Haagensen's Grave signs

Haagensen's Grave signs are a group of signs that when present in patients of carcinoma breast indicate inoperability.
These signs were identified by Haagensen and Stout in a review of the clinical features of patients of breast cancer treated at their hospital in the 1940s. Presence of these signs were associated with a 0% probablity of 5 year cure and 50% risk of local recurrence.
The grave signs as given by the duo include:

1. Skin ulceration
2. Fixation of tumor to the chest wall
3. Axillary nodes > 2.5 cm in diameter
4. Edema of < 1/3rd of the skin of breast
5. Presence of fixed axillary nodes

They felt that presence of only one of these criterias didnot indicate inoperability per se but the probablity of cure with surgery was minimal if two signs were present.
In addition the authors also identified a subset of patient with extremely poor outcome. These patients included:

1. Extensive skin edema ( >50% skin involved)
   
2. Satellite skin nodules
3. Inflammatory type of cancer
4. Clinically involved SCF and Internal Mammary nodes
5. Edema of arms
6. Presence of any TWO grave signs given above.
   

The importance of this study of 1139 patients was that id defined the criteria of operability of patients. Patients with one grave sign were considered operable - but those with two grave signs or those with features of extremely poor outcome were not.
This system was used by the Columbia Clinical Classification System which was the standard of staging in carcinoma breast.
The system is as follows:

Stage A	No skin edema, ulceration, or solid fixation of the tumor to the chest wall. Axillary nodes are not involved clinically
Stage B	No skin edema, ulceration, or solid fixation of the tumor to the chest wall. Clinically involved nodes, but less than 2.5 cm in transverse diameter and not fixed to overlying skin or deeper structures of the axilla
Stage C	Any one of the five grave signs of advanced breast carcinoma:
	(1) Edema of the skin of limited extent (involving less than one-third of the skin over the breast)
	(2) Skin ulceration
	(3) Solid fixation of the tumor to the chest wall
	(4) Massive involvement of axillary lymph nodes (measuring 2.5 cm or more in transverse diameter)
	(5) Fixation of the axillary nodes to overlying skin or deeper structures of the axilla
Stage D	All other patients with more advanced breast carcinoma, including:
	(1) A combination of any two or more of the five grave signs listed under stage C
	(2) Extensive edema of the skin (involving more than one-third of the skin over the breast)
	(3) Satellite skin nodules
	(4) The inflammatory type of carcinoma
	(5) Clinically involved supraclavicular lymph nodes
	(6) Internal mammary metastases as evidenced by a parasternal tumor
	(7) Edema of the arm
	(8) Distant metastases

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Carcinoid Syndrome

Carcinoid syndrome is the most common systemic syndrome caused by carcinoid Tumors. The syndrome describes a symptom complex resulting from the secretion various bioactive amines secreted by carcinoid tumors. In addition to carcinoid syndrome other bioactive substances may also be secreted by the tumor especially in case of foregut carcinoids.
These include:

1. GI peptides: Most commonly Pancreatic Polypeptide secreted.
2. Ectopic ACTH secretion - Cushing Syndrome
3. Acromegaly - Growth hormone releasing factor (NOT GF per se!!).
4. Somatostatinoma Syndrome: Seen in Duodenal carcinoids - the syndrome is characterized by Insulin defeciency (DM and IGT - Often with ketoacidosis like Type I DM) ; Cholelithiasis - Due to defeciency of CCK - PZ enzyme - leading to impaired GB motility ; Steatorrhea - Secondary to pancreozyme defeciency - malabsorbtion ; Achlorhydria - secondary to Gastrin secretion inhibition.

Carcinoid Syndrome is characterized by several symptoms which can occur in a variety of combinations.
Overall about 8% of all patients have carcinoid syndrome - more common in patients with hepatic mets and larger tumors. The most common type is ileal carcinoids.
The main symptoms are:

• Flushing :
  
• Seen in 30 -60% patients
• Precipated by stress / exercise or certain foods and medicines
• Occurs due to excess secretion of serotonin by the tumor - majority is stored in platlets and a small amount reaches the systemic circulation,
• The typical flushing episode is a diffuse erythema of the face, neck and upper trunk associated with lacrimation, sweating, palpitations and itching.
• Flushing in case of bronchial carcinoids is more intense , prolonged and diffuse and associated with greater degree of symptoms
• In case of gastric carcinoids the flushing is patchy but intensly pruritic.
• Usually flushing lasts for 2 -5 mins but may be prolonged.
• Diarrhea:
• Typically in the form of watery diarrhea - it is secondary to decresed transit time due to increased colonic motility.
• Again serotonin is believed to be causative for the symptom,
• Diarrhea is associated with flushing in 85% patients and typically associated with an episode of flushing
• It may be associated with abdominal pain too.
• Cardiac Manifestations:
• These are in the form of fibrosis of the endomyocardium - secondary to TGF - beta production by the increased serotonin exposure
  
• As a result of the fibrosis there is Pulmonic stenosis as the valve is fibrosed in the closed position and there is also Tricuspid Regurgitation as the TV is fibrosed in the open position.
• Cardiac manifestations will be seen iin 10-66% of the patients but the severity is not related to the syndrome.
• Other manifestations:
• Wheeze due to asthma
• Pellagra like skin leison due to nicotinamide defeciency
• RA and athalgia
• Retroperitoneal fibrosis - uretral fibrosis and pyronnies disease

Diagnosis rests on the demonstration of raised 5-HIAA level in the urine - levels above 8 mg in a 24 hour sample is considered suggestive with symptoms.
Atypical carcinoid syndrome is seen in case of foregut carcinoids - here the serotonin is not formed but there is excretion of 5 - Hydroxy tryptamine which is converted to serotonin prior to excretion in the kidney - so that the urine shows increased serotonin excretion without increased serum serotonin.
Diagnostic accuracy is increased by the the measurement of urine and platelet serotonin estimations.

Presence of carcinoid syndrome is a poor prognostic factor - as they are usually in the presence of metastatic disease,

Treatment is directed towards possible surgical extripation of any removable tumor and hepatic mets specially if solitary or small.
Pharmacological treatment aims to ameliorate the symptoms by:

• Heart Failure - Diuretics
• Wheezing - bronchodilators
• Diarrhea - Loperamide + Serotonin receptor antagonists.
• Preventing action of serotonin:
• Blocking synthesis : Parachlorophenylalanine and alfa methyl dopa - obsolete.
  
• Serotonin receptor antagonists:
• Cyproheptadine, Ketanserine, Methesergide - Block 5 HT 1 and 5 HT2 receptors.
• 5HT 3 receptor antagonists - Ondansetrone, Alosetrone, tropisetron - control nause , diarrhea and flushing.
• Somatostatin analouges: These reduce secretion of serotonin and ameliorate the symptoms
• These are now the drugs of choice to control carcinoid syndrome.
• Octerotide and Lanreotide are used.
• Octreotide is started in doses of 100mg TDS S/C increased gradually - the main S/E are chronic like Steatorrhea, Cholelitiasis and DM
  
• Control is maintained for 1 year in 60% of the patients.
• Lanreotide is a sustained release preperation.
• Interferon Alfa - Has been used in combination with Octreotide - useful in combination with hepatic artery embolization. Can be combined with octreotide in patients resistent to either agent alone.
• Chemotherapy:
• Systemic Chemotherapy : DTIC + Adriamycin+ 5 FU with streptozotocin
• Chemoembolization - Adriamycin, Mitomycin C, Cisplatin and 5 FU
  

Carcinoid Tumors

Oberndorfer introduced the term carcinoid in 1907 to describe tumors that behaved more indolently than adenocarcinomas. These are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. They are neuroendocrine tumors and share certain common features with other NETs:

1. Monotonous cellular morphology
2. No reliable discriminator of malignancy - invasion and mets are the two features - so FNAC is useless.
3. Have electron dense secretory granules in EM scopy
4. Have small clear vesicles corresponding to the synaptic vesicles of neurons
5. Synthesize and secrete several BIOACTIVE amines and peptides eg:
1. NSE - General marker for APUDomas
   
2. Serotonin - Specific marker for Carcinoids - MC foregut and hindgut carcinoids - these are Masson Reaction -ve
   
3. Chrmogranin - General marker for NET
   
4. Synaptophysin - General marker for NET
6. React with Silver  - two reactions known:
1. Fixation of Silver and reduction - ARGENTAFFIN reaction (Masson) - Midgut carcinoids have this postive and serotonin negative
   
2. Fixation of Silver only - ARGYROPHILLIC reaction
   

Other examples of Neurendocrine tumors are:

• Pheochromocytomas
• MTC
• Pancreatic Endocrine Tumors
• Malignant Melanomas

As per the latest figures of the SEER database:

1. Foregut carcinoids account for 38.9 % of all carcinoids
2. Midgut carcinoids account for 46.8 % of all carcinoids
3. Hindgut carcinoids account for 18.5 % of all carcinoids

The most common sites for carcinoids are as follows:

1. Trachea/ Bronchi and Lungs = 25%
2. Small Intestine (Duodenum + Ileum + Jejunum) = 19%
3. Rectum = 18%
4. Colon and Appendix = 10%
   
5. Stomach = 6%

Features of Carcinoids according to site of origin:

• Midgut carcinoids are different from the rest two as:
• These often secrete serotonin and result most commonly in Carcinoid Syndrome
• Bone Mets are uncommon
• Blood and Urine biochemistry will revel the secretory pattern - 5 -HT and 5-HIAA
• The tumors reduce silver - argentoffin reaction positive.
  
• The the secretory granules are pleomorphic in shape but have a uniform density
• Uniform grwoth pattern
  
• Foregut and hindgut carcinoids on the other hand share some features like:
• Secrete 5-HTP not serotonin
• Therefore carcinoid syndrome is less common - however atypical carcinoid syndrome is common
• Bone Mets are common
  
• Blood and urine biochemistry reveal 5-HTP and 5-HIAA as well Histamine secretion
• Fix but NOT REDUCE silver - agyrophilic but not argentoffinic
• Secretory granules are uniform in shape but have variable density.
• Mixed Growth pattern - Trabecular or Solid
• Although these tumors are less commonly associated with carcinoid syndrome per se however they are more commonly associated with carcinoid crisis.
  

More differences can be found in this spreadsheet.
Foregut includes:

• UGI tract upto the Duodenum 2nd part
• Respiratory Tract
• GB / Pancreas/ Bile duct
  

Midgut includes:

• GI tract upto the transverse colon right half - drainage of SMA
  
• Ovary /Testis
• Cervix
• Liver

Special Features of Carcinoids at different sites - Important as classification systems rely on the site wise division

• Small Intestine:
• Overall account for almost 20% of all carcinoids
• Most occur within 2 feet  of the ileocecal valve (70%)
  
• Most are < 2 cm size (70%)
  
• Are associated with serotonin production and carcinoid syndrome
• Are associated with a fibrous desmoplastic reaction - so present with obstruction or ischemic necrosis
• Mets are seen in 70% if the size is > 2cm
• MC site of mets is the liver (60%)
• Median age of onset is 63 yrs.
• MC symptoms are related to abdominal pain and symptoms related to GI bleeding.
• Detection is difficult:
• Somatostatin Receptor Scintigraphy and CT are better detecting hepatic mets and bone mets - SRS should be the initial study for localization of mets. The approved agent for the scan is Indium Diethylenetriamine pentaacetic acid phenylanalys octreotide.
  
• Angiography more sensitive than CT for detecting liver mets.
• Treatment:
• For any small intestinal carcinoid the recommendation is wide local resection with dissection of the lymphnode areas with primary anastomosis.
  

• Stomach:
• Three subtypes are known:
• Type I: Associated with atrophic gastritis leading to secondary hypergastrinemia associated with MEN - I
  
• Type II: Associated with ZES in the setting of MEN - I and associated with primary hypergastrinemia
• Type III: Sporadic in nature and not associated with hypergastrinemia
• Paradoxically the Type III is least common and most aggressive. These are more commonly associated with carcinoid syndrome.
• MC detected by UGIE like duodenal carcinoids.
• Treatment:
• Endoscopic excision if tumor is < 2cm and for Type I and II carcinoids
• For tumors > 2 cm and Type III - Total gastrectomym with nodal clearance is recommended.
  
• Rectal:
• These are the most common type of hindgut carcinoid - the colonic carcinoids are MC seen in the region of the ileocecal valve
• Account for almost 18% of all carcinoids.
  
• These are commonly occuring in the anterolateral wall in the upper 1/3rd of the the rectum
• The tumors are mostly less than 2 cm size (c.f. small intestine carcinoids)
• Mets are seen in 70% if the size > 2cm
• Median age of onset is usually older around 66 yrs
• MC symptoms are bleeding and alteration of bowel habits.
• Detected by endoscopy.
• Treatment is:
• Localized the size is < 2cm.
• APR is recommended for tumors > 2 cm or those with muscalaris propria invasion - however all patients will die of metastatic disease
• For appendicular carcinoids < 1cm simple appendictomy is adequate
• For appendicular carcinoids > 1 cm a Rt hemicolectomy is recommended.
  
• Pulmonary Carcinoids:
• These accout for 25% of all carcinoids
  
• Not related with smoking.
  
• Considered to be a part of a continuum which includes the entity of small cell carcinoma
• 3 / 4 subtypes are said to occur: The classification scheme dividing these into 4 types given by Hage et al is the latest scheme
  
• Typical carcinoids are type I (KCC -I) - <2 mitoses per 2 mm2 - No necrosis - 85 - 100% 5 yr survival
  
• Atypical Carcinoids are Type II (KCC - II) - > 2 but <10 mitoses per 2 mm2 - punctate necrosis - 40 -70% 5 yr survival
  
• Large cell neuroendocrine tumor (KCC - III) - > 10 mitosis per 2 mm 2 and large areas of necrosis - 15 - 40% survival
  
• Small cell cancer
• Median age of onset is 63 years.
• MC symptoms are pneumonia, hemoptysis, and cough.
• MC detected on radiological investigations - on CXR these appear as opacities with sharp margins - Hilar nodal mets are usually absent.

The Important Prognostic Features associated with carcinoid tumors are:

• Site of presentation: Small bowel and pancreatic carcinoids have the poorest prognosis while appendicular and pulmonary are the best.
• Size of the tumor : Size > 2 cm associated with mets
• Pathological features:
• Atypical carcinoid in lung - necrosis and more mitosis
• Type III carcinoid in stomach - not associated with hypergastrinemia
• Extent of tumor invasion
  
• Presence of nodal invasion
• Mets - particularly hepatic mets.
• Highest probablity of metstatic disease is seen in pancreatic and small bowel carcinoids
• Lowest probablity is seen in rectal and laryngeal mets.
  
• Yound age
• Presence of carcinoid syndrome and high urinary 5 -HIAA excretion are associated with poorer prognosis.
  

The overll 5 yr survival for patients with localized disease is around 80% , for regional diseas is 50 -60% and those with mets 20%.

Ependymomas

Tumors arising from the ependymal cells lining the CSF pathways.
Ependymal cells are found in the :

• Cerebral Ventricles
  
• Vestigial Central Canal

Most commonly arise in the periventricular area.
Site of origin:

• Infratentorial location (60%) > Supratentorial location (40%)
  
• MC origin 4th ventricle.
  
• 4th ventricle > Spinal cord > Lateral Ventricles > 3rd Ventricles
  
• In supratentorial location tumors are intraventricular in 50% and parenchymal in 50%

Histology:

• Three Grades are known:
  
  • Grade I : Myxopapillary (arise in the cauda equina and filum terminale - excellent prognosis with excision alone)
    
  • Grade II: Majority of ependymomas with an intermediate prognosis
    
    • Cellular
      
    • Papillary
      
    • Clear Cell
      
    • Tanycytic
      
  • Grade III: Anaplastic astrocytoma with intermediate prognosis.

Clinical Features:
MC present with features of raised ICT
Account for 5% of the adult gliomas and 10% of childhood CNS tumors
Have bimodal incidence peak:

• 5 years
  
• 34 years

Diagnosis:

• CT / MRI are the imaging modality of choice
  
• CSF examination is done to rule out CSF spread
  
• Presence of a calcified mass leison in the ventricle correlates with an ependymoma
  
• Surgical excision is necessary for diagnosis

Treatment:

• MSR followed by adjuvant RT
  
• Not needed in Gr I ependymomas
  
• In others needed
  
• Need for CSI determined by risk of CSF spread:
  
  • Depends on:
    
    • Location : Infratentorial (5%) > Supratentorial (3%)
      
    • Grade : High grade (8%) > Low grade (4%)
      
  • Infratentorial, high grade leisons have 14%incidence of CSF spread.
    
  • Indications of CSI in ependymomas:
    
    • High grade, infratentorial leisons
      
    • Positive CSF cytology
      
    • Demonstrable radiological extension
      
    • All ependymoblastomas.
      
  • Radiation Dose:
    
    • 54 Gy by localized field around the tumor + margins
      
    • 30 -36 Gy to CSI if indicated
      
  • Radiation results:
    
    • With RT + Sx survival for Grade II ependymomas is in the range of 60 - 80% at 5 years
      
    • In case of anaplastic ependymomas the survival is lesser to the tune of 20 - 40%.
      
    • Ependymoblastomas have a poorer prognosis.
      
    • Pattern of failure: With localized fields predominent pattern of failure is local.

Future efforts:

• Integration of chemotherapy like TMZ - so far CCT has no benefit in Ependymomas
  
• Boosting the tumor volume with more conformal radiation techniques:
  
  • 3D CRT / IMRT
    
  • Stereotactic Radiosurgery
    
  • Hyperfractionated RT

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New Techniques in Radiotherapy

From: santam, 16 hours ago

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A summary of recent innovations in radiation oncology focussing on the principles of different techniques and their application. An overview of clinical results has also been given. Dealt with are 3D CRT , IMRT, IGRT, Adaptive Radiotherapy, Image Guided Brachytherapy, Stereotactic Radiotherapy and their clinical applications. The slideshow has been reposted in slideshare for download by all. Please be aware that it is a large download of 27 MB and is in the ODP format - meaning it can be seen in open office available free of cost at this place .


SlideShare Link

IMRT and 3 D CRT in Cervical Cancers

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Here is my presentation on IMRT and 3DCRT in carcinoma cervix. I have included a review of the contemporary literature for reference.

Radiofrequency Ablation

1. Principle

• High-frequency alternating current applied via an electrode(s) placed within the tissue generates ionic agitation as the ions attempt to change directions and follow the alternating current, thereby creating localised friction heat.

• Uses heat generated from ionic agitation inside the tissues after application of a RF current.

• The heat produces a rim of necrosis around a RFA needle.

2. Uses

1. Hepatocellular Cancers

1. Indications

• Tumors less than 3 cm size

• Away from the hepatic hilum

• Deep seated tumors

1. Contraindications

• 5 cm

• Multifocal tumors

• Tumors with major vessel invasion

• Tumors situated peripherally or near portal tracts

2. Breast Cancers

Localized breast cancers as an attempt for BCS

3. Lung Cancers

Tumors which are unresectable

4. Hepatic Mets

Primarily in colorectal CA mets 1 - 3 in number

3. Methods

1. Equipment

1. RFA Probe

Contains several needles which when extruded assume an umbrella like configuration

Uses 400 - 500 KHz AC current

Can produce a zone of necrosis with a diameter of 7 cm

2. RFA Generator

Generates RFA current between 400 - 500 KHz

1. Method

Imaging of the tumor to determine extent

Sedation and analgesia

Probe insertion under LA / GA

deployment of needles

Application of RFA energy

Removal while sealing the tract with heat

3. Grounding Pads

Allow an electrical circuit to form with patient and the RFA needle

4. Disadvantages

Cant be used for larger or multiple tumors

Regional failure can occur

Cant be used for tumors close to major vessels or nerves

Requires special imaging guidance and planning

Expense of needle

5. Advantages

Minimally invasive procedure - can be done percutaneously

Minimal pain

Time 20 - 30 min

Good control of the necrosis area

Can be repeated multiple times

04/11/2007 1/2

Tumor markers in Cancers

A spread sheet of the salient features in various tumor markers used in Cancers.
Here is the Link


The Page will be updated regularly so keep checking

Linear Accelearator Construction

Definition: It is a device that uses high frequency electromagnetic waves to accelerate charged particles, such as electrons to high energies through a linear tube.

Types of linear accelerator design:

1. Standing wave design
2. Traveling wave design

In the latter design there is a dummy load, which absorbs the excess power and prevents a reflected wave. In the standing wave design, there is reflection of the waves at both the ends of the structure, so that combinations of forward and reverse directed waves give rise to a standing wave design.

Principle:

Whether standing or traveling wave design linear accelerators used in medical purposes, accelerate electrons along electromagnetic waves or frequency in the microwave region that is around 3000 Hz.

Components of a linear accelerator:

1. The Magnetron

2. The Klystron

3. Accelerator tube

4. Gantry & treatment head:

a. Transmission target

b. Flattening filter, and scattering foil.

c. Dose monitoring chambers.

d. Collimators:

i. Photons

1. Primary collimator.

2. Secondary collimators

3. Multileaf collimators.

ii. Electrons

History:

The first medical linear accelerator was installed in the Hammersmith Hospital in United Kingdom, and Henry Kaplan was the first person to use it in Stanford in USA.

Description of each component:

1. D. C. power source is an independent power source for the machine.
2. The Moderator generates pulses off high-voltage direct current for both the Electron gun, and the Magnetron at the same time.
3. The electron gun consists of a metal filament and electrons are emitted by the principle of thermionic emission. The electrons have a energy of 50 KeV.
4. The Magnetron is a device, which generates microwaves.
1. Principle: In order to generate these microwaves, electrons are emitted from a cathode filament. A DC electric field is applied between the cathode and the anode while the static magnetic field is applied perpendicular to the plane of cross section of the cavities. Under the influence of the pulsed DC field, electrons are accelerated. Simultaneously due to the magnetic field, they begin moving in complex spirals.
2. Each Magnetron is a cylindrical structure containing a central cathode and an outer anode, with resonant cavities inside. As the Electron spiral into these cavities, they radiate microwave pulses.
3. Each microwave pulse has a frequency of 3000Hz.
5. The Klystron is a microwave amplifier. It needs a microwave oscillator to function.
1. Principle: An electron stream being accelerated across a potential difference is intercepted by a microwave beam. The electron velocity gets altered and these are separated into bunches. The electron bunches enter a cavity where they induce a charge which slows them down. As the electrons slow down they loose energy by radiation which is radiated as microwaves.
2. The high powered microwaves are then injected into the accelerator tube via the wave guide where they are used to set up a electromagnetic field.
6. The Accelerator tube is a long tube made of copper with diaphragms with holes where an electromagnetic wave is setup from the klystron / magnetron and electrons generated from the gun are accelerated. The principle is akin to the surfers of waves in ocean. The electron beam generated is usually of 3mm diameter.
7. The treatment head is the heavily shielded part of the machine where the electron beam or photon beam exits the machine and it contains:
1. Bending Magnets: Allow the electron beam to be bent at 90 or 270 degrees prior to striking the transmission target
2. Transmission target: Made up of a heavy metal where high speed electrons strike and generate an x-ray beam. The transmission target also “hardens” the beam by removing all the low energy photons. It is called a transmission target as all photons are passing through the target before emerging out.
3. Flattening filter: The beam emitted from the target is forward peaked and a flattening filter is placed in the pathway to ensure that the beam is flat across the field.
4. Dose monitoring chambers: Are special sealed ion chambers which monitor the:

i. Dose rate

ii. Integrated dose

iii. Field symmetry.

5. Scattering foils: Allow the thin electron pencil beam to be scattered using thin lead films so that a useful beam can be obtained.
6. Collimators: 4 types of collimators exist :

i. Primary Collimators: Where the beam is shaped into the useful size and unwanted photons are removed.

ii. Secondary Collimators: Allow customized shaping of the beam by two pairs of movable lead blocs which move in a fashion such that the edge is always parallel to the beam. The maximum field size is 40 x 40 cm when projected at the isocenter.

iii. Multileaf collimators.

iv. Electron Collimators: Are special devices called electron cones used to generate the electron field shape. These are usually attached to the machine externally.

7. Light localization system: Allows a visual reference to the x ray beam being generated.
8. Secondary trays: Allow mounting of accessories like shielding blocks and wedges underneath the treatment head.
7. Gantry: This entire assembly is mounted on a gantry which is usually isocentrically mounted i.e. the axis of rotation of the gantry, couch and collimator pass through the same point.