Lupus erythematosus
 - chronic discoid lupus is primarily limited to the skin, while SLE can involve the skin and other systems.
 - pathogenesis: light and other external agents plus deposition of DNA (planted antigen) and immune complexes in the basement membrane.
 Histology:
 - basal cells along the dermal-epidermal junction and hair shafts (reason for alopecia) are vacuolated (liquefactive degeneration)
 - thickening of lamina densa as a reaction to injury.
 - immunofluorescent studies reveal a band of immunofluorescence (band test) in involved skin of chronic discoid lupus or involved/uninvolved skin of SLE.
 - lymphocytic infiltrate at the dermal-epidermal junction and papillary dermis.  

Alcoholic (nutritional, Laennec’s) cirrhosis

Pathology
 
Liver is at first enlarged (fatty change), then return to normal size and lastly, it becomes slightly reduced in size (1.2 kg or more).
- Cirrhosis is micronodular then macronodular then mixed.   

M/E  
Hepatocytes:-  show fatty change that decreases progressively. Few hepatocytes show increased intracytoplasmic haemochromatosis. 
b. Fibrous septa:-  Regular margins between it and regenerating nodules.
 -Moderate lymphocytic infiltrate.      
 – Slight bile ductular proliferation.
 
Prognosis:-   It Progresses slowly over few years. 

Megaloblastic anaemia

Metabolism: B12(cyanocobalamin) is a coenzyme in DNA synthesis and for maintenance of nervous system. Daily requirement 2 micro grams. Absorption in terminal ileum in the presence gastric intrinsic factor. It is stored in liver mainly-

Folic acid (Pteroylglutamic acid) is needed for DNA synthesis.. Daily requirement 100 micro grams. Absorption in duodenum  and jejunum

Causes of deficiency .-

- Nutritional deficiency-
- Malabsorption syndrome.
- Pernicious anaemia (B12).
- Gastrectomy (B12).
- Fish tapeworm infestation (B12).
- Pregnancy and puerperium (Folic acid mainly).
- Myeloproliferative disorders (Folic acid).
- Malignancies (Folic acid).
- Drug induced (Folic-acid)

Features:

(i) Megaloblastic anaemia.
(ii) Glossitis.
(iii) Subacute combined degeneration (in B12deficiency).

Blood picture :

- Macrocytic normochromic anaemia.
- Anisocytosis and poikilocytosis with Howell-Jolly bodies and  basophilic stippling.
- Occasional megalo blasts may be-seen.
- Neutropenia with hypersegmented neutrophills and macropolycytes.
- Thrombocytopenia.
- Increased MVC and MCH with normal or decreased MCHC.

Bone marrow:

- Megaloblasts are seen. They are larger with a more open stippled chromatin. The nuclear maturation lags behind. the cytoplasmic maturation. Maturation arrest is seen (more of early forms).
- Immature cells of granulocyte series are also larger.
 -Giant stab forms (giant metamyelocytes).
 

Gout
This is a disorder caused by the tissue accumulation of excessive amounts of uric acid, an end product of purine metabolism. It is marked by recurrent episodes of acute arthritis, sometimes accompanied by the formation of large crystalline aggregates called tophi & chronic joint deformity. All of these are the result of precipitation of monosodium urate crystals from supersaturated body fluids. Not all individuals with hyperuricemia develop gout; this indicates that influences besides hyperuricemia contribute to the pathogenesis. Gout is divided into primary (90%) and secondary forms (10%). 

Primary gout designates cases in whom the basic cause is unknown or when it is due to an inborn metabolic defect that causes hyperuricemia.

In secondary gout the cause of the hyperuricemia is known.

Pathologic features 

The major morphologic manifestations of gout are
1. Acute arthritis
2. Chronic tophaceous arthritis
3. Tophi in various sites, and
4. Gouty nephropathy

Acute arthritis

- The synovium is edematous and congested,
- There is an intense infiltration of the synovium & synovial fluid by neutrophils.
- Long, slender, needle-shaped monosodium urate crystals are frequently found in the cytoplasm of the neutrophils as well as in small clusters in the synovium.

Chronic tophaceous arthritis:

- This evolves from repetitive precipitation of urate crystals during acute attacks. The urates can heavily encrust the articular surfaces and form visible deposits in the synovium.
- The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells, forming a pannus that destroys the underlying cartilage, and leading to erosions of subjacent bone.
- In severe cases, fibrous or bony ankylosis occurs, resulting in loss of joint function. 

Tophi

These are the pathognomonic hallmarks of gout.
- Tophi can appear in the articular cartilage, periarticular ligaments, tendons, and soft tissues, including the ear lobes. Superficial tophi can lead to large ulcerations of the overlying skin.
- Microscopically, they are formed by large aggregations of urate crystals surrounded by an intense inflammatory reaction of lymphocytes, macrophages, and foreign-body giant cells, attempting to engulf the masses of crystals.

Gouty nephropathy

- This refers to the renal complications associated with urate deposition including medullary tophi, intratubular precipitations and renal calculi. Secondary complications such as pyelonephritis can occur, especially when there is urinary obstruction.

Pathogenesis

- Although the cause of excessive uric acid biosynthesis in primary gout is unknown in most cases, rare patients have identifiable enzymatic defects or deficiencies that are associated with excess production of uric acid.
- In secondary gout, hyperuricemia can be caused by increased urate production (e.g., rapid cell lysis during chemotherapy for lymphoma or leukemia) or decreased excretion (chronic renal failure), or both. Reduced renal excretion may also be caused by drugs such as thiazide diuretics, because of their effects on uric acid tubular transport.
- Whatever the cause, increased levels of uric acid in the blood and other body fluids (e.g., synovium) lead to the precipitation of monosodium urate crystals. The precipitated crystals are chemotactic to neutrophils & macrophages through activation of complement components C3a and C5a fragments. This leads to a local accumulation of neutrophils and macrophages in the joints and synovial membranes to phagocytize the crystals. The activated neutrophils liberate destructive lysosomal enzymes. Macrophages participate in joint injury by secreting a variety of proinflammatory mediators such as IL-1, IL-6, and TNF. While intensifying the inflammatory response, these cytokines can also directly activate synovial cells and cartilage cells to release proteases (e.g., collagenases) that cause tissue injury.

- Repeated bouts of acute arthritis, however, can lead to the permanent damage seen in chronic tophaceous arthritis.

b Pseudogout (chondrocalcinosis) (Calcium pyrophosphate crystal deposition disease). Pseudogout typically first occurs in the age 50 years or older. It involves enzymes that lead to accumulation and eventual crystallization of pyrophosphate with calcium. The pathology in pseudogout involves the recruitment and activation of inflammatory cells, and is reminiscent of gout. The knees, followed by the wrists, elbows,
shoulders, and ankles, are most commonly affected. Approximately 50% of patients experience significant joint damage.

Infectious Arthritis can cause rapid joint destruction and permanent deformities. Microorganisms can lodge in joints during hematogenous dissemination, by direct inoculation or by contiguous spread from osteomyelitis or a soft tissue abscess.

Suppurative Arthritis is a subtype of infectious arthritis in which the bacteria seed the joint during episodes of bacteremia. Haemophilus influenzae predominates in children under age 2 years, S. aureus is the main causative agent in older children and adults, and gonococcus is prevalent during late adolescence and young adulthood. 

There is sudden onset of pain, redness, and swelling of the joint with fever, leukocytosis, and elevated ESR. In 90% of nongonococcal suppurative arthritis, the infection involves only a single joint-usually the knee. Joint aspiration is typically purulent, and allows identification of the causal agent. 

Cartilage-Forming Tumors

1. Osteochondroma (Exostosis) is a relatively common benign cartilage-capped outgrowth attached by a bony stalk to the underlying skeleton. Solitary osteochondromas are usually first diagnosed in late adolescence and early adulthood (male-to-female ratio of 3:1); multiple osteochondromas become apparent during childhood, occurring as multiple hereditary exostosis, an autosomal dominant disorder. Inactivation of both copies of the EXT gene (a tumor suppressor gne) in chondrocytes is implicated in both sporadic and hereditary osteochondromas. Osteochondromas develop only in bones of endochondral origin arising at the metaphysis near the growth plate of long tubular bones, especially about the knee. They tend to stop growing once the normal growth of the skeleton is completed. Occasionally they develop from flat bones (pelvis, scapula, and ribs). Rarely, exostoses involve the short tubular bones of hands and feet.

Pathological features

• Osteochondromas vary from 1-20cm in size.
• The cap is benign hyaline cartilage. 
• Newly formed bone forms the inner portion of the head and stalk, with the stalk cortex merging with cortex of the host bone.
Osteochondromas are slow-growing masses that may be painful. Osteochondromas rarely progress to chondrosarcoma or other sarcoma, although patients with the multiple hereditary exostoses are at increased risk of malignant transformation. 

2. Chondroma 

It is a benign tumor of hyaline cartilage. When it arises within the medullary cavity, it is termed enchondroma; when on the bone surface it is called juxtacortical chondroma. Enchondromas are usually diagnosed in persons between ages 20 and 50 years; they are typically solitary and located in the metaphyseal region of tubular bones, the favored sites being the short tubular bones of the hands and feet. Ollier disease is characterized by multiple chondromas preferentially involving one side of the body. Chondromas probably develop from slowly proliferating rests of growth plate cartilage.

Pathological features 

• Enchondromas are gray-blue, translucent nodules usually smaller than 3 cm.
• Microscopically, there is well-circumscribed hyaline matrix and cytologically benign chondrocytes.
Most enchondromas are detected as incidental findings; occasionally they are painful or cause pathologic fractures. Solitary chondromas rarely undergo malignant transformation, but those associated with enchondromatosis are at increased risk. 

3. Chondrosarcomas are malignant tumors of cartilage forming tissues. They are divided into conventional chondrosarcomas and chondrosarcoma variants. Each of these categories comprises several distinct types, some defined on microscopic grounds & others on the basis of location within the affected bone, for e.g. they are divided into central (medullary), peripheral (cortical), and juxtacortical (periosteal). The common denominator of chondrosarcoma is the production of a cartilaginous matrix and the lack of direct bone formation by the tumor cells (cf osteosarcoma). Chondrosarcomas occur roughly half as frequently as osteosarcomas; most patients age 40 years or more, with men affected twice as frequently as women 

Pathological features 
Conventional chondrosarcomas arise within the medullary cavity of the bone to form an expansile glistening mass that often erodes the cortex. They exhibit malignant hyaline or myxoid stroma. Spotty calcifications are typically present. The tumor grows with broad pushing fronts into marrow spaces and the surrounding soft tissue. Tumor grade is determined by cellularity, cytologic atypia, and mitotic activity. Low-grade tumors resemble normal cartilage. Higher grade lesions contain pleomorphic chondrocytes with frequent mitotic figures with multinucleate cells and lacunae containing two or more chondrocytes. Dedifferentiated chondrosarcomas refers to the presence of a poorly differentiated sarcomatous component at the periphery of an otherwise typical low-grade chondrosarcoma. Other histologic variants include myxoid, clear-cell and mesenchymal chondrosarcomas. Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs. A slowly growing lowgrade tumor causes reactive thickening of the cortex, whereas a more aggressive high-grade neoplasm destroys the cortex and forms a soft tissue mass. There is also a direct correlation between grade and biologic behavior. 
Size is another prognostic feature, with tumors larger than 10 cm being significantly more aggressive than smaller tumors. High-grade Chondrosarcomas metastasize hematogenously, preferentially to the lungs and skeleton.

Malignant Diseases of Skin
 
1. Bowen's disease refers to a carcinoma in situ on sun-exposed skin or on the vulva, glans a penis, or oral mucosa which has an association, in some cases, with a visceral malignancy.
2. Skin cancers associated with ultraviolet light damage include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.
3. A basal cell carcinoma is the MC malignant tumor of the skin and occurs on sunexposed, hair-bearing surfaces.
 - Locally aggressive, infiltrating cancers arising from the basal cell layer of the epidermis and infiltrate the underlying superficial dermis.
 - they do not metastasize
 - BCC are commonly located on the face on the inner aspect of the nose, around the orbit and the upper lip where they appear as raised nodules containing a central crater with a pearly-colored skin surface and vascular channels.
 - microscopically, they have cords of basophilic staining cells originating from the basal cell layer infiltrating the dermis.
 - they commonly recur if they are not totally excised, because they are frequently multifocal. 
- the basal cell nevus syndrome is an autosomal-dominant disorder characterized by the development of basal cell carcinomas early in life with associated abnormalities of bone, skin, nervous system, eyes, and reproductive system.