Difference between revisions of "Basics"

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==Pathology simplified==
==Pathology simplified==
===Blue & pink===
H&E is the standard...
H&E is the standard...
*Too much '''PINK''' = DEAD ([[necrosis]]).
*Too much '''PINK''' = DEAD ([[necrosis]]).
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In words:
In words:
*''Blue is bad and pink is dead!''<ref>Often said by STC.</ref>
*''Blue is bad and pink is dead!''<ref>Streutker, C. 8 June 2013.</ref>


Note:
Note:
*Lymph nodes are very blue... they aren't necessarily bad.
*There is a lengthy list of things that are blue and ''not'' "bad"... that why a pathology residency is years.
**[[Lymph node]]s are very blue... they aren't necessarily bad.
**Reactive processes can be very blue... they aren't bad.
 
===Three questions===
Pathology can be boiled down to:
#What is it?
#*Biopsies.
#Did I get it all?
#*Resections.
#Did I get the right thing?
#*Most other things.


==Terms==
==Terms==
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*''Argyrophilic'' means has an affinity for silver<ref>URL: [http://www.merriam-webster.com/medical/argyrophilic http://www.merriam-webster.com/medical/argyrophilic]. Accessed on: 29 August 2011.</ref><ref>URL: [http://en.wiktionary.org/wiki/argyrophilic http://en.wiktionary.org/wiki/argyrophilic]. Accessed on: 29 August 2011.</ref>/loves silver/stains with silver.
*''Argyrophilic'' means has an affinity for silver<ref>URL: [http://www.merriam-webster.com/medical/argyrophilic http://www.merriam-webster.com/medical/argyrophilic]. Accessed on: 29 August 2011.</ref><ref>URL: [http://en.wiktionary.org/wiki/argyrophilic http://en.wiktionary.org/wiki/argyrophilic]. Accessed on: 29 August 2011.</ref>/loves silver/stains with silver.
===Morphologic patterns===
===Morphologic patterns===
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
{{Main|Morphologic patterns}}
! Name of pattern
This covers things like ''cribriform'', ''hobnail'', ''herring bone'' and many others.
! Meaning
! DDx (incomplete/abbrev. list)
! Image
|-
| Hobnail
| basement membrane area < area exposed to luminal surface
| [[angiosarcoma]], clear cell carcinoma
| [http://commons.wikimedia.org/wiki/File:Epithelioid_angiosarcoma_-_high_mag.jpg angiosarcoma - high mag. (WC)]
|-
| Storiform
| spiral appearance ''or'' cartwhell pattern<ref>Storiform. dictionary.com. URL: [http://dictionary.reference.com/browse/storiform http://dictionary.reference.com/browse/storiform]. Accessed on: April 24, 2009.</ref>
| [[solitary fibrous tumour]], [[DFSP]], [[dermatofibroma]], [[UPS]]
| [http://commons.wikimedia.org/w/index.php?title=File:Storiform_pattern_-_intermed_mag.jpg DFSP - intermed. mag. (WC)],[http://commons.wikimedia.org/wiki/File:Solitary_fibrous_tumour_intermed_mag.jpg SFT - intermed. mag. (WC)]
|-
| Fascicular
| the long axis of the (spindle) cells are perpendicular to one another in adjacent bundles of cells
| [[leiomyoma]], [[leiomyosarcoma]]
| [http://commons.wikimedia.org/wiki/File:Cutaneous_leiomyosarcoma_-_intermed_mag.jpg leiomyosarcoma - intermed. mag. (WC)], [http://cal.vet.upenn.edu/projects/derm/Home/UNCLASS/heman.htm Hemangiopericytoma (upenn.edu)]
|-
| Plexiform
| web-like formation<ref>URL: [http://www.mondofacto.com/facts/dictionary?plexiform http://www.mondofacto.com/facts/dictionary?plexiform]. Accessed on: March 9, 2010.</ref>
| [[plexiform neurofibroma]], [[MPNST]], plexiform lesion of [[pulmonary hypertension]]
| [http://www.flickr.com/photos/bc_the_path/1715728630/ plexiform lesion of Pulm. HTn (flickr.com)]
|-
| Cribriform
| pierced with small holes<ref>URL: [http://dictionary.reference.com/browse/cribriform http://dictionary.reference.com/browse/cribriform]. Accessed on: 8 August 2011.</ref>
| cribriform [[DCIS]], cribriform [[HGPIN]], cribriforming in a [[tubular adenoma]] with high-grade dysplasia, endometrioid endometrial carcinoma
| [http://www.breastpathology.info/Sloane/Images/dcis/crib3b-400.jpg cribriform DCIS (breastpathology.info)]<ref name=sloane/>
|-
| Solid ''or'' Sheeting
| no architecture - back-to-back cells with no pattern apparent / no spaces between cells
| solid DCIS, poorly-differentiated carcinoma
| [http://www.breastpathology.info/Sloane/Images/dcis/solid1-400.jpg solid DCIS (breastpathology.info)]<ref name=sloane/>
|-
| Micropapillary
| nipple like projections without a fibrovascular core (papillary = nipple-like<ref>URL: [http://dictionary.reference.com/browse/papillary http://dictionary.reference.com/browse/papillary]. Accessed on: 8 August 2011.</ref>)
| micropapillary DCIS, micropapillary HGPIN
| [http://www.breastpathology.info/Sloane/Images/dcis/micropap1-400.jpg micropapillary DCIS (breastpathology.info)]<ref name=sloane/>
|-
| Papillary
| nipple-like projection with a fibrovascular core
| [[papillary thyroid carcinoma]]
| [http://commons.wikimedia.org/wiki/File:Papillary_renal_cell_carcinoma_high_mag.jpg papillary RCC - high mag. (WC)]
|-
| Flat
| board-like, does not have a projection above the surface
| flat DCIS
| [http://www.breastpathology.info/Sloane/Images/dcis/flat1-400.jpg flat DCIS 1 (breastpathology.info)],<ref name=sloane/> [http://www.breastpathology.info/Sloane/Images/dcis/flat2-400.jpg flat DCIS 2 (breastpathology.info)]<ref name=sloane>URL: [http://www.breastpathology.info/Sloane/dcis.html http://www.breastpathology.info/Sloane/dcis.html]. Accessed on: 8 August 2011.</ref>
|-
| Herring bone
| like herring bone (technique) for climbing a hill in cross country skiing; books on a shelf, where they have partially fallen over -- on the one shelf to the left and the one below to the right
| [[fibrosarcoma]], [[synovial sarcoma]], [[MPNST]]
| [http://commons.wikimedia.org/wiki/File:Malignant_peripheral_nerve_sheath_tumour_-_intermed_mag.jpg MPNST intermed. mag.(WC)], [http://commons.wikimedia.org/wiki/File:Malignant_peripheral_nerve_sheath_tumour_-_high_mag.jpg MPNST - high mag.(WC)]
|-
| [[Trabecular]] ''or'' cords
| trabecula = ''little beam''<ref>URL: [http://dictionary.reference.com/browse/trabecula http://dictionary.reference.com/browse/trabecula]. Accessed on: 26 December 2010.</ref>; quasi-linear arrangement of cells
| normal liver lobule, [[Sertoli cell tumour]]
| [http://commons.wikimedia.org/wiki/File:Sertoli_cell_tumour_low_mag.jpg Sertoli cell tumour - low mag. (WC)], [http://commons.wikimedia.org/wiki/File:Papillary_thyroid_carcinoma_tall_cell_var_intermed_mag.jpg PTC - intermed. mag. (WC)].
|-
| Nested (nesting)
| islands of cells with a circular outline
| neuroendocrine tumours
| [http://commons.wikimedia.org/wiki/File:Small_intestine_neuroendocrine_tumour_low_mag.jpg neuroendocrine tumour - low mag. (WC)]
|-
| Biphasic
| two patterns; e.g. nests of cells and stroma
| [[synovial sarcoma]], [[DSRCT]], [[alveolar RMS]]
| [http://commons.wikimedia.org/wiki/File:Desmoplastic_small_round_cell_tumour_-_high_mag.jpg DSRCT - high mag. (WC)]
|}


===Nuclear destruction words===
===Nuclear destruction words===
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Image:  
Image:  
*[http://upload.wikimedia.org/wikipedia/en/5/51/Nuclear_changes.jpg Karyolysis, pyknosis, karyorrhexis (wikimedia.org)].
*[http://en.wikipedia.org/wiki/File:Nuclear_changes.jpg Karyolysis, pyknosis, karyorrhexis (WP)].


==DDx in medicine==
===Erosions and ulcers===
*Ulcer = lesion through skin or mucous membrane.
*Erosion = limited to the mucosa - superficial ulceration.
**In dermatopathology - through the epidermis.
 
Image:
<gallery>
Image:Ulcers,_fissures,_and_erosions.svg | Ulcers and erosions - schematic. (WC)
</gallery>
====Microscopic - erosion====
Features - require 1 and 2:
#Loss of epithelium.
#Vital response at site of lost epithelium.
#*[[Neutrophil]]ic infiltrate.
#*+/-Fibrin.
#*+/-Cellular debris.
 
Image:
*[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400158/figure/f4-cln_67p705/ Mucosal erosion (nih.gov)].<ref name=pmid22892912>{{Cite journal  | last1 = Arashiro | first1 = RT. | last2 = Teixeira | first2 = MG. | last3 = Rawet | first3 = V. | last4 = Quintanilha | first4 = AG. | last5 = Paula | first5 = HM. | last6 = Silva | first6 = AZ. | last7 = Nahas | first7 = SC. | last8 = Cecconello | first8 = I. | title = Histopathological evaluation and risk factors related to the development of pouchitis in patients with ileal pouches for ulcerative colitis. | journal = Clinics (Sao Paulo) | volume = 67 | issue = 7 | pages = 705-10 | month = Jul | year = 2012 | doi =  | PMID = 22892912 | PMC = 3400158 | URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400158/}}</ref>
 
==The general differential diagnosis==
Mnemonic ''CINE-TV-DATE'':
Mnemonic ''CINE-TV-DATE'':
*Congenital.
*Congenital.
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In diagnostic pathology, most stuff falls into the ''neoplastic'' category.
In diagnostic pathology, most stuff falls into the ''neoplastic'' category.


===Cytologic features & malignancy===
===Features of malignancy===
It is said that usually:<ref name=boerner>S. Boerner. 12 September 2011.</ref>
====Cytologic features of malignancy====
It is said that:<ref name=boerner>S. Boerner. 12 September 2011.</ref>
#It is the nuclear abnormalities that make a cell malignant.  
#It is the nuclear abnormalities that make a cell malignant.  
#The cytoplasm that gives one clues as to the cell of origin.
#The cytoplasm that gives one clues as to the cell of origin.
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| weak
| weak
|-
|-
| Nuclear-to-cytoplasmic ratio
| [[Nuclear-to-cytoplasmic ratio]]
| strong
| strong
|-
|-
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§ mitoses are seen in poorly differentiated tumour and regeneration.  High mitotic rate in the context of unremarkable nuclear morphology is usually not malignant.
§ mitoses are seen in poorly differentiated tumour and regeneration.  High mitotic rate in the context of unremarkable nuclear morphology is usually not malignant.


===Basic pathologic [[DDx]] of malignancy===
====Other features====
As a pathologist, this should ''always'' be the first question:
In the context of [[soft tissue lesions]], it is said that the two most important features of malignancy are:
#[[Necrosis]].
#High vascularity.
 
Notes:
*Benign soft tissue lesions may have marked [[nuclear atypia]] and abundant mitotic activity.
 
===General differential diagnosis of malignant lesion===
This should ''always'' be considered:
<center>
<center>
<!--
<!--
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{{familytree | | | |A11| | | | |A11 = Malignancy          }}
{{familytree | | | |A11| | | | |A11 = Malignancy          }}
{{familytree | |,|-|-|^|-|-|.|}}
{{familytree | |,|-|-|^|-|-|.|}}
{{familytree | B11 | | | | B12 |B11=Primary|B12=Metastatic }}
{{familytree | B11 | | | | B12 |B11=Primary|B12=[[metastasis|Metastatic]] }}
{{familytree/end}}
{{familytree/end}}
</center>
</center>
Q. Why? <br>
Q. Why? <br>
A. The site of the tumour can considerably change the differential diagnosis. <br><br>
A. (1) The site of the tumour can considerably change the differential diagnosis. (2) The management is usually totally different.<br><br>
After primary vs. metastasis:
 
===A general clinico-histomorphologically motivated differential diagnosis of malignancy===
<center>
<center>
<!--
<!--
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{{familytree | | | | | | | | | | | A | | | | | | | | | | |A=Malignancy}}
{{familytree | | | | | | | | | | | A | | | | | | | | | | |A=Malignancy}}
{{familytree | |,|-|-|-|v|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| |}}
{{familytree | |,|-|-|-|v|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| |}}
{{familytree | B | | C | | D | | E | | F | |G |B=Epithelial<br>(Carcinoma)|C=Mesenchymal<br>(Sarcoma)|D=Germ cell<br>tumour|E=Neuroendocrine<br>carcinoma|F=Lymphoid<br>(Lymphoma)|G=Malignant<br>melanoma}}
{{familytree | B | | C | | D | | E | | F | |G |B=Epithelial<br>(Carcinoma)|C=Mesenchymal<br>([[Sarcoma]])|D=[[Germ cell tumours|Germ cell<br>tumour]]|E=[[Neuroendocrine carcinoma|Neuroendocrine<br>carcinoma]]|F=Hematologic|G=[[Melanoma|Malignant<br>melanoma]]}}
{{familytree/end}}
{{familytree/end}}
</center>
</center>


Notes:
Notes:
*''Melanoma'', i.e. ''[[malignant melanoma]]'', is a separate category as it can look like almost anything under the microscope.
*''[[Malignant melanoma]]'', also ''melanoma'', is a separate category as it can look like almost anything under the microscope.
*''[[Lymphoma]]'' includes leukemia.
*''Hematologic'' includes [[lymphoma]], [[leukemia]], [[plasma cell neoplasms]] and others.
*The above is a useful clinical classification. The problem is it isn't that useful for difficult cases as:
**Germ cell tumours are often not distinctive.
**Numerous epithelioid sarcomas can mimic carcinomas.
**Spindle cell carcinomas can mimic sarcomas very well.
**Neuroendocrine differentiation  is not always readily apparent.
**The ''[[modified general morphologic DDx of malignancy]]'' is better for approaching difficult tumours.
Memory device ''HMN GEM'': hematologic, melanoma, neuroendocrine carcinoma, germ cell, epithelial, mesenchymal.


===Morphologic grouping===
====Morphologic categorization====
=====Factors to consider=====
Factors to consider when attempting to group by morphology:
Factors to consider when attempting to group by morphology:
#Cell shape (spindle cell, epithelioid, plasmacytoid, mixed).
#Cell size (small or large) - size in relation to a neutrophil or [[red blood cell]].
#Cell cohesion - dyscohesive vs. cohesive.
#Cell cohesion - dyscohesive vs. cohesive.
#*If one sees several groups of 5+ cells... probably cohesive.
#*If one sees several groups of 5+ cells... probably cohesive.
#*Presence of cell cohesion strongly disfavours lymphoma.
#*Presence of cell cohesion strongly disfavours lymphoma.
#Cell size - in relation to a neutrophil or red blood cell.
#Cytoplasm - abundance (scant, moderate, abundant).
#Cytoplasm - abundance (scant, moderate, abundant).
#*Eosinophilic cytoplasm disfavours lymphoma.
#*Eosinophilic cytoplasm disfavours lymphoma.
#*Oncocytic - possessing copious eosinophilic granular cytoplasm.
#**Benign lesions composed of oncocytes - oncocytoma
#**Oncocytic metaplasia (alteration of cytoplasm) can effect all or a part of a lesion.
#**Oncocytic neoplasms are common in the kidneys, thyroid and salivary glands.
#**Oncocytic change increases with age
#**May represent senescent accumulation of mitochondria in secretory epithelial.
#Chromatin - coarseness (fine, granular).
#Chromatin - coarseness (fine, granular).
#Nucleoli - number (absent, present, multiple).
#Nucleoli - number (absent, present, multiple).
#*Large [[nucleoli]] (nucleoli seen with the 10x objective) pretty much exclude neuroendocrine.
#*Large [[nucleoli]] (nucleoli seen with the 10x objective) pretty much exclude neuroendocrine.


Probable category by morphology:
======Types of cells======
*Carcinoma = cohesive, relatively large (>~2X neutrophil), +/-nucleolus, +/-gland formation (circular structures), often moderate to abundant cytoplasm.
{| class="wikitable sortable"
*Sarcoma = cohesive, composed of spindle cells (cells taper at both ends, nucleus oval/cigar-shaped).
! Type
*Germ cell tumour = appearance often similar to ''carcinoma''.
! Morphology
*Neuroendocrine carcinoma = cohesive, fine granular chromatin and no nucleolus.
! Significance
*Lymphoma = dyscohesive, relatively small (usually <=2X neutrophil diameter), usu. scant basophilic (blue) cytoplasm.
|-
*Melanoma = classically pigmented, often a prominent [[red nucleolus]], a mix of spindle cells and epithelioid cells, mix of cohesive and dyscohesive cells.
| [[Spindle cell]]
| tapered at both ends<ref>URL: [http://www.medterms.com/script/main/art.asp?articlekey=25657 http://www.medterms.com/script/main/art.asp?articlekey=25657]. Accessed on: 18 January 2010.</ref>
| suggestive of sarcoma - compatible with melanoma and some carcinomas
|-
| Epithelioid cell
| cell shape round/oval, nucleus round/oval, looks like epithelium (cell borders touch neighbouring cells - collectively form a barrier)
| suggests epithelial lesion (carcinoma) - compatible with others
|-
| [[Small round blue cell tumour]]/lymphoid:
| small cells with scant cytoplasm - usually round; "small" is classically 2x a "resting lymphocyte" diameter †
| common in children; in adults often lymphoma
|-
| Small lymphoid ([[small cell lymphoma]]).
| "small" in the context of lymphoid is classically ~1x a "resting lymphocyte" diameter; often not malignant by cytology
| suggests [[small cell lymphoma]], reactive changes or infection
|-
| Plasmacytoid cell
| resemble a plasma cell: eccentric nucleus, moderate basophilic cytoplasm, +/-"clockface" chromatin pattern (clumping of chromatin at the periphery of the nucleus), +/-perinuclear hof (crescentic cytoplasmic clearing adjacent to the nucleus; represents abundant Golgi apparatus
| suggests [[plasma cell neoplasm]] or infection
|}
 
Note:
*† Diameter of a "resting lymphocyte" ~ diameter of a [[red blood cell]] (RBC) ~ 8 micrometres.
**Most carcinoma cells are 3-4x the size of a RBC.


====Dyscohesive vs. cohesive====
======Dyscohesive versus cohesive======
Deciding cells are dyscohesive vs. cohesive is important, as it is a strong determinant of whether one is dealing with a lymphoid lesion or not.
Deciding cells are dyscohesive vs. cohesive is important, as it is a strong determinant of whether one is dealing with a lymphoid lesion or not.


{| class="wikitable"
{| class="wikitable sortable"
!|
!|
!| Cell spacing
!| Cell spacing
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*Basophilic cytoplasm.
*Basophilic cytoplasm.


===Histomorphologic classification===
=====Probable category by morphology=====
Types of cells:
*Carcinoma = cohesive, relatively large (>~2X neutrophil), +/-nucleolus, +/-gland formation (circular structures), often moderate to abundant cytoplasm.
*[[Spindle cell]]:
*Sarcoma = cohesive, composed of spindle cells (cells taper at both ends, nucleus oval/cigar-shaped).
**Tapered at both ends.<ref>URL: [http://www.medterms.com/script/main/art.asp?articlekey=25657 http://www.medterms.com/script/main/art.asp?articlekey=25657]. Accessed on: 18 January 2010.</ref>
*Germ cell tumour = appearance often similar to ''carcinoma'', site (location) very useful - esp. gonadal, midline, retroperitoneal.
**Suggests mesenchyme, i.e. sarcoma, compatible with melanoma and some carcinomas.
*[[Neuroendocrine carcinoma]] = cohesive, fine granular chromatin and no [[nucleolus]].
*Plasmacytoid cell.
*Lymphoma = dyscohesive, relatively small (usually <=2X neutrophil diameter), usu. scant basophilic (blue) cytoplasm.
**Resemble a plasma cell: eccentric nucleus, moderate basophilic cytoplasm, +/-"clockface" chromatin pattern (clumping of chromatin at the periphery of the nucleus), +/-perinuclear hof (crescentic cytoplasmic clearing adjacent to the nucleus; represents abundant Golgi apparatus).  
*Melanoma = classically pigmented, often a prominent [[red nucleolus]], a mix of spindle cells and epithelioid cells, mix of cohesive and dyscohesive cells.
*Epithelioid cell.
 
**Looks like epithelium - cell borders touch neighbouring cells so that the cells collectively form a barrier.
===A practical histomorphologic differential diagnosis of malignancy===
*[[Small round blue cell tumour]]:
====General morphologic DDx of malignancy====
**Small cells with scant cytoplasm.
{{familytree/start}}                     
***"Small" is classically 2x a "resting lymphocyte" diameter.
{{familytree  | | | | | | | A01 | | | | | | | | A01=Malignancy}}
****Diameter of a "resting lymphocyte" ~ diameter of a [[red blood cell]] (RBC) ~ 8 micrometres.
{{familytree  | |,|-|-|-|v|-|^|-|v|-|-|-|.| | |}}
****Most carcinoma cells are 3-4x the size of a RBC.
{{familytree  | B01 | | B02 | | B03 | | B04 | |B01=[[Large epithelioid tumours]]|B02=[[spindle cell lesions|Spindle cell tumours]]|B03=[[small round cell tumours|Small blue cell tumours]]|B04=[[Pleomorphic tumours]]}}
{{familytree/end}}
 
====Modified general morphologic DDx of malignancy====
<center>
{{familytree/start}}
{{familytree | | | | | | | | | | | A | | | | | | | | | | |A=Malignancy}}
{{familytree | |,|-|-|-|v|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| |}}
{{familytree | B | | C | | D | | E | | F | |G |B=[[Large epithelioid tumours]]|C=[[spindle cell lesions|Spindle cell tumours]]|D=[[small round cell tumours|Small blue cell tumours]]|E=[[Pleomorphic tumours]]|F=[[Clear cell tumours]]|G=[[myxoid lesions|Myxoid tumours]]}}
{{familytree/end}}
</center>
 
The above is more useful than the ''general clinico-histomorphologically motivated differential diagnosis of malignancy''.
 
==Differential diagnosis by site==
{{Main|Short power list}}
It is essential to have a concept of what is common.  The ''[[short power list]]'' gives a short [[differential diagnosis]] for the common sites.
 
{{Main|Long power list}}
The ''[[long power list]]'' is a longer list for the common sites.


==Finding the elements==
==Finding the elements==
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*Apoptotic cell -- has nuclear condensation (pyknosis), eosinophilic cytoplasm.
*Apoptotic cell -- has nuclear condensation (pyknosis), eosinophilic cytoplasm.


Images:
====Images====
<gallery>
Image:Atypical_mitosis.jpg| Mitoses and an atypical mitosis. (WC)
Image:Tripolar_Mitosis_-_breast_carcinoma.jpg| Tripolar mitosis. (WC)
</gallery>
www:
*[http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab4/IMAGES/MITOSIS%20IN%20GUT.JPG Mitoses (vetmed.vt.edu)].
*[http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab4/IMAGES/MITOSIS%20IN%20GUT.JPG Mitoses (vetmed.vt.edu)].
*[http://commons.wikimedia.org/wiki/File:Atypical_mitosis.jpg Mitoses and an atypical mitosis (WC)].
*[http://commons.wikimedia.org/wiki/File:Tripolar_Mitosis_-_breast_carcinoma.jpg Tripolar mitosis (WC)].
*[http://www.flickr.com/photos/euthman/426956752/ Starburst mitosis (flicker.com)].
*[http://www.flickr.com/photos/euthman/426956752/ Starburst mitosis (flicker.com)].


====Phases of mitosis====
====Phases of mitosis====
*Prophase. - chromatin condenses to chromosomes.
*Prophase - chromatin condenses to chromosomes.
*Metaphase - chromosome aligned.
*Metaphase - chromosome aligned.
*Anaphase - spindles separated.
*Anaphase - spindles separated.
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*A collection of PMNs... think about ''necrosis'' and ''abscess''.
*A collection of PMNs... think about ''necrosis'' and ''abscess''.


===Lymph node metstatsis===
===Lymph node metastasis===
{{Main|Lymph node metastasis}}
{{Main|Lymph node metastasis}}
*Take a good to look at the tumour first.
*Take a good to look at the tumour first.
*Tumour in a node is often better differentiated than the most poorly differentiated part in the primary site.
*Tumour in a node is often better differentiated than the most poorly differentiated part in the primary site.
*Subcapsular space - the first place to look for mets.
*Subcapsular space - the first place to look for mets.
*Lymph node metstasis are usually obvious.
*Lymph node metastasis are usually obvious.
*Histiocytes may be difficult to separate from tumour - especially initially.
**There are of course exceptions, e.g. [[small cell carcinoma]], [[invasive lobular carcinoma]].
**Histiocytes (usually) are in germinal centres, i.e. the node architecture helps.
*Histiocytes may be difficult to separate from tumour - especially for the novice.
**Malignant cells, generally, have to have malignant features, i.e. the NC ratio is abnormal, there is [[nuclear pleomorphism]].
**Histiocytes may be found in the germinal centres, i.e. the node architecture helps.
**Malignant cells, generally, have to have malignant features, i.e. the [[NC ratio]] is abnormal, there is [[nuclear pleomorphism]].
*Several things can mimic metastases - see ''[[Lymph node metastasis]]''.


See: ''[[Lymph node]]'' article for a detailed description of cell types in a lymph node.
See: ''[[Lymph node]]'' article for a detailed description of cell types in a lymph node.


===Signet ring cells===
===Signet ring cell carcinoma===
Definition:
{{Main|Signet ring cell carcinoma}}
*Signet ring cells resemble [http://www.engravingarts.com/sales/LVX2.jpg signet rings (image)].
*It has been said that there are two types of pathologists... those that have missed SRCs ''and'' those that will miss SRCs.
**They contain a large amount of mucin, which pushes the nucleus to the cell periphery. The pool of mucin in a signet ring cell mimics the appearance of a finger hole and the nucleus mimics the appearance of the face of the ring in profile.


Microscopy:
Microscopic:
*Typically 2-3x the size of a lymphocyte.
*Cells resemble signet rings:
**They contain a large amount of mucin, which pushes the nucleus to the cell periphery.
**The pool of mucin in a signet ring cell mimics the appearance of a finger hole.
**The nucleus mimics the appearance of the face of the ring in profile.
*Cells typically 2-3x the size of a lymphocyte.
**Smaller than the typical adipocyte.
**Smaller than the typical adipocyte.
*Often have a [http://en.wikipedia.org/wiki/File:Crescent.svg cresentic-shaped] nucleus, or ovoid nucleus.
*Often have a crescent-shaped ''or'' ovoid nucleus.
**Capillaries sectioned on their lumen have endothelial cells-- the nuclei of these are more spindled.
**Capillaries sectioned on their lumen have endothelial cells -- the nuclei of these are more spindled.
*SRCs are usually close to friend (another SRC)
*SRCs are usually close to friend -- another SRC.
**This helps differentiate SRCs from capillaries sectioned on their lumen.
**This helps differentiate SRCs from capillaries sectioned on their lumen.
*The mucin is often clear on H&E... but maybe eosinophilic.
*The mucin is often clear on H&E... but maybe eosinophilic.
DDx:
*[[Fat atrophy]].


Stains:
Stains:
Line 337: Line 378:
*Alican blue-PAS stain.
*Alican blue-PAS stain.


Images:
====Images====
*[http://commons.wikimedia.org/wiki/File:Signet_ring_cells_5.jpg SRCs (H&E) by Nephron (WC)].
<gallery>
*[http://commons.wikimedia.org/wiki/File:Gastric_signet_ring_cell_carcinoma_histopatholgy_(2)_PAS_stain.jpg SRC AL-PAS stain (WC)].
Image:Signet_ring_cells_5.jpg |SRCs - H&E stain. (WC/Nephron)
*[http://commons.wikimedia.org/wiki/File:Gastric_signet_ring_cell_carcinoma_histopatholgy_(1).jpg SRC H&E stain (WC)].
Image:Gastric_signet_ring_cell_carcinoma_histopatholgy_(2)_PAS_stain.jpg | SRCs - AL-PAS stain. (WC)
Image:Gastric_signet_ring_cell_carcinoma_histopatholgy_(1).jpg | SRC - H&E stain. (WC)
</gallery>
www:
*[http://www.engravingarts.com/sales/LVX2.jpg Signet rings (engravingarts.com)].


Comment:
*It has been said that there are two types of pathologists... those that have missed SRCs ''and'' those that will miss SRCs.


===Necrosis===
===Necrosis===
Line 361: Line 404:
*[http://www.nature.com/bmt/journal/v39/n9/fig_tab/1705646f1.html Necrosis (nature.com)].
*[http://www.nature.com/bmt/journal/v39/n9/fig_tab/1705646f1.html Necrosis (nature.com)].
*[http://moon.ouhsc.edu/kfung/jty1/Com08/Com08Image/Com801-1-09.gif Necrosis (ouhsc.edu)].<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/Com08/Com801-1-Diss.htm http://moon.ouhsc.edu/kfung/jty1/Com08/Com801-1-Diss.htm]. Accessed on: 3 November 2010.</ref>
*[http://moon.ouhsc.edu/kfung/jty1/Com08/Com08Image/Com801-1-09.gif Necrosis (ouhsc.edu)].<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/Com08/Com801-1-Diss.htm http://moon.ouhsc.edu/kfung/jty1/Com08/Com801-1-Diss.htm]. Accessed on: 3 November 2010.</ref>
*[http://commons.wikimedia.org/wiki/File:Cat_scratch_disease_-_very_high_mag.jpg Necrosis in cat scratch disease (WC)].
<gallery>
*[http://commons.wikimedia.org/wiki/File:Histiocytic_necrotizing_lymphadenitis_-_very_high_mag.jpg Necrosis in histiocytic necrotizing lymphadenitis (WC)].
Image:Cat_scratch_disease_-_very_high_mag.jpg | Necrosis in [[cat scratch disease]]. (WC/Nephron)
*[http://commons.wikimedia.org/wiki/File:Systemic_lupus_erythematosus_lymphadenopathy_-_high_mag.jpg Necrosis in SLE lymphadenopathy (WC)].
Image:Histiocytic_necrotizing_lymphadenitis_-_very_high_mag.jpg | Necrosis in [[histiocytic necrotizing lymphadenitis]]. (WC/Nephron)
Image:Systemic_lupus_erythematosus_lymphadenopathy_-_high_mag.jpg | Necrosis in [[SLE lymphadenopathy]]. (WC/Nephron)
</gallery>


==Granulomas==
==Granulomas==
*Granulomas can be elusive to the novice.
{{Main|Granuloma}}
*Plural of ''granuloma'' was ''granulomata''; ''granulomas'' (an anglicized version) is, however, now generally accepted.
 
===Definition of granuloma===
*Many definitions exist.
*The term is used rather loosely by clinicans.
**Radiologists occasionally call small lung nodules "granulomas".
 
====Strict pathologic definition====
Robbins definition:
*Chronic inflammatory reaction characterized by the focal accumulation of activated macrophages, often with an epithelioid appearance.<ref name=Ref_PBoD82>{{Ref PBoD|82}}</ref>
**"Epithelioid" cells = cells whose morphology resembles that of epithelial cells; the cells appear to adhere to one another.
 
Adams definition - it's short & sweet:
*A compact collection of macrophages.<ref name=pmid937513>{{cite journal |author=Adams DO |title=The granulomatous inflammatory response. A review.  |journal=American Journal of Pathology |volume=84 |issue=1 |pages=164&ndash;191 |year=1976 |pmid=937513 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2032357/?tool=pubmed}}</ref>
**The macrophages must form a small ball/cluster of cells, i.e. touch one another.
 
Other pathologic definitions include the presence of:<ref name=pmid937513/>
*Plasma cells.
*Lymphocytes.
*Epithelioid macrophages.
 
Notes:
*The textbook answer for what is a granuloma is: "A collection of epitheliod macrophages."
**Granulomas are often associated with lymphocytes.
 
===Features that assist one in finding granulomas===
#Collection of cells that have abundant bubbly cytoplasm - '''most useful feature'''.
#*Image: [http://commons.wikimedia.org/wiki/File:Granuloma_20x.jpg Granulomas showing abundant bubbly cytoplasm (WC)].
#'''Multinucleated [[giant cells]]''' - these are easy to identify if you've seen some before.
#*Individual/singular multinucleated giant cells are not diagnostic of a granuloma... but should raise one's suspicion of one being present.
#*Image: [http://commons.wikimedia.org/wiki/File:Asteroid_body_intermed_mag.jpg Granulomas with multinucleated giant cells in sarcoidosis (WC)].
#Necrosis - too much pink (on H&E stained sections).
#*Image: [http://commons.wikimedia.org/wiki/File:Necrogran10x.jpg Granuloma with necrosis (WC)].
 
Notes:
*Small round collection of lymphocytes - without a capsule (as seen in lymph nodes).
**If there are no macrophages... it's a ''lymphoid nodule''.
 
====As a list====
Features:<ref>GS. 26 January 2010.</ref>
#Foamy/bubbly cytoplasm, abundant - '''low power'''.
#Epithelioid morphology - cell borders ''near'' indistinct - '''key feature'''.
#"Footprint" pattern nuclei/bean-shaped nuclei - '''key feature'''.
#*Macrophages usu. have an ovoid nucleus.
#+/-Nucleoli, small.
#+/-Fibrosis.
#+/-Pallisading at edge.
 
===Classification of granuloma===
====Histologic classification====
#Necrosing (also ''caseating'').
#*More likely to be infectious.
#*Examples: Tuberculosis (TB).
#Non-necrosing.
#*Less likely to be infectious.
#*Examples: Crohn's disease, sarcoidosis, drug reaction.
 
Whether necrosis is present in a granuloma is affected by the immune function, e.g. a [[HIV]]/AIDS patient may have non-necrosing granulomata due to TB.
 
Notes:
*A few people differentiate between ''caseating'' (fragments of recognizable tissue) and ''necrosing'' (dead debris only).<ref name=pmid17257125>{{Cite journal  | last1 = El-Zammar | first1 = OA. | last2 = Katzenstein | first2 = AL. | title = Pathological diagnosis of granulomatous lung disease: a review. | journal = Histopathology | volume = 50 | issue = 3 | pages = 289-310 | month = Feb | year = 2007 | doi = 10.1111/j.1365-2559.2006.02546.x | PMID = 17257125 }}</ref>
*Infectious non-necrosing infections: Mycobacterium avium complex (MAC), cryptococcus, immunosuppressed individual.<ref name=pmid17257125/>
 
====Etiologic classification====
#Infectious, e.g. tuberculosis, MAC, leprosy, [[syphilis]], cat-scratch disease, schistosomiasis,<ref name=Ref_PCPBoD8_47>{{Ref PCPBoD8|47}}</ref> fungal infection.
#Neoplastic, e.g. [[seminoma]].
#Autoimmune, e.g. [[Wegener's granulomatosis]], [[Churg-Strauss syndrome]].
#Allergic, e.g. [[hypersensitivity pneumonitis]].
#Foreign body, e.g. pulmonary talcosis, silicosis, berylliosis.<ref name=Ref_PCPBoD8_47>{{Ref PCPBoD8|47}}</ref>
#Drug reaction.
#Idiopathic, e.g. [[sarcoidosis]].
 
Notes:
*Memory device: ''DNF AAII'' = drug reaction, neoplasm, foreign body, allergy, autoimmune, idiopathic, infection.
 
===Lung granulomata===
There are many causes.<ref name=pmid17257125/>
 
Infectious:
*Myocbacterial: Tuberculosis, MAC, other.
*Fungal: [[Histoplasmosis]], [[Cryptococcosis]], [[Blastomycosis]], [[Coccidioidomycosis]].
*Aspiration pneumonia.
Non-infectious:
*Pneumoconioses/[[hypersensitivity pneumonitis]]: Talcosis, Berylliosis.
Idiopathic/autoimmune:
*[[Sarcoidosis]].
*[[Wegener's granulomatosis]].
*[[Churg-Strauss disease]].
*[[Rheumatoid nodules]].
 
===Special granulomas===
====Fibrin ring granuloma====
*Classically associated with ''Q fever''.
**DDx:<ref name=pmid11881318>{{cite journal |author=Tjwa M, De Hertogh G, Neuville B, Roskams T, Nevens F, Van Steenbergen W |title=Hepatic fibrin-ring granulomas in granulomatous hepatitis: report of four cases and review of the literature |journal=Acta Clin Belg |volume=56 |issue=6 |pages=341–8 |year=2001 |pmid=11881318 |doi= |url=}}</ref> infections (Coxiella burneti (causes Q fever), [[CMV]], [[EBV]] + others), drug reaction, malignancy (e.g. Hodgkin lymphoma<ref name=pmid8514044>{{cite journal |author=de Bayser L, Roblot P, Ramassamy A, Silvain C, Levillain P, Becq-Giraudon B |title=Hepatic fibrin-ring granulomas in giant cell arteritis |journal=Gastroenterology |volume=105 |issue=1 |pages=272–3 |year=1993 |month=July |pmid=8514044 |doi= |url=}}</ref>).
*Appearance:
**Epithelioid macrophages (i.e. a granuloma) surrounding a fibrin ring with a clear (lipid-filled) vacuole at its center.
***Images:
****[http://en.gooword.com/picture/864449/ FRG (gooword.com)].
****[http://www.pathconsultddx.com/pathCon/largeImage?pii=S1559-8675(06)70951-2&figureId=fig1 FRG (pathconsultddx.com)].<ref>URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675(06)70951-2 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675(06)70951-2]. Accessed on: 9 December 2010.</ref>


==Common morphologic problems==
==Common morphologic problems==
Line 475: Line 421:
*'''S'''mooth muscle cells (SMCs).
*'''S'''mooth muscle cells (SMCs).


Images:
=====Images=====
*[http://commons.wikimedia.org/wiki/File:Ovarian_fibroma_-_high_mag.jpg Collagen - ovarian fibroma (WC)].
<gallery>
*[http://commons.wikimedia.org/wiki/File:Cardiac_amyloidosis_high_mag_he.jpg Amyloid - cardiac amyloidosis (WC)].
Image:Cardiac_amyloidosis_high_mag_he.jpg | Cardiac amyloid. (WC/Nephron)
Image:Laminations_in_a_thrombus_-_high_mag.jpg | Fibrin in a thrombus. (WC/Nephron)
Image:Ovarian_fibroma_-_high_mag.jpg | Collagen in an ovarian fibroma. (WC/Nephron)
Image:Glatte_Muskelzellen.jpg | Smooth muscle. (WC/Polarlys)
</gallery>


====Smooth muscle cells (SMCs) vs. fibrous tissue====
====Smooth muscle cells (SMCs) vs. fibrous tissue====
Line 496: Line 446:
*Schwann cells (found in nerve): nuclei = wavy appearance, thin. (???)
*Schwann cells (found in nerve): nuclei = wavy appearance, thin. (???)


===DDx of (brown) granular crap===
===Pigmented material===
*[[AKA]] brown/black granular crap.
 
DDx of granular stuff/pigment:
DDx of granular stuff/pigment:
#Lipofuscin - especially in old people.
#Lipofuscin - especially in old people.
#Hemosiderin.
#Hemosiderin.
#Bile - found in hepatocytes, yellow.
#Bile - found in hepatocytes, yellow.
#Foreign material (tattoo pigment, anthracotic pigment).
#Foreign material (tattoo pigment, anthracotic pigment, [[amalgam tattoo]]).
#Melanin.
#Melanin.


Notes:
Notes:
*Granular stuff should prompt consideration of ''malignant melanoma''.
*Granular stuff should prompt consideration of ''malignant melanoma''.
*Memory device: '''''M'''änner '''l'''ieben '''f'''eine '''BH'''s'' = Melanin, Lipofuscin, Foreign, Bile, Hemosiderin.
*Memory device ''BH MILF''   = Bile, Homogentisic acid, Melanin, Iron (hemosiderin), Lipofuscin, Foreign material.
*''Homogentisic acid'' found in ''alkaptonuria'',<ref name=Ref_PCPBoD8_20>{{Ref PCPBoD8|20}}</ref>can be considered the sixth (black) pigment.
*''Homogentisic acid'' found in ''alkaptonuria'',<ref name=Ref_PCPBoD8_20>{{Ref PCPBoD8|20}}</ref>can be considered the sixth (black) pigment.
**Gentisic = jen-TIS-ik.<ref>URL: [http://dictionary.reference.com/browse/gentisic+acid http://dictionary.reference.com/browse/gentisic+acid]. Accessed on: 11 January 2012.</ref>


====[[Stains]] that can help sort it out====
====[[Stains]] that can help sort it out====
*Prussian blue (iron stain) for hemosiderin.
*Prussian blue (iron stain) for hemosiderin.
*Melan A for melanin.
*[[Fontana-Masson stain]] (or ''Melan A'') for melanin.
*[[PAS stain]]<ref name=pmid5463681 >{{cite journal |author=Kovi J, Leifer C |title=Lipofuscin pigment accumulation in spontaneous mammary carcinoma of A/Jax mouse |journal=J Natl Med Assoc |volume=62 |issue=4 |pages=287–90 |year=1970 |month=July |pmid=5463681 |pmc=2611776 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2611776/pdf/jnma00512-0077.pdf}}</ref> ''or'' Kluver-Barrera for lipofuscin.
*[[PAS stain]]<ref name=pmid5463681 >{{cite journal |author=Kovi J, Leifer C |title=Lipofuscin pigment accumulation in spontaneous mammary carcinoma of A/Jax mouse |journal=J Natl Med Assoc |volume=62 |issue=4 |pages=287–90 |year=1970 |month=July |pmid=5463681 |pmc=2611776 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2611776/pdf/jnma00512-0077.pdf}}</ref> ''or'' Kluver-Barrera for lipofuscin.


Line 525: Line 478:
{{main|Pathology and food}}
{{main|Pathology and food}}


==Clinician talk==
===General surgeon talk===
*"[[R2 resection]]" = macroscopic tumour left. 
*"[[R1 resection]]" = microscopic tumour left.
*"[[R0 resection]]" = clean margin macroscopically & microscopically.


Generally, positive margins suck; in locally advanced rectal cancer survival, in one study,<ref>{{cite journal |author=Larsen SG, Wiig JN, Dueland S, Giercksky KE |title=Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer |journal=Eur J Surg Oncol |volume=34 |issue=4 |pages=410–7 |year=2008 |month=April |pmid=17614249 |doi=10.1016/j.ejso.2007.05.012 |url=}}</ref> five year survival was found to be 60%, 31% and 0% for R0, R1, and R2 resections respectively.
==Tumour remaining==
{{Main|Surgical margins}}
''R classification'':<ref>URL: [http://www.informedicalcme.com/colon-cancer/tnm-stage-groupings/ http://www.informedicalcme.com/colon-cancer/tnm-stage-groupings/]. Accessed on: 27 March 2012.</ref>
*"RX resection" = residual tumour cannot be assessed.
*"R0 resection" = clean margin macroscopically & microscopically.
*"R1 resection" = microscopic tumour left.
*"R2 resection" = macroscopic tumour left. 
 
Surgeons use this terminology. Essentially, it is the margin status. It is nice when the surgeon's assessment and the pathologist's are in agreement.


===Oncologist talk===
Note:
*Generally, positive margins suck. For example, in locally advanced rectal cancer, in one study,<ref name=pmid17614249>{{cite journal |author=Larsen SG, Wiig JN, Dueland S, Giercksky KE |title=Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer |journal=Eur J Surg Oncol |volume=34 |issue=4 |pages=410–7 |year=2008 |month=April |pmid=17614249 |doi=10.1016/j.ejso.2007.05.012 |url=}}</ref> five year survival was found to be 60%, 31% and 0% for R0, R1, and R2 resections respectively.
 
==Clinician talk==
===Performance status===
*ECOG - score from 1-5 for performance status.<ref name=pmid7165009>{{cite journal |author=Oken MM, Creech RH, Tormey DC, ''et al.'' |title=Toxicity and response criteria of the Eastern Cooperative Oncology Group |journal=Am. J. Clin. Oncol. |volume=5 |issue=6 |pages=649–55 |year=1982 |month=December |pmid=7165009 |doi= |url=}}</ref>
*ECOG - score from 1-5 for performance status.<ref name=pmid7165009>{{cite journal |author=Oken MM, Creech RH, Tormey DC, ''et al.'' |title=Toxicity and response criteria of the Eastern Cooperative Oncology Group |journal=Am. J. Clin. Oncol. |volume=5 |issue=6 |pages=649–55 |year=1982 |month=December |pmid=7165009 |doi= |url=}}</ref>
**ECOG =  Eastern Cooperative Oncology Group.
**ECOG =  Eastern Cooperative Oncology Group.
Line 586: Line 546:


Note:
Note:
*Most of the resident [[microscope]]s, at U of T, have an eye piece diameter of 22 mm. Therefore, the field diameter at 40 X is approximately 22 mm / 40 X ~= 0.55 mm and the field of view is pi/4*(0.55 mm)^2 = 0.2376 mm^2.
*Most modern [[microscope]]s, have an eye piece diameter of 22 mm. Therefore, the field diameter at 40 X is approximately 22 mm / 40 X ~= 0.55 mm and the field of view is pi/4*(0.55 mm)^2 = 0.2376 mm^2.


==Pathology reports==
==Pathology reports==
There is no universal standard; however, there is a push to standardize by the ''Association of Directors of Anatomic and Surgical Pathology'',<ref>URL: [http://www.adasp.org/papers/position/Standardization.htm http://www.adasp.org/papers/position/Standardization.htm]</ref> among others.
{{Main|Pathology reports}}
 
The key point in report writing is that the report should be precise, complete and easy-to-understand.  
Standards lead to uniformity and consistency.<ref name=pmid7878300>{{cite journal |author=Leslie KO, Rosai J |title=Standardization of the surgical pathology report: formats, templates, and synoptic reports |journal=Semin Diagn Pathol |volume=11 |issue=4 |pages=253–7 |year=1994 |month=November |pmid=7878300 |doi= |url=}}</ref>
 
Something close to a standard is laid-out in by Goldsmith et al..<ref name=pmid18834219>Reporting guidelines for clinical laboratory reports in surgical pathology. Goldsmith JD, Siegal GP, Suster S, Wheeler TM, Brown RW. Arch Pathol Lab Med. 2008 Oct;132(10):1608-16. PMID 18834219.</ref>


===Standards===
===Standards===
Based on a PubMed search,<ref>URL: [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=PureSearch&db=PubMed&details_term=standardization,%20surgical%20pathology%20report Pubmed search for ''standardization, surgical pathology report'']. </ref> the first papers on the topic of standards were written in 1992!<ref name=pmid1574498>{{cite journal |author=Rosai J, Bonfiglio TA, Corson JM, ''et al.'' |title=Standardization of the surgical pathology report |journal=Mod. Pathol. |volume=5 |issue=2 |pages=197–9 |year=1992 |month=March |pmid=1574498 |doi= |url=}}</ref><ref name=pmid1574486>{{cite journal |author=Frable WJ, Kempson RL, Rosai J |title=Quality assurance and quality control in anatomic pathology: standardization of the surgical pathology report |journal=Mod. Pathol. |volume=5 |issue=2 |pages=102a–102b |year=1992 |month=March |pmid=1574486 |doi= |url=}}</ref>
There is no universal standard; however, there is a push to standardize by the ''Association of Directors of Anatomic and Surgical Pathology'',<ref>URL: [http://www.adasp.org/papers/position/Standardization.htm http://www.adasp.org/papers/position/Standardization.htm]</ref> among others.


====Checklists====
====Checklists====
{{Main|CAP checklists}}
The College of American Pathologists (CAP) has checklists for cancer - [http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=committees%2Fcancer%2Fcancer_protocols%2Fprotocols_index.html&_state=maximized&_pageLabel=cntvwr CAP protocols].
The College of American Pathologists (CAP) has checklists for cancer - [http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=committees%2Fcancer%2Fcancer_protocols%2Fprotocols_index.html&_state=maximized&_pageLabel=cntvwr CAP protocols].


Line 604: Line 562:
Surgeons know that checklists work and that they save lives.<ref name=pmid19158173>{{cite journal |author=Soar J, Peyton J, Leonard M, Pullyblank AM |title=Surgical safety checklists |journal=BMJ |volume=338 |issue= |pages=b220 |year=2009 |pmid=19158173 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19158173}}</ref>
Surgeons know that checklists work and that they save lives.<ref name=pmid19158173>{{cite journal |author=Soar J, Peyton J, Leonard M, Pullyblank AM |title=Surgical safety checklists |journal=BMJ |volume=338 |issue= |pages=b220 |year=2009 |pmid=19158173 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19158173}}</ref>
Pilots have been using checklists since the 1930s.
Pilots have been using checklists since the 1930s.
An excellent book about checklists is: ''The checklist manifesto'' by Harvard surgeon Dr. Atul Gawande.<ref>Gawande A. The checklist manifesto: How to get things right. Metropolitan Books. 2009. URL: [http://www.amazon.com/dp/0805091742 http://www.amazon.com/dp/0805091742]. ISBN-13 978-0805091748.</ref>


===Standard diagnostic notation===
===Standard diagnostic notation===
Line 617: Line 573:
Gallbladder, cholecystectomy:<br>
Gallbladder, cholecystectomy:<br>
- Acute cholecystitis.
- Acute cholecystitis.
==Lab talk==
{{Main|Cutting}}
Tissue cutting terms - these often vary from lab-to-lab:<ref>URL: [http://www.mailman.srv.ualberta.ca/pipermail/patho-l/2002-July/016955.html http://www.mailman.srv.ualberta.ca/pipermail/patho-l/2002-July/016955.html]. Accessed on: 18 October 2011.</ref>
*Recut = cut off the top of the block.
*Serial sections = make several cuts off the top of the block and look at all of 'em.
*Level = trim the block ~30 micrometres --throw away trimmed tissue-- and then cut a section to look at.
*Deeper = trim the block ~100 micrometres --throw away trimmed tissue-- and then cut a section to look at.


==See also==
==See also==
*[[Granulation tissue]].
*[[Granulation tissue]].
*[[No truth in names]].
*[[Blood work]].
*[[Quality]].


==References==
==References==

Latest revision as of 03:29, 14 July 2016

This article serves as an introduction to anatomical pathology and discusses the basics.

Pathology simplified

Blue & pink

H&E is the standard...

  • Too much PINK = DEAD (necrosis).
  • Too much BLUE = BAD.

In words:

  • Blue is bad and pink is dead![1]

Note:

  • There is a lengthy list of things that are blue and not "bad"... that why a pathology residency is years.
    • Lymph nodes are very blue... they aren't necessarily bad.
    • Reactive processes can be very blue... they aren't bad.

Three questions

Pathology can be boiled down to:

  1. What is it?
    • Biopsies.
  2. Did I get it all?
    • Resections.
  3. Did I get the right thing?
    • Most other things.

Terms

Staining

Morphologic patterns

This covers things like cribriform, hobnail, herring bone and many others.

Nuclear destruction words

There are several fancy terms:[5]

  • Karyolysis = nuclear fading/dissolution.
  • Pyknosis = nuclear shrinkage.
  • Karyorrhexis = nuclear fragmentation.

Image:

Erosions and ulcers

  • Ulcer = lesion through skin or mucous membrane.
  • Erosion = limited to the mucosa - superficial ulceration.
    • In dermatopathology - through the epidermis.

Image:

Microscopic - erosion

Features - require 1 and 2:

  1. Loss of epithelium.
  2. Vital response at site of lost epithelium.

Image:

The general differential diagnosis

Mnemonic CINE-TV-DATE:

  • Congenital.
  • Inflammatory.
  • Neoplastic.
  • Endocrine.
  • Trauma.
  • Vascular.
  • Degenerative.
  • Autoimmune.
  • Toxic.
  • Everything else (iatrogenic, idiopathic, psychiatric).

In diagnostic pathology, most stuff falls into the neoplastic category.

Features of malignancy

Cytologic features of malignancy

It is said that:[7]

  1. It is the nuclear abnormalities that make a cell malignant.
  2. The cytoplasm that gives one clues as to the cell of origin.

Nuclear features and malignancy:[7]

Feature Strength in predicting malignancy?
Large nuclear size weak
Nuclear-to-cytoplasmic ratio strong
Nuclear pleomorphism weak
Nucleoli shape (angulated, spiked, complex) strong
Nucleoli size weak - generally; strong if like in a RS cell
High nucleoli number weak negative; finding favours benign
Chromatin hyperchromasia weak
Chromatin granularity strong
Nuclear membrane irregularities strong (clefting, flat edges, sharp angles),
scalloped (suggests benign)
Mitoses weak §
Atypical mitoses strong

§ mitoses are seen in poorly differentiated tumour and regeneration. High mitotic rate in the context of unremarkable nuclear morphology is usually not malignant.

Other features

In the context of soft tissue lesions, it is said that the two most important features of malignancy are:

  1. Necrosis.
  2. High vascularity.

Notes:

  • Benign soft tissue lesions may have marked nuclear atypia and abundant mitotic activity.

General differential diagnosis of malignant lesion

This should always be considered:

 
 
 
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary
 
 
 
Metastatic

Q. Why?
A. (1) The site of the tumour can considerably change the differential diagnosis. (2) The management is usually totally different.

A general clinico-histomorphologically motivated differential diagnosis of malignancy

 
 
 
 
 
 
 
 
 
 
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epithelial
(Carcinoma)
 
Mesenchymal
(Sarcoma)
 
Germ cell
tumour
 
Neuroendocrine
carcinoma
 
Hematologic
 
Malignant
melanoma

Notes:

  • Malignant melanoma, also melanoma, is a separate category as it can look like almost anything under the microscope.
  • Hematologic includes lymphoma, leukemia, plasma cell neoplasms and others.
  • The above is a useful clinical classification. The problem is it isn't that useful for difficult cases as:
    • Germ cell tumours are often not distinctive.
    • Numerous epithelioid sarcomas can mimic carcinomas.
    • Spindle cell carcinomas can mimic sarcomas very well.
    • Neuroendocrine differentiation is not always readily apparent.
    • The modified general morphologic DDx of malignancy is better for approaching difficult tumours.

Memory device HMN GEM: hematologic, melanoma, neuroendocrine carcinoma, germ cell, epithelial, mesenchymal.

Morphologic categorization

Factors to consider

Factors to consider when attempting to group by morphology:

  1. Cell shape (spindle cell, epithelioid, plasmacytoid, mixed).
  2. Cell size (small or large) - size in relation to a neutrophil or red blood cell.
  3. Cell cohesion - dyscohesive vs. cohesive.
    • If one sees several groups of 5+ cells... probably cohesive.
    • Presence of cell cohesion strongly disfavours lymphoma.
  4. Cytoplasm - abundance (scant, moderate, abundant).
    • Eosinophilic cytoplasm disfavours lymphoma.
    • Oncocytic - possessing copious eosinophilic granular cytoplasm.
      • Benign lesions composed of oncocytes - oncocytoma
      • Oncocytic metaplasia (alteration of cytoplasm) can effect all or a part of a lesion.
      • Oncocytic neoplasms are common in the kidneys, thyroid and salivary glands.
      • Oncocytic change increases with age
      • May represent senescent accumulation of mitochondria in secretory epithelial.
  5. Chromatin - coarseness (fine, granular).
  6. Nucleoli - number (absent, present, multiple).
    • Large nucleoli (nucleoli seen with the 10x objective) pretty much exclude neuroendocrine.
Types of cells
Type Morphology Significance
Spindle cell tapered at both ends[8] suggestive of sarcoma - compatible with melanoma and some carcinomas
Epithelioid cell cell shape round/oval, nucleus round/oval, looks like epithelium (cell borders touch neighbouring cells - collectively form a barrier) suggests epithelial lesion (carcinoma) - compatible with others
Small round blue cell tumour/lymphoid: small cells with scant cytoplasm - usually round; "small" is classically 2x a "resting lymphocyte" diameter † common in children; in adults often lymphoma
Small lymphoid (small cell lymphoma). "small" in the context of lymphoid is classically ~1x a "resting lymphocyte" diameter; often not malignant by cytology suggests small cell lymphoma, reactive changes or infection
Plasmacytoid cell resemble a plasma cell: eccentric nucleus, moderate basophilic cytoplasm, +/-"clockface" chromatin pattern (clumping of chromatin at the periphery of the nucleus), +/-perinuclear hof (crescentic cytoplasmic clearing adjacent to the nucleus; represents abundant Golgi apparatus suggests plasma cell neoplasm or infection

Note:

  • † Diameter of a "resting lymphocyte" ~ diameter of a red blood cell (RBC) ~ 8 micrometres.
    • Most carcinoma cells are 3-4x the size of a RBC.
Dyscohesive versus cohesive

Deciding cells are dyscohesive vs. cohesive is important, as it is a strong determinant of whether one is dealing with a lymphoid lesion or not.

Cell spacing Cell membrane Cytoplasm, abundance Cytoplasm, staining
Cohesive equal spacing or 3-D clusters or intracellular bridges visible & opposed (in >50% of cells) scant to abundant any
Dyscohesive unequal spacing, thin space surrounds cell not apparent usually scant usually basophilic
Value/utility equal or 3-D clusters suggests cohesive, pericellular space/rim suggests dyscohesive visible opposed membrane r/i cohesive abundant usu. cohesive eosinophilic usu. cohesive

Strong predictors of cohesive:

  • Intracellular bridges.
  • 3-D clusters.
  • Nuclear moulding.

Weak predictors of cohesive:

  • Eosinophilic cytoplasm.
  • Abundant cytoplasm.
  • >2 X RBC diameter (most lymphoma smaller).

Weak predictors of dyscohesive:

  • Pericellular space/rim.
  • Scant cytoplasm.
  • Basophilic cytoplasm.
Probable category by morphology
  • Carcinoma = cohesive, relatively large (>~2X neutrophil), +/-nucleolus, +/-gland formation (circular structures), often moderate to abundant cytoplasm.
  • Sarcoma = cohesive, composed of spindle cells (cells taper at both ends, nucleus oval/cigar-shaped).
  • Germ cell tumour = appearance often similar to carcinoma, site (location) very useful - esp. gonadal, midline, retroperitoneal.
  • Neuroendocrine carcinoma = cohesive, fine granular chromatin and no nucleolus.
  • Lymphoma = dyscohesive, relatively small (usually <=2X neutrophil diameter), usu. scant basophilic (blue) cytoplasm.
  • Melanoma = classically pigmented, often a prominent red nucleolus, a mix of spindle cells and epithelioid cells, mix of cohesive and dyscohesive cells.

A practical histomorphologic differential diagnosis of malignancy

General morphologic DDx of malignancy

 
 
 
 
 
 
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Large epithelioid tumours
 
Spindle cell tumours
 
Small blue cell tumours
 
Pleomorphic tumours
 

Modified general morphologic DDx of malignancy

 
 
 
 
 
 
 
 
 
 
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Large epithelioid tumours
 
Spindle cell tumours
 
Small blue cell tumours
 
Pleomorphic tumours
 
Clear cell tumours
 
Myxoid tumours

The above is more useful than the general clinico-histomorphologically motivated differential diagnosis of malignancy.

Differential diagnosis by site

It is essential to have a concept of what is common. The short power list gives a short differential diagnosis for the common sites.

The long power list is a longer list for the common sites.

Finding the elements

Mitoses

  • Nucleus darker (hyperchromatic) - key feature.
  • No nuclear membrane - key feature.
  • In prophase chromatin may have a scalloped border/beaded border.[9]

DDx:

  • Apoptotic cell -- has nuclear condensation (pyknosis), eosinophilic cytoplasm.

Images

www:

Phases of mitosis

  • Prophase - chromatin condenses to chromosomes.
  • Metaphase - chromosome aligned.
  • Anaphase - spindles separated.
  • Telophase - reversal of prophase.

Neutrophils

  • Little dots = the multilobular nucleus - key feature.
  • Neutrophils are often found with friends, i.e. lymphocytes, plasma cells.

DDx of little specs:

  • Nuclear debris - apoptotic cell.
    • Apoptotic cell -- has nuclear condensation (pyknosis), eosinophilic cytoplasm.

Notes:

  • AKA PMNs - polymorphonuclearcyte, polymorphonuclear cell.
  • You find PMNs by their nucleus; on a histologic section don't bother looking for the cell membrane (they are usually impossible to see).
  • A collection of PMNs... think about necrosis and abscess.

Lymph node metastasis

  • Take a good to look at the tumour first.
  • Tumour in a node is often better differentiated than the most poorly differentiated part in the primary site.
  • Subcapsular space - the first place to look for mets.
  • Lymph node metastasis are usually obvious.
  • Histiocytes may be difficult to separate from tumour - especially for the novice.
    • Histiocytes may be found in the germinal centres, i.e. the node architecture helps.
    • Malignant cells, generally, have to have malignant features, i.e. the NC ratio is abnormal, there is nuclear pleomorphism.
  • Several things can mimic metastases - see Lymph node metastasis.

See: Lymph node article for a detailed description of cell types in a lymph node.

Signet ring cell carcinoma

  • It has been said that there are two types of pathologists... those that have missed SRCs and those that will miss SRCs.

Microscopic:

  • Cells resemble signet rings:
    • They contain a large amount of mucin, which pushes the nucleus to the cell periphery.
    • The pool of mucin in a signet ring cell mimics the appearance of a finger hole.
    • The nucleus mimics the appearance of the face of the ring in profile.
  • Cells typically 2-3x the size of a lymphocyte.
    • Smaller than the typical adipocyte.
  • Often have a crescent-shaped or ovoid nucleus.
    • Capillaries sectioned on their lumen have endothelial cells -- the nuclei of these are more spindled.
  • SRCs are usually close to friend -- another SRC.
    • This helps differentiate SRCs from capillaries sectioned on their lumen.
  • The mucin is often clear on H&E... but maybe eosinophilic.

DDx:

Stains:

  • PAS stain.
  • Alican blue-PAS stain.

Images

www:


Necrosis

Features:

  • Dead cells - pink (on H&E).
    • Anucleate cells ("Ghost cells")/outlines of cells - usu. subtle.
      • Fluffy appearance.
  • +/-Neutrophils (very common).

DDx of necrosis:

  • Fibrin.

Images (necrosis):

Granulomas

Common morphologic problems

DDx of pink stuff (on H&E)

The ABCs of pink:

  • Amyloid.
  • Blood clot (organized); fibrin.
  • Collagen (fibrous tissue).
  • Smooth muscle cells (SMCs).
Images

Smooth muscle cells (SMCs) vs. fibrous tissue

Fibroblasts (fibrous tissue):

  • Wavy nuclei with pointy ends.
  • Less nuclei.

SMCs:

  • Elliptical nuclei.
  • More nuclei.

Remembering the above:

  • SMCs are stretched; ergo, not wavy.
  • Fibrous tissue is fibrous... more protein... less cells; ergo, less nuclei.
  • Fibroblast = football-like.
  • Cigar-shaped nuclei (SMCs) are affected by cigars (smoking causes vascular disease).

Notes:

  • Schwann cells (found in nerve): nuclei = wavy appearance, thin. (???)

Pigmented material

  • AKA brown/black granular crap.

DDx of granular stuff/pigment:

  1. Lipofuscin - especially in old people.
  2. Hemosiderin.
  3. Bile - found in hepatocytes, yellow.
  4. Foreign material (tattoo pigment, anthracotic pigment, amalgam tattoo).
  5. Melanin.

Notes:

  • Granular stuff should prompt consideration of malignant melanoma.
  • Memory device BH MILF = Bile, Homogentisic acid, Melanin, Iron (hemosiderin), Lipofuscin, Foreign material.
  • Homogentisic acid found in alkaptonuria,[11]can be considered the sixth (black) pigment.
    • Gentisic = jen-TIS-ik.[12]

Stains that can help sort it out

Staining

Basic knowledge of stain is important. The above article starts with H&E and goes from there.

Immunohistochemistry

If the special stains don't help... there is immunohistochemistry.

Food and pathology


Tumour remaining

R classification:[14]

  • "RX resection" = residual tumour cannot be assessed.
  • "R0 resection" = clean margin macroscopically & microscopically.
  • "R1 resection" = microscopic tumour left.
  • "R2 resection" = macroscopic tumour left.

Surgeons use this terminology. Essentially, it is the margin status. It is nice when the surgeon's assessment and the pathologist's are in agreement.

Note:

  • Generally, positive margins suck. For example, in locally advanced rectal cancer, in one study,[15] five year survival was found to be 60%, 31% and 0% for R0, R1, and R2 resections respectively.

Clinician talk

Performance status

  • ECOG - score from 1-5 for performance status.[16]
    • ECOG = Eastern Cooperative Oncology Group.

ECOG score:

  • ECOG 0: healthy.
  • ECOG 1: ambulatory, no strenuous activity.
  • ECOG 2: limited to self-care in bed <50% of time.
  • ECOG 3: difficult to care for self in bed >50% of time.
  • ECOG 4: bed bound.
  • ECOG 5: dead.

Pathology & pathologists

Fixation & lifestyle

Pathologist have a great lifestyle 'cause tissue takes long to fix; the penetration of tissue by formalin is 1 mm/hour.[17]

Malignancy & inflammation

If there is lots of inflammation... and you're thinking cancer you should probably back-off, i.e. tend toward benign. Inflammation can make cells look more malignant than they might be if left alone.

Miscellaneous

Infectious stuffs

Images: http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/Gram3.htm

  • Staphylococcus - in clusters.
  • Streptococcus - in chains.


Microscopes

  • Pathologists throw around the term high power field (HPF).
    • "HPF" has no agreed upon definition and, IMHO, should never be used without a non-ambiguous definition.

HPF generally refers to the area seen with the largest magnification objective (40x), i.e. the field at 400x (as the eye piece magnification is usually 10x). The field size varies significantly from microscope to microscope.

Estimating field of view

FOV = Deye piece x 1/Mobj.

Where:

  • FOV = field of view.
  • Deye piece = diameter of eye piece (this is usually inscribed on the side of the eye piece).
  • Mobj = magnification of the objective.

Example:

  • Deye piece = 22 mm
  • Mobj = 40x (largest magnification objective)

Applying the formula:

  • FOV = 22 mm / 40
  • FOV = 0.55 mm

Note:

  • Most modern microscopes, have an eye piece diameter of 22 mm. Therefore, the field diameter at 40 X is approximately 22 mm / 40 X ~= 0.55 mm and the field of view is pi/4*(0.55 mm)^2 = 0.2376 mm^2.

Pathology reports

The key point in report writing is that the report should be precise, complete and easy-to-understand.

Standards

There is no universal standard; however, there is a push to standardize by the Association of Directors of Anatomic and Surgical Pathology,[18] among others.

Checklists

The College of American Pathologists (CAP) has checklists for cancer - CAP protocols.

Pathologists will probably use more checklists in the future... they are deemed effective in a number of places inside and outside of medicine. Surgeons know that checklists work and that they save lives.[19] Pilots have been using checklists since the 1930s.

Standard diagnostic notation

Site, operation/procedure:
- Tissue type diagnosis.


Example:
Gallbladder, cholecystectomy:
- Acute cholecystitis.

Lab talk

Tissue cutting terms - these often vary from lab-to-lab:[20]

  • Recut = cut off the top of the block.
  • Serial sections = make several cuts off the top of the block and look at all of 'em.
  • Level = trim the block ~30 micrometres --throw away trimmed tissue-- and then cut a section to look at.
  • Deeper = trim the block ~100 micrometres --throw away trimmed tissue-- and then cut a section to look at.

See also

References

  1. Streutker, C. 8 June 2013.
  2. URL:http://pancreaticcancer2000.com/page1.htm. Accessed on: 3 June 2010.
  3. URL: http://www.merriam-webster.com/medical/argyrophilic. Accessed on: 29 August 2011.
  4. URL: http://en.wiktionary.org/wiki/argyrophilic. Accessed on: 29 August 2011.
  5. http://upload.wikimedia.org/wikipedia/en/5/51/Nuclear_changes.jpg
  6. Arashiro, RT.; Teixeira, MG.; Rawet, V.; Quintanilha, AG.; Paula, HM.; Silva, AZ.; Nahas, SC.; Cecconello, I. (Jul 2012). "Histopathological evaluation and risk factors related to the development of pouchitis in patients with ileal pouches for ulcerative colitis.". Clinics (Sao Paulo) 67 (7): 705-10. PMC 3400158. PMID 22892912. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400158/.
  7. 7.0 7.1 S. Boerner. 12 September 2011.
  8. URL: http://www.medterms.com/script/main/art.asp?articlekey=25657. Accessed on: 18 January 2010.
  9. URL: http://www.microbehunter.com/wp/wp-content/uploads/2009/lily_prophase.jpg and http://www.microbehunter.com/2009/12/06/mitosis-stages-of-the-lily/. Accessed on: 3 November 2010.
  10. URL: http://moon.ouhsc.edu/kfung/jty1/Com08/Com801-1-Diss.htm. Accessed on: 3 November 2010.
  11. Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 20. ISBN 978-1416054542.
  12. URL: http://dictionary.reference.com/browse/gentisic+acid. Accessed on: 11 January 2012.
  13. Kovi J, Leifer C (July 1970). "Lipofuscin pigment accumulation in spontaneous mammary carcinoma of A/Jax mouse". J Natl Med Assoc 62 (4): 287–90. PMC 2611776. PMID 5463681. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2611776/pdf/jnma00512-0077.pdf.
  14. URL: http://www.informedicalcme.com/colon-cancer/tnm-stage-groupings/. Accessed on: 27 March 2012.
  15. Larsen SG, Wiig JN, Dueland S, Giercksky KE (April 2008). "Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer". Eur J Surg Oncol 34 (4): 410–7. doi:10.1016/j.ejso.2007.05.012. PMID 17614249.
  16. Oken MM, Creech RH, Tormey DC, et al. (December 1982). "Toxicity and response criteria of the Eastern Cooperative Oncology Group". Am. J. Clin. Oncol. 5 (6): 649–55. PMID 7165009.
  17. Gross rounds. 14 August 2009.
  18. URL: http://www.adasp.org/papers/position/Standardization.htm
  19. Soar J, Peyton J, Leonard M, Pullyblank AM (2009). "Surgical safety checklists". BMJ 338: b220. PMID 19158173. http://bmj.com/cgi/pmidlookup?view=long&pmid=19158173.
  20. URL: http://www.mailman.srv.ualberta.ca/pipermail/patho-l/2002-July/016955.html. Accessed on: 18 October 2011.

External links