Difference between revisions of "Haematopathology"

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Understanding of '''haematopathology''' is important in [[anatomical pathology]], as '''haematologic malignancies''' are often in the (clinical) differential diagnosis and may mimic ''[[small blue round cell tumours]]'' or ''[[breast|lobular breast carcinoma]]''.
Understanding of '''haematopathology''' is important in [[anatomical pathology]], as '''haematologic malignancies''' are often in the (clinical) differential diagnosis and may mimic ''[[small blue round cell tumours]]'' or ''[[breast|lobular breast carcinoma]]''.


==Bone marrow==
The lymph node is discussed below; however, details are covered in the ''[[lymph node]]'' article and ''[[lymph node pathology]]'' article.
{{main|Bone}}
Bone marrows are important for understanding haematopathology.  They are dealt with in the ''[[bone]]'' article.


==Normal lymph node==
=Bone marrow=
===Normal (clinical)===
{{main|Bone marrow}}
*Round.
Bone marrows are important for understanding haematopathology. They are dealt with in the ''[[bone marrow|bone]]'' article.
*"Soft".
*Mobile.


===Pathologic (clinical) - associations===
=Normal lymph node=
*Rubbery = suggestive of lymphoma.
{{main|Lymph node}}
*Fixed (immobile) = suggestive of cancer.
{{main|Lymph node pathology}}
*Tender (hurts when ya touch it) = suggestive of infection.
 
===Radiologic & clinical===
*Elongated = may be cancer.
*"Large" = could be cancer or infection.
 
===Malignant - statistical associations===
Nodes with metstases tend to be:
*Hard.
*Ellipical (as opposed to circular) on section.
*"Large".
*May be immobile (fixed to a surrounding structure).
 
Note:
*"Large" depends on the location in the body.
 
===Gross pathologic exam===
Normal:
*Firm (relative to adipose tissue).
*Glissening surface when cut.
 
Pathologic:
*White lesions, espically irregular = suggestive of carcinoma.
*white, glissening, with lobulated surface - "fish flesh" = suggestive of lymphoma.


===Microscopic===
===Microscopic===
{{main|Lymph node}}
The microscopic lymph node architecture in described the ''[[lymph node]]'' article, along with B cell maturation and lymph node cell types.
The microscopic lymph node architecture in described the ''[[lymph node]]'' article, along with B cell maturation and lymph node cell types.


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**Plasma cells.
**Plasma cells.


==Heparin-induced thrombocytopenia==
=Haematologic neoplasia=
*Thrombocytopenia due to heparin.<ref>[http://emedicine.medscape.com/article/1357846-overview http://emedicine.medscape.com/article/1357846-overview]</ref>
Historically, haematologic neoplasias were split into leukemia (disease of the bone marrow & blood) and lymphoma (disease in discrete masses -- usually lymph nodes). In the modern day, this distinction has blurred.
 
Classification:
*Type 1 - in first two days of exposure - considered non-immune and considered not to be serious.
*Type 2 - in the first 4-10 days - considered serious.
 
Diagnosis (simplified):
*50% decline in platelets - within 4-10 days of starting heparin.
*HIT assay - several exist.<ref>[http://emedicine.medscape.com/article/1357846-diagnosis http://emedicine.medscape.com/article/1357846-diagnosis]</ref>


==Lymphoma classification==
==Myelodysplastic syndrome==
Lymphomas can be divided into:
{{Main|Myelodysplastic syndrome}}
*Hodgkin's lymphoma.
At first approximation, these can be thought of as "pre-leukemia/lymphoma".
*Non-Hodgkin's lymphoma (NHL).


Other categorizations:
==Leukemia==
*T cell lymphomas (rare).
{{Main|Leukemia}}
*B cell lymphomas (more common).
These predominantly have blood/bone marrow involvement.


Two most common NHLs:
==Lymphoma==
*Follicular lymphoma (FL).
{{main|Lymphoma}}
*Diffuse large B-cell lymphoma (DLBCL).
These form masses. They typically arise from lymph nodes or aggregates of lymphocytes.


===Lymphoma as a med student===
==Plasma cell lesions==
*Acute lymphoid leukemia (ALL) - predominantly in '''smALL''' people, i.e. children.
{{Main|Plasma cell neoplasms}}
*Acute myeloid leukemia (AML).
*Chronic myeloid leukemia (CML).
*Chronic lymphoid leukemia (CLL) - relatively good prognosis.


===Histology===
==Myeloproliferative neoplasms==
*Lymphomas = cells look discohesive, may be difficult to differentiate from poor differentiated carcinoma.
{{main|Myeloproliferative neoplasms}}
*Auer rods = Acute myeloid leukemia.
This subset of haematopathology includes, among others, polycythemia vera. Historically, these were not classified as neoplasias.
**Granular cytoplasmic rod (0.5-1 x4-6 micrometres).
*Reed-Sternberg cells = Hodgkin's lymphoma.
**Large cell - very large nucleus.
***Classically binucleated.
*Russell bodies = Plasmacytoma (+others).
**Eosinophilic, large, homogenous immunoglobulin-containing inclusions.<ref name=pmid3979421>{{cite journal |author=Alanen A, Pira U, Lassila O, Roth J, Franklin RM |title=Mott cells are plasma cells defective in immunoglobulin secretion |journal=Eur. J. Immunol. |volume=15 |issue=3 |pages=235–42 |year=1985 |month=March |pmid=3979421 |doi= |url=}}</ref>
***''Mott cell'' is a cell that contains Russell bodies.<ref name=pmid3979421/>


===IHC===
=Specific diagnoses=
*CD45+.
==Hemophagocytic syndrome==
**AKA ''common lymphocyte antigen''.
{{main|Hemophagocytic syndrome}}
**Useful to differentiate from carcinomas (e.g. small cell carcinoma).
===General===
*CD3 -- T cell marker (all T cells).
*Rare.
**CD4 -- subset of T cells.
**CD8 -- subset of T cells.
*CD20 -- B cell marker.
**CD19 -- B cell marker - used for flow cytometry.
*CD10 -- follicular cell ???
*CD30 -- Hodgkin's lymphoma (most sensitive).
 
==Hodgkin's lymphoma==
*Abbreviated ''HL''.
 
===Clinical===
Sx:<ref name=Ref_WMSP567>{{Ref WMSP|567}}</ref>
*Fever, night sweats, weight loss.
*Infections (due to immune dysfunction).
 
Diagnosis:
*HL cannot be diagnosed with standard flow cytometry (FC) - but has been diagnosed with specialized FC.<ref>{{cite journal |author=Fromm JR, Thomas A, Wood BL |title=Flow cytometry can diagnose classical hodgkin lymphoma in lymph nodes with high sensitivity and specificity |journal=Am. J. Clin. Pathol. |volume=131 |issue=3 |pages=322–32 |year=2009 |month=March |pmid=19228638 |doi=10.1309/AJCPW3UN9DYLDSPB |url=}}</ref>
===Histology===
*Reed-Sternberg cell (by definition).
**Large binucleated cell.
**Macronucleolus - approximately the size of a RBC.
 
===HL subtypes===
Types:<ref name=Ref_WMSP567/>
*Classical HL (CHL) - ~95% of HL.
*Nodular lymphocyte-predominant HL (NLPHL) - ~5% of HL.
 
 
===Classical HL===
There are four CHL subtypes:<ref name=Ref_WMSP567/>
#Nodular sclerosis CHL - ~70% of CHL.
#*Mixed cellular background - T cell, plasma cells, eosinophils, neutrophils and histiocytes.
#*Nodular sclerosing fibrosis - thick strands fibrosis.
#Mixed cellularity CHL - ~20-25% of CHL.
#*Like nodular sclerosis - but no fibrosis.
#Lymphocyte-rich CHL - rare.
#*T lymphocytes only (no mix of cells).
#Lymphocyte-depleted CHL - rare.
#*Assoc. with HIV infection.
 
Memory device:
*The subtypes prevalence is in reverse alphabetical order.
 
===Nodular lymphocyte-predominant HL===
*AKA ''lympho-histiocytic variant''.
 
Features:
*The diagnostic cells in this variant: relatively small, lobulated nucleus, small nucleoli.
 
Image:
*[http://webpathology.com/image.asp?case=388&n=16 Popcorn cell (webpathology.com)].
 
===IHC===
Abbreviated panel:<ref name=Ref_WMSP568>{{Ref_WMSP|568}}</ref>
*CD30 Reed-Sternberg cells (RSCs) +ve ~98%
*CD15 Reed-Sternberg cells +ve ~80%, stains neutrophils.
*CD45 '''often negative''' in RSCs.
*CD20 may stain RSCs.
*PAX5 +ve.<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>
 
Additional - for completeness:
*CD3 (T lymphocytes)
 
NLPHL IHC '''differs''' from the classical HL:<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>
*LCA +ve.
*CD20 +ve.
*CD10 +ve.
*Bcl-6 +ve.
*EMA +ve.
*CD30 -ve
*CD15 -ve.
 
==Follicular lymphoma==
*A very common type of lymphoma.
*Express Bcl-2.<ref name=pmid18359244>PMID 18359244.</ref>


===Microscopic===
===Microscopic===
Features:
Features:
*Abundant abnormal lymphoid follicles.
*Macrophages eat RBCs, WBCs.


===IHC===
==Heparin-induced thrombocytopenia==
Features:<ref name=pmid18359244/>
*Thrombocytopenia due to heparin.<ref name=emed_hit>URL: [http://emedicine.medscape.com/article/1357846-overview http://emedicine.medscape.com/article/1357846-overview]. Accessed on: 17 May 2011.</ref>
*CD10+/-.
*CD5-.
*CD23-/+.
*CD43-.
*CD11c-.


===Molecular===
Classification:
*t(14;18) in 70-95% of cases; involves bcl-2 gene.<ref name=pmid18359244/>
*Type 1 - in first two days of exposure - considered non-immune and considered not to be serious.
*Type 2 - in the first 4-10 days - considered serious.


==Diffuse large B-cell lymphoma==
Diagnosis (simplified):
*Abbreviated ''DLBCL''.
*50% decline in platelets - within 4-10 days of starting heparin.
 
*HIT assay - several exist.<ref name=emed_hit>URL: [http://emedicine.medscape.com/article/1357846-overview http://emedicine.medscape.com/article/1357846-overview]. Accessed on: 17 May 2011.</ref>
===Microscopic===
Features:<ref name=Ref_PBoD676>{{Ref PBoD|676 (???)}}</ref>
*Large cells -- 4-5 times the diameter of a small lymphocytes.
*Typically have marked cell-to-cell variation in size and shape.
*Cytoplasm usu. basophilic and moderate in abundance.
*+/-Prominent nucleoli, may be peripheral and/or multiple.
 
Notes:
*Large bizarre cells can occasionally mimic Reed-Sternberg cells, seen in Hodgkin lymphoma.
 
==Burkitt's lymphoma==
===General===
*Abbreviated ''BL''.
*Extremely high proliferative rate & rate of apoptosis.
 
===Subtypes===
*Three subtypes recognized:<ref name=pmid12610094>{{cite journal |author=Bellan C, Lazzi S, De Falco G, Nyongo A, Giordano A, Leoncini L |title=Burkitt's lymphoma: new insights into molecular pathogenesis |journal=J. Clin. Pathol. |volume=56 |issue=3 |pages=188–92 |year=2003 |month=March |pmid=12610094 |pmc=1769902 |doi= |url=http://jcp.bmj.com/cgi/pmidlookup?view=long&pmid=12610094}}</ref>
#Endemic:
#*Found in Africa.
#*EBV (Epstein-Barr virus) associated.<ref name=pmid12610094/>
#Non-endemic:
#*Typical of the BL seen in the western world; EBV negative.
#Immunodeficiency associated:
#*Associated with HIV infection.
 
===Pathophysiology===
*Origin cell: germinal centre B cells (favoured) vs. memory B cells.<ref name=pmid12610094/>
*Common translocation t(8;14).<ref name=pmid12610094/>
 
===Cytologic definition===
*t(8;14) (q24;q32) translocation + a few variants or c-myc rearrangement.<ref name=pmid12610094/>
 
===Histology===
*"Starry-sky pattern".
**The ''stars'' in the pattern are: tingible-bodies laden macrophages.
***''[[Tingible-bodies macrophages]]'' = macrophages containing dead body of apoptotic tumor cells.
*Tumour cells:<ref name=pmid12610094/>
**Medium size.
**Round nuclei.
**Multiple nucleoli.
**Relatively abundant cytoplasm.
 
Image: [http://en.wikipedia.org/wiki/File:Burkitt_lymphoma,_H%26E.jpg Starry-sky pattern - Ed Uthman (www.wikipedia.org)].
 
==Plasmacytoma==
===General===
*Malignancy derived from the plasma cells.
*Histologic component of ''multiple myeloma''; to diagnose multiple myeloma other (non-pathology) criteria are needed.
 
===Microscopic===
*Cells with "clock face" nuclei.
*Russell bodies:
**Eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions.
***Images: [http://www.healthsystem.virginia.edu/internet/hematology/hessimages/russell-bodies-website-arrow.jpg Russel bodies (healthsystem.virginia.edu)], [http://www.pathguy.com/lectures/russ2.jpg Russel bodies (pathguy.com)] - several in one cell.
*Dutcher bodies - intranuclear crystalline rods.
*Prominent ''perinuclear hof'' - cresent shaped lucency at the nuclear membrane (due to large Golgi apparatus).
 
Images: [http://ashimagebank.hematologylibrary.org/cgi/content/full/2004/0126/100984 http://ashimagebank.hematologylibrary.org/cgi/content/full/2004/0126/100984].


DDx:
==Disseminated intravascular coagulation==
*Neuroendocrine carcinoma - nucleus often has a plasmacytoid (plasma cell) look.
*Commonly abbreviated ''DIC''.
 
==Acute myeloid leukemia==
===General===
===General===
*May afflicits young adult.
*Usually associated with sepsis or septic shock.<ref>URL: [http://emedicine.medscape.com/article/779097-overview http://emedicine.medscape.com/article/779097-overview]. Accessed on: 23 October 2010.</ref>
*Males>females.


===Complications===
Clinical:
*Chloroma - soft tissue mass.
*Schistocytes (red blood cell fragmentation).
*Leukostasis.
**Occurs - lungs and brain.<ref>AML. Harrison's 16th Ed.</ref>
*Hyperviscosity syndrome.
*Spontaneous bleeding with low platelet counts.


===Classification===
===Gross===
There are two classifications:
Features:<ref>{{Ref HospAuto|209}}</ref>
#FAB (French-American-British) - based on histologic appearance/maturation.
*Pleural petechial haemorrhages.
#WHO classification.
 
===Histology===
*Auer rods - not required to diagnose.<ref>AG. 8 July, 2009.</ref>
**Cytoplasmic granular rods in blast cells.
***Dimensions: approx. 0.5-1 x 4-6 micrometres.
**Images: [http://en.wikipedia.org/wiki/File:Auer_rods.PNG Auer rods (WP)], [http://www.healthsystem.virginia.edu/internet/hematology/HessImages/Acute-myelogenous-leukemia-M4-100x-Auer-rods-website-arrow.jpg Auer rods (virginia.edu)].
 
==Anaplastic large cell lymphoma==
===General===
*Abbreviated '''ALCL'''.
*May look a lot like a carcinoma.
**Often subcapsular in LNs.
*Usually T-cell derived.
*Alk IHC:
** +ve = good prognosis.
** -ve = bad prognosis.
 
DDx:
*Hodgkin's lymphoma.


===Microscopic===
===Microscopic===
Features:
Features:<ref name=Ref_PBoD8_670>{{Ref PBoD8|670}}</ref>
*Large cells with eosinophilic cytoplasm.
*Microvascular occlusion.
*Usu. appear cohesive.
*May be subcapsular.
*Large multinucleated cell - "wreath cell" - '''key feature'''.


===IHC===
Notes:
Features:
*Microvascular occlusion is also seen in [[thrombotic microangiopathies]].
*Variable CD30 +ve. (???)
*CD45 +ve. (???)


==Table of B-cell lymphoma==
=Cytometry - population cell marker quantification=
{| class="wikitable"
{{main|Cytometry}}
! Name
! Location
! Size of cells
! IHC
! Translocations
! Clinical
! Other
|-
| Follicular lymphoma
| Follicle
| Small, centrocytes, centroblasts
| CD10, bcl-6
| t(14,18)
| Clinical ?
| Other ?
|-
| Burkitt's lymphoma
| Follicle
| Large cells
| CD10, bcl-6
| t(8;14) (q24;q32)
| Rapid growth
| "Starry sky"
|-
| Diffuse large B cell lymphoma
| Follicle (?)
| Large 4-5X of lymphocyte
| MIB-1 >40%
| none/like follicular l.
| Poor prognosis
| Common among lymphomas
|-
| Name
| Location
| Size of cells
| IHC
| Translocations
| Clinical
| Other
|}


==Population cell marker quantification==
===Two techniques===
Two techniques:
#[[Flow cytometry]].
*Flow cytometry.
#Laser scanning cytometry (LSC).
*Laser scanning cytometry (LSC).


Common markers:
===Common markers===
*CD3, CD4, CD8, CD5, CD7.
*CD3, CD4, CD8, [[CD5]], CD7.
*CD19, CD20, FMC7.
*CD19, [[CD20]], FMC7.
*Kappa, lambda.
*Kappa, lambda.


Normal:
===Normal===
*T-cells to B-cells usually 1:1.
*T-cells to B-cells usually 1:1.
*In reactive nodes T-cell predominate.
*In reactive nodes T-cells predominate.
*Normal thymic tissue has cells that are positive for both CD4 and CD8.
*Normal thymic tissue has cells that are positive for both CD4 and CD8.
*Kappa (k) and lambda (l) are not expressed by the same cell.
*Kappa (k) and lambda (l) are not expressed by the same cell.
Line 370: Line 112:


GS guidelines - non-malignant is:<ref>GS. LSC Procedure. March 11, 2010.</ref>
GS guidelines - non-malignant is:<ref>GS. LSC Procedure. March 11, 2010.</ref>
*CD19 ~= CD20
*CD19 ~= CD20.
*CD5 = CD3
*CD5 = CD3.
*CD2 > CD3 and CD5
*CD2 > CD3 and CD5.
*CD4 + CD8 ~= CD3
*CD4 + CD8 ~= CD3.
*CD7 = the smalest number of T-cell
*CD7 = the smallest number of T-cell.


Abnormal:
===Abnormal===
*CD4>CD8 predominance classically seen in:
See ''[[cytometry]]''.
**Sarcoidosis.
**Hodgkin's lymphoma.
*T cell lymphoma - loss of one of the T-cell markers (CD2, CD3, CD5 or CD7).


===Sample report===
=Abnormal sign out=
B-Cell Associated Markers
<pre>
*CD10.
Lymph Node, Right Posterior Triangle of Neck, Excision:
**Germinal centre marker.
- Lymphoid tissue with abnormal architecture, predominantly small cells.
**+ve in: follicular l., Burkitt l., precursor lymphoblastic leukemia.
- Case will be sent to hematopathology for opinion.
*CD19.
</pre>
**B cell marker.
**Should be ~=CD20.
*CD20.
**B cell marker.
**Should be ~=CD20.
*CD23.
**+ve in CLL/SLL.
*FMC7
**B cell marker.
*Kappa+CD19/20+.
**B cell clonality.
*Lambda+CD19/20+
**B cell clonality.
T-Cell Associated Markers
*CD3.
**CD3 ~= CD4 + CD8.
**Usually: CD2 > CD3 > CD7.
*CD5.
**Usually: CD2 > CD5 > CD7.
*CD4.
**CD3 ~= CD4 + CD8.
*CD8.
**CD3 ~= CD4 + CD8.
*CD7.
**Usually least prevalent T cell marker; < CD2, < CD3, < CD5.
*CD2.
**Usually most prevalent T cell marker; > CD3, > CD5, > CD7.
NK-Cell Associated Markers
*CD56.
*CD16.
Miscellaneous Markers
*CD11c.
*CD14.


==See also==
=See also=
*[[Stomach]].
*[[Stomach]].
*[[Lymph nodes]].
*[[Lymph nodes]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


[[Category:Haematopathology]]
[[Category:Haematopathology]]

Latest revision as of 15:44, 5 March 2017

Understanding of haematopathology is important in anatomical pathology, as haematologic malignancies are often in the (clinical) differential diagnosis and may mimic small blue round cell tumours or lobular breast carcinoma.

The lymph node is discussed below; however, details are covered in the lymph node article and lymph node pathology article.

Bone marrow

Main article: Bone marrow

Bone marrows are important for understanding haematopathology. They are dealt with in the bone article.

Normal lymph node

Main article: Lymph node
Main article: Lymph node pathology

Microscopic

The microscopic lymph node architecture in described the lymph node article, along with B cell maturation and lymph node cell types.

The cells of the lymph node:

  • Germinal center:
    • Centrocytes - cleaved nucleus.
    • Centroblasts - large dark, mitotically active, medullary aspect of germinal center.
    • Tingible body macrophages.
    • Follicular dendritic cells.
  • Paracortex:
    • T lymphocytes.
    • Interdigitating dendritic cells.
  • Mantle zone:
    • Immunoblasts (Memory B cells) - small lymphocytes.
  • Medulla:
    • B lymphocytes.
    • Plasma cells.

Haematologic neoplasia

Historically, haematologic neoplasias were split into leukemia (disease of the bone marrow & blood) and lymphoma (disease in discrete masses -- usually lymph nodes). In the modern day, this distinction has blurred.

Myelodysplastic syndrome

Main article: Myelodysplastic syndrome

At first approximation, these can be thought of as "pre-leukemia/lymphoma".

Leukemia

Main article: Leukemia

These predominantly have blood/bone marrow involvement.

Lymphoma

Main article: Lymphoma

These form masses. They typically arise from lymph nodes or aggregates of lymphocytes.

Plasma cell lesions

Main article: Plasma cell neoplasms

Myeloproliferative neoplasms

Main article: Myeloproliferative neoplasms

This subset of haematopathology includes, among others, polycythemia vera. Historically, these were not classified as neoplasias.

Specific diagnoses

Hemophagocytic syndrome

Main article: Hemophagocytic syndrome

General

  • Rare.

Microscopic

Features:

  • Macrophages eat RBCs, WBCs.

Heparin-induced thrombocytopenia

  • Thrombocytopenia due to heparin.[1]

Classification:

  • Type 1 - in first two days of exposure - considered non-immune and considered not to be serious.
  • Type 2 - in the first 4-10 days - considered serious.

Diagnosis (simplified):

  • 50% decline in platelets - within 4-10 days of starting heparin.
  • HIT assay - several exist.[1]

Disseminated intravascular coagulation

  • Commonly abbreviated DIC.

General

  • Usually associated with sepsis or septic shock.[2]

Clinical:

  • Schistocytes (red blood cell fragmentation).

Gross

Features:[3]

  • Pleural petechial haemorrhages.

Microscopic

Features:[4]

  • Microvascular occlusion.

Notes:

Cytometry - population cell marker quantification

Main article: Cytometry

Two techniques

  1. Flow cytometry.
  2. Laser scanning cytometry (LSC).

Common markers

  • CD3, CD4, CD8, CD5, CD7.
  • CD19, CD20, FMC7.
  • Kappa, lambda.

Normal

  • T-cells to B-cells usually 1:1.
  • In reactive nodes T-cells predominate.
  • Normal thymic tissue has cells that are positive for both CD4 and CD8.
  • Kappa (k) and lambda (l) are not expressed by the same cell.
  • Rule-of-thumb for normal k:l range is: <6:1 and 1:<3.[5]
    • Lambda dominance is less common.

GS guidelines - non-malignant is:[6]

  • CD19 ~= CD20.
  • CD5 = CD3.
  • CD2 > CD3 and CD5.
  • CD4 + CD8 ~= CD3.
  • CD7 = the smallest number of T-cell.

Abnormal

See cytometry.

Abnormal sign out

Lymph Node, Right Posterior Triangle of Neck, Excision:
- Lymphoid tissue with abnormal architecture, predominantly small cells.
- Case will be sent to hematopathology for opinion.

See also

References

  1. ↑ 1.0 1.1 URL: http://emedicine.medscape.com/article/1357846-overview. Accessed on: 17 May 2011.
  2. ↑ URL: http://emedicine.medscape.com/article/779097-overview. Accessed on: 23 October 2010.
  3. ↑ Burton, Julian L.; Rutty, Guy N. (2010). The Hospital Autopsy A Manual of Fundamental Autopsy Practice (3rd ed.). Oxford University Press. pp. 209. ISBN 978-0340965146.
  4. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 670. ISBN 978-1416031215.
  5. ↑ SB. March 10, 2010.
  6. ↑ GS. LSC Procedure. March 11, 2010.
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