Mechanisms of Invasion and Metastases

Local Invasion:

• Almost all benign tumors grow as cohesive expansile masses
• Remain localized to their site of origin
• Do not have the capacity to infiltrate, invade, or metastasize to distant sites
• Usually have rim of fibrous capsule that separates them from host tissue
• Rim is composed of stroma of the native tissues as its parenchymal cells atrophy under the pressure of expanding tumor
• Tends to be contained as a discrete, readily palpable, and easily movable mass
• Some benign tumors can be encapsulated (example = hemangiomas)
• The growth of malignant tumors is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue
• Poorly separated from surrounding normal tissue
• Slowly expanding malignant tumors may develop an apparently enclosing fibrous capsule; capsule has breaks along its margin
• Invasiveness is one of most reliable features (next to metastases) to differentiates malignant from benign tumors
• Carcinoma in situ – displays the cytologic features of malignancy w/out invasion of the basement membrane
• Example = carcinoma of the uterine cervix
• Can be considered one step removed from invasive cancer
• In time, most become invasive

Example of Disturbance of Growth:

• Progression in cervix from normal squamous epithelium to squamous cell carcinoma in situ
• Mild dysplasia is present when abnormal organization and cellular atypia is confined to the lower one third of the epithel layer
• Moderate dysplasia – 1/3 to 2/3 of epithelium is involved
• Severe dysplasia – indistinguishable from CIS since the full thickness of the epithelium is involved
• In each of these situations the basement membrane is intact
• Abnormal process is confined to the epith layer

Continuum:

• Progression of cellular dysplasia to carcinoma-in-situ- to locally invasive carcinoma followed by metastases

Metastases:

• Tumor implants discontinuous with the primary tumor
• Unequivocally marks a tumor as malignant b/c benign neoplasms do not metastasize
•  With few exceptions, all cancers can metastasize
•  Exceptions are gliomas and basal cell carcinomas of the skin – both are highly invasive but rarely metastasize
• More aggressive, more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize
• Strongly reduces the possibility of cure
• About 30% of newly dx pts w/ solid tumors have metastases

Mechanisms of Invasion and Metastases:

1.      Clonal Expansion, growth, diversification, and angiogenesis

2.      Metastatic subclone adheres to and invades basement membrane

3.      Passes t/ ECM

4.      Intravasation

5.      Interaction w/ host lymphoid cells

6.      Tumor cell embolus

7.      Adhesion to basement membrane

8.      Extravasation

9.      Metastatic deposit

10.  Angiogenesis

11.  Growth

Factors in Invasion and Metastases:

Pathways of Spread:

1.      Direct seeding of body cavities or surfaces

2.      Lymphatic spread

3.      Hematogenous spread

Direct seeding of body cavities or surfaces:

• May occur whenever a malignant neoplasm penetrates into an open field
• Most often is the peritoneal cavity, but also can be any other cavity
• Esp common of carcinomas arising from ovaries à coats all peritoneal surfaces w/ cancerous glaze
• Pseudomyxoma peritonei – mucus secreting ovary and appendiceal carcinomas fill peritoneal cavity w/ gelatinous neoplastic mass

Lymphatic Spread:

• Most common p’way for initial dissemination of carcinomas
• Sarcomas also use this p’way
• Pattern of lymph node involvement follows the natural routes of drainage
• Local lymph nodes may be bypassed b/c of venous-lymphatic anastomoses, or b/c inflamm or radiation has obliterated channels
• Regional nodes serve as effective barriers to further dissemination, at least for a while
• Tumor-specific immune response may participate
• Enlargement of lymph nodes may be caused by:

1.      Spread and growth of cancer cells

2.      Reactive hyperplasia

• Nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion

Hematogenous Spread:

1. Typical of sarcomas, but also used by carcinoma
2.  Arteries have thicker walls, are less readily penetrated than are veins
3. Arterial spread may occur when tumor cells pass t/ pulmonary capillary beds or pulmonary arteriovenous shunts, or pulmonary metastases give rise to tumor emboli
4. Venous invasion: blood-borne cells follow the venous flow, draining the site of the neoplasm
5.  Liver and lungs are most frequently involved secondarily in venous dissemination

• All portal area drainage flows to liver
• All caval blood flows to lungs

Grading and staging of cancer Grading criteria Degree of differentiation (e.g., low, intermediate, or high grade) Nuclear features, invasiveness Staging criteria  Most important prognostic factor TNM system Universal system Progresses from the least to the most important prognostic factor T refers to tumor size  ≥2cm correlates with metastatic ability. N refers to whether lymph nodes are involved.  M refers to extranodal metastases (e.g., liver, lung). Other systems For individual cancers  Duke staging for intestinal cancer

Cell Markers and Genetic Abnormalities for Hodgkin and Non-Hodgkin Lymphomas

HODGKIN LYMPHOMA

Hodgkin lymphoma with a Reed-Sternberg cell

In the center of the photomicrograph is a classic Reed-Sternberg cell,a binucleate cell with large “owl’s eyes” eosinophilic nucleoli.

Hodgkin lymphoma, nodular sclerosis variant

Note the nodules of lymphocytes and other hematopoietic cells divided by broad fibrous septae.

Hodgkin lymphoma, mixed cellularity variant

Note the Reed-Sternberg cell (arrowhead). The other cell types in this image are reactive (only the Reed-Sternberg cell is neoplastic) and include neutrophils, lymphocytes, and, prominently in this image,eosinophils.

NON-HODGKIN LYMPHOMA

Spleen, non-Hodgkin lymphoma. This spleen exhibits uniform multicentric involvement of the white pulp by a malignant lymphoma. These changes contribute to generalized splenomegaly.

Follicular lymphoma

This lymph node exhibits the characteristic low power features of follicular lymphoma, tightly packed lymphoid follicles of approximately equal size.

Follicular lymphoma involves this hilar lymph node. The black material (arrow) represents normal lymphoid parenchyma with anthracotic pigment displaced 

to one side by the expanding tan lymphomatous process.

Diffuse large B-cell lymphoma

The photomicrograph shows a sheet of monotonous large neoplastic cells with prominent nucleoli.

Burkitt lymphoma

This photomicrograph illustrates the characteristic low power features of Burkitt lymphoma, a sheet of neoplastic cells interspersed with punctate clearings (“starry sky pattern”). The punctate clearings are macrophages engulfing cellular debris. Burkitt lymphoma is an aggressive rapidly growingneoplasm with abundant cellular turnover, hence the presence of the macrophages

Hairy cell leukemia

In the upper left corner is a single neoplastic lymphoid cell. Note the fine hair-like projections from its surface.


General Category Specific Name of Genetic Abnormality of Lymphoma Lymphoma Cell Markers (if associated with one)

Hodgkin lymphoma 

• NS-HL CD 15, 30+ EBV
• MC-HL CD 15, 30+ EBV+
• LP-HL CD 20, EMA + CD 15, 30

Non-Hodgkin lymphoma 

• Follicular lymphoma CD 19,20, and 10+ t(14;18)–bcl-2 surface Ig, bcl-2+ 3q27 abnormalities

• Diffuse large B-cell CD 19,20, and 79a+ t(14;18)–bcl-2 lymphoma Surface Ig+ 3q27 abnormalities

• Burkitt lymphoma CD 10, 19 and 20+ t(8;14)–MYC Bcl-6 and surface Ig+

• Precursor T-cell lymphoblastic Tdt, CD 2 and 7+ Abnormalities of TAL1 leukemia/lymphoma

• Mantle cell lymphoma CD 19,20 and 5+ t(11;14)–cyclin D1 Surface Ig+ CD23

• MALToma CD19, 20 t(1;14)–bcl-10 t(11;18)

• Hairy cell leukemia CD 19, 20, 11c and 103 TRAP+

NS-HL, nodular sclerosis Hodgkin lymphoma; EBV, Epstein-Barr virus; EMA, epithelial membrane antigen; MC-HL, mixed cellularity Hodgkin lymphoma; LPHL,
lymphocyte predominant Hodgkin lymphoma; TRAP, tartrate-resistant acid phosphatase.

Developmental dysplasia of the hip (DDH)

Definition

• A spectrum of disorders ranging from complete dislocation of the femoral head to a reduced hip joint with acetabular dysplasia

Types:

1. Complete hip dislocation.

2. Partial hip subluxation.

3. Hip dysplasia (incomplete development).

Risk factors:

• family history - may reflect laxity of ligaments
• Race- common in white 
• Breech  presentation - Exaggerated positioning in acute flexion and adduction in utero may occur
• Female sex - the presence of maternal relaxin in the fetal circulatory system
• large fetal size 
• First born child

Galeazzi's test

• With the child is lying on a flat surface, flex the hips and knees so the heels rest flat on the table, just distal to the buttock . 
• A dislocated hip is signaled by relative shortening of the thigh compared with the normal leg, as shown by the difference in knee height level. 
• This test is almost always useless in children under 1 year of age and is negative if dislocation is bilateral.

Barlow's test

• This is a provocative test that picks up an unstable but located hip; it is unsuitable for a dislocated hip. 
• Thighs are gently grasped in the hand, with the thumb at the lesser trochanter and fingers at the greater trochanter . The hip is adducted slightly and gently pushed posteriorly with the palm. 
• Detection of "pistoning," or the sensation of the femoral head subluxating over the posterior rim of the acetabulum, is a positive finding.

Ortolani's test:

• This test detects hips that are already dislocated. 
• The flexed limb is grasped as in Barlow's test. The hip is abducted while the femur is gently lifted with the fingers at the greater trochanter. 
• In a positive test, there will be a sensation of the hip reducing back into the acetabulum. 

Clinical Manifestations

In newborn:

• We can diagnose DDH in this period by positive Ortolani’s test or Barlow’s test.
• Asymmetry of the skin fold may help, but its not specific. 
• Shortening of the limb at this age doesn’t exist.
• We cant use X-rays because the acetabulum and proximal femur are cartilaginous and wont be shown on X-ray.
• USG is the best method to Dx.

In the early childhood:

• Parents notice asymmetry of creases of groin, limitation of movement of affected hip or click every time hip is moved

In older children:

• Complaints of limping, waddling gait (bilateral DDH), Trendelenburg’s gait (unilateral DDH), lumbar lordosis, limitation of hip abduction, etc…

X-ray

Von Rosen view:

hips abducted 45º & medially rotated.

Anteroposterior.

We draw a line through the central axis of the femoral shaft.

        in normal hip ( ossific nucleus )will be inside the acetabulum.

        in dislocated hip it will be above acetabulum.

Delayed development of ossific nucleus / smaller

Horizontal line of Hilgenreiner:

   drawn between upper ends of tri-radiate cartilage of the acetabulum.

Vertical line of Perkins:

  drawn from the lateral edge of the acetabulum vertical to horizontal line.

4 quadrants:

Normal hip: the ossification center of the femoral hip lower medial quadrant.

Dislocated hip: upper lateral quadrant.

Acetabular index:

    angle between horizontal line of Hilgenreiner and the line between the two edges of the acetabulum.

    normal hip 20º-300 

    dilocated or dysplastic hip ≥ 30º

Shenton’s line:

    semicircle between femoral neck and upper arm of obturator foramen, in dislocated hip this line is broken.

Treatment:

The earlier the better. 

Exact treatment depends on patient age at presentation and degree of involvement

Goal is to:

1.Flex and abduct hips.

2.Reduce femoral head and maintaining it.

Reduction can be achieved by closed manipulation , traction followed by closed reduction and opened reduction  

 maintenance can be done using plaster cast(frog leg or Batchelor) or splint (von Rosen’s splint)

• Acetabular reconstruction procedure
• Salter’s osteotomy
• Chiari’s pelvic displacement osteotomy 
• Pemberton’s pericapsular osteotomy

• From (0-6 months)  

A dislocated hip at this age may spontaneously reduce over 2-3 weeks if the hip is held in a position of flexion. 

Reduction by closed manipulation and maintained with plaster cast or splint

• From 6 months -2 year

Gentle closed reduction of the dislocation under a general anesthetic and maintenance of a located position for 2-3 months in a hip spica cast usually stabilize the joint

• From the age of 2-6 years:

open reduction with osteotomy

• 6-10 years

No treatment for bilateral
Open reduction with reconstruction for unilateral

• After 10 years

Only indication for treatemnt is pain. If only one hip affected total hip replacement may be done.

Pathogenesis of Disseminated Intravascular Coagulation (DIC)

• Consumptive Coagulopathy
• Widespread coagulation leading to thrombin formation all over body and consumption of all platelets and coagulation factors.
• Everything is consumed, and there are thrombi all over body.
• Bleeding and vessel occlusion at the same time

• Which LAB parameters will be abnormal???
• All that you can think of….
• Bleeding time, PT, aPTT, D-dimer, Fibrin Split Products

CORONARY ARTERIES

From: Ascending aorta
To: Myocardium 

Right coronary artery. Originates from the anterior (new nomenclature: right) aortic sinus. It passes anteriorly between the pulmonary trunk and the right auricle to reach the atrioventricular sulcus in which it runs down the anterior surface of the right cardiac border and then onto the inferior surface of the heart. It terminates at the junction of the atrioventricular sulcus and the posterior interventricular groove by anastomosing with the circumflex branch of the left coronary artery and giving off the posterior interventricular (posterior descending) artery. It supplies the right atrium and part of the left atrium, the sinuatrial node in 60% of cases, the right ventricle, the posterior part of the inter- ventricular septum and the atrioventricular node in 80% of cases.
Left coronary artery. Arises from the left posterior (new nomenclature: left) aortic sinus. It passes laterally, posterior to the pulmonary trunk and anterior to the left auricle to reach the atrioventricular groove where it divides into an anterior interventricular (formally left anterior descending) artery and circumflex branches.
The circumflex artery runs in the atrio- ventricular sulcus around the left border of the heart to anastornose with the right coronary artery. The anterior inter-ventricular artery descends on the anterior surface of the heart in the anterior interventricular groove and around the apex of the heart into the posterior interven-
tricular groove where it anastomoses with the posterior interventricular branch of the right coronary artery. The left coronary artery supplies the left atrium, left ventricle, anterior interventricular septum, sinuatrial
node in 40% of cases and the atrioven- tricular node in 20%.
Dominance. In approximately 10% of hearts the posterior interventricular artery arises from the circumflex artery (left coronary) and then most of the left ventricle and interventricular septum are supplied by the
left coronary artery. The heart is said to have left cardiac dominance.