.
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Pathology - Bullous pemphigoid
It is an immunobullous dermatological condition characterized by the presence of autoantibodies targeting epidermal hemidesmosomal proteins.
Epidemiology • The most prevalent immunobullous skin disorder, however still an uncommon condition with an annual incidence of 7 per million individuals. • The majority of cases occur in older adults over the age of 70. Aetiology • Generation of autoantibodies targeting epidermal hemidesmosomal proteins. • The principal antigens are identified as BPAg1 and BPAg2.
Pathogenesis • Antibody binding results in complement fixation and the influx of inflammatory cells, notably eosinophils. • Direct cytotoxic effects disrupt the hemidesmosomes that anchor the epidermis to the dermis, causing complete separation of the epidermis from the dermis.
Presentation • Characteristic skin lesions consist of substantial, tight, intact blisters that arise on either normal or erythematous skin. • Preferred locations include the lower trunk, inner thighs, forearms, axillae, and groin regions.
Histopathology • Biopsies reveal a subepidermal blister populated by numerous eosinophils. • The underlying dermis exhibits edema and is infiltrated by a significant inflammatory response rich in eosinophils. Direct immunofluorescence on perilesional skin demonstrates linear deposition of IgG and C3 along the basement membrane zone.
Prognosis • Mortality rates remain low with suitable immunosuppressive protocols. • The majority of problems are associated with therapy.
It is an immunobullous dermatological condition characterized by the presence of autoantibodies targeting epidermal hemidesmosomal proteins.
Epidemiology • The most prevalent immunobullous skin disorder, however still an uncommon condition with an annual incidence of 7 per million individuals. • The majority of cases occur in older adults over the age of 70. Aetiology • Generation of autoantibodies targeting epidermal hemidesmosomal proteins. • The principal antigens are identified as BPAg1 and BPAg2.
Pathogenesis • Antibody binding results in complement fixation and the influx of inflammatory cells, notably eosinophils. • Direct cytotoxic effects disrupt the hemidesmosomes that anchor the epidermis to the dermis, causing complete separation of the epidermis from the dermis.
Presentation • Characteristic skin lesions consist of substantial, tight, intact blisters that arise on either normal or erythematous skin. • Preferred locations include the lower trunk, inner thighs, forearms, axillae, and groin regions.
Histopathology • Biopsies reveal a subepidermal blister populated by numerous eosinophils. • The underlying dermis exhibits edema and is infiltrated by a significant inflammatory response rich in eosinophils. Direct immunofluorescence on perilesional skin demonstrates linear deposition of IgG and C3 along the basement membrane zone.
Prognosis • Mortality rates remain low with suitable immunosuppressive protocols. • The majority of problems are associated with therapy.
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Pathology - Erythema multiforme
Definition: An inflammatory dermatosis characterized by unique targetoid lesions clinically and an interface reaction pattern histologically.
Epidemiology: • Fairly prevalent. • Primarily impacts the youth, encompassing youngsters.
Etiology • The majority of cases are associated with current or prior infections of the herpes simplex virus (HSV), which may not always be clinically evident. • Additional infectious organisms, such as Mycoplasma, have been implicated. • Pharmaceuticals are also acknowledged as a causative factor. Pathogenesis • Believed to signify a delayed-type hypersensitivity response to HSV antigens conveyed to the skin via circulating lymphocytes.
Presentation: Discrete circular erythematous patches, measuring 1–2 cm, with central darkening that may form blisters, referred to as 'target' lesions. • The majority of instances pertain to the extremities. • Mild oral involvement is prevalent.
Histopathology • Biopsies reveal interface dermatitis typified by a superficial lymphohistiocytic inflammatory infiltrate, substantial basal cell vacuolar degeneration, and keratinocyte death. • Instances of significant basal cell destruction may lead to subepidermal clefting and blister formation.
Prognosis: Most instances are self-limiting; however, recurring episodes are prevalent.
Definition: An inflammatory dermatosis characterized by unique targetoid lesions clinically and an interface reaction pattern histologically.
Epidemiology: • Fairly prevalent. • Primarily impacts the youth, encompassing youngsters.
Etiology • The majority of cases are associated with current or prior infections of the herpes simplex virus (HSV), which may not always be clinically evident. • Additional infectious organisms, such as Mycoplasma, have been implicated. • Pharmaceuticals are also acknowledged as a causative factor. Pathogenesis • Believed to signify a delayed-type hypersensitivity response to HSV antigens conveyed to the skin via circulating lymphocytes.
Presentation: Discrete circular erythematous patches, measuring 1–2 cm, with central darkening that may form blisters, referred to as 'target' lesions. • The majority of instances pertain to the extremities. • Mild oral involvement is prevalent.
Histopathology • Biopsies reveal interface dermatitis typified by a superficial lymphohistiocytic inflammatory infiltrate, substantial basal cell vacuolar degeneration, and keratinocyte death. • Instances of significant basal cell destruction may lead to subepidermal clefting and blister formation.
Prognosis: Most instances are self-limiting; however, recurring episodes are prevalent.
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Pathology - Granuloma annulare
Definition: An inflammatory dermatosis often characterized by annular lesions clinically and necrobiotic granulomatous inflammation histologically.
Epidemiology: Prevalent. Aetiology • Predominantly unknown in most instances. • Borrelia infection has been associated with a limited number of instances.
Pathogenesis • Current information indicates it constitutes a cutaneous reaction pattern to undefined antigens.
Presentation • Localized lesions of granuloma annulare manifest as flesh-colored or red papules that coalesce to form an annular lesion of 1–5 cm. • Acral regions are typically involved, particularly the knuckles and fingers.
Histopathology • The dermis exhibits a palisading granuloma, defined by a core region of degraded (necrobiotic) collagen encircled by radially oriented histiocytes, lymphocytes, and fibroblasts. • Mucin is frequently observed within the necrobiotic focal area. • Sometimes, the process results in a more nuanced ill-defined lesion in the dermis instead of a conventional well-formed palisaded granuloma (interstitial granuloma annulare).
Prognosis: Approximately 50% of cases resolve after two years of commencement, however recurrences are rather frequent.
Definition: An inflammatory dermatosis often characterized by annular lesions clinically and necrobiotic granulomatous inflammation histologically.
Epidemiology: Prevalent. Aetiology • Predominantly unknown in most instances. • Borrelia infection has been associated with a limited number of instances.
Pathogenesis • Current information indicates it constitutes a cutaneous reaction pattern to undefined antigens.
Presentation • Localized lesions of granuloma annulare manifest as flesh-colored or red papules that coalesce to form an annular lesion of 1–5 cm. • Acral regions are typically involved, particularly the knuckles and fingers.
Histopathology • The dermis exhibits a palisading granuloma, defined by a core region of degraded (necrobiotic) collagen encircled by radially oriented histiocytes, lymphocytes, and fibroblasts. • Mucin is frequently observed within the necrobiotic focal area. • Sometimes, the process results in a more nuanced ill-defined lesion in the dermis instead of a conventional well-formed palisaded granuloma (interstitial granuloma annulare).
Prognosis: Approximately 50% of cases resolve after two years of commencement, however recurrences are rather frequent.
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Pathology - Squamous cell carcinoma
Definition: A malignant epidermal tumor with squamous differentiation.
Epidemiology: Common tumors constitute around 15% of all skin cancers. • The majority occur on sun-exposed skin of older individuals with fair complexions.
Aetiology • The majority are associated with cumulative exposure to UV radiation. • Immunosuppression elevates the risk. Transplant recipients are especially susceptible to the development of numerous tumors. Carcinogenesis • The majority originate from actinic keratoses, which are dysplastic epidermal lesions that develop on sun-damaged skin. UV light, especially UVB, causes DNA damage in genes that regulate development, such as KRAS and CDK4.
Presentation • Dermal plaques or nodules, frequently exhibiting a keratinized surface crust. • Ulceration may occur.
Histopathology • Atypical squamous epithelial cells are observed in nests, sheets, and cords, originating from the epidermis and infiltrating the underlying dermis. • Tumors are classified as well, moderately, or poorly differentiated based on the degree of keratinization.
Prognosis: • The majority are primarily locally infiltrative upon diagnosis and can be effectively treated with surgical excision. Factors contributing to recurrence or metastasis encompass invasion depth, poor differentiation, perineural invasion, restricted excision, and immunosuppression.
Pathological classification of cutaneous carcinomas Primary tumor (T) pT1: tumor is 2 cm or smaller in diameter. pT2: tumor exceeds 2 cm in size. pT3: tumor infiltrates muscle, bone, cartilage, jaws, and orbit. pT4: tumor infiltrates the skull base and axial skeleton. Regional lymphatic nodes (N) pN1: solitary nodal metastasis measuring less than 3 cm in size. pN2: solitary nodal metastasis ranging from 3 to 6 cm in size or several nodal metastases, with none exceeding 6 cm. pN3: any nodal metastasis over 6 cm
Definition: A malignant epidermal tumor with squamous differentiation.
Epidemiology: Common tumors constitute around 15% of all skin cancers. • The majority occur on sun-exposed skin of older individuals with fair complexions.
Aetiology • The majority are associated with cumulative exposure to UV radiation. • Immunosuppression elevates the risk. Transplant recipients are especially susceptible to the development of numerous tumors. Carcinogenesis • The majority originate from actinic keratoses, which are dysplastic epidermal lesions that develop on sun-damaged skin. UV light, especially UVB, causes DNA damage in genes that regulate development, such as KRAS and CDK4.
Presentation • Dermal plaques or nodules, frequently exhibiting a keratinized surface crust. • Ulceration may occur.
Histopathology • Atypical squamous epithelial cells are observed in nests, sheets, and cords, originating from the epidermis and infiltrating the underlying dermis. • Tumors are classified as well, moderately, or poorly differentiated based on the degree of keratinization.
Prognosis: • The majority are primarily locally infiltrative upon diagnosis and can be effectively treated with surgical excision. Factors contributing to recurrence or metastasis encompass invasion depth, poor differentiation, perineural invasion, restricted excision, and immunosuppression.
Pathological classification of cutaneous carcinomas Primary tumor (T) pT1: tumor is 2 cm or smaller in diameter. pT2: tumor exceeds 2 cm in size. pT3: tumor infiltrates muscle, bone, cartilage, jaws, and orbit. pT4: tumor infiltrates the skull base and axial skeleton. Regional lymphatic nodes (N) pN1: solitary nodal metastasis measuring less than 3 cm in size. pN2: solitary nodal metastasis ranging from 3 to 6 cm in size or several nodal metastases, with none exceeding 6 cm. pN3: any nodal metastasis over 6 cm
