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'''Hodgkin's lymphoma''', abbreviated ''HL'', a malignancy that afflicts people in the prime of their life. It usually has a good prognosis.  
{{ Infobox diagnosis
| Name      = Classical Hodgkin lymphoma
| Image      = Hodgkin_lymphoma_cytology_large.jpg
| Width      =
| Caption    = HL mixed cellularity - cytology.
| Micro      = Reed-Sternberg cell (large binucleated cell (>= 45 micrometres), +/-multinucleated, +/-horseshoe-like shape, [[macronucleolus]] - approximately the size of a RBC (~8 micrometers)), well-defined cell border, abundant cytoplasm.
| Subtypes  = nodular sclerosis CHL, mixed cellularity CHL, lymphocyte-rich CHL, lymphocyte-depleted CHL
| LMDDx      = [[diffuse large B cell lymphoma]] (esp. ''T-cell/histiocytic-rich LBCL''), [[anaplastic large cell lymphoma]],
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma
| Stains    =
| IHC        = CD30 Reed-Sternberg cells (RSCs) +ve ~98%, CD15 Reed-Sternberg cells +ve ~80% (also stains neutrophils), CD45 ''often negative'' in RSCs, CD20 -ve/+ve, PAX5 +ve
| EM        =
| Molecular  =
| IF        =
| Gross      =
| Grossing  =
| Site      = usu. [[lymph node]] - classically in the neck
| Assdx      =
| Syndromes  =
| Clinicalhx = young adults, older adults (bimodal distribution)
| Signs      = lymphadenopathy - usu. neck, +/-[[B symptoms]] (fever, night sweats, weight loss)
| Symptoms  =
| Prevalence = common
| Bloodwork  =
| Rads      =
| Endoscopy  =
| Prognosis  = usu. good, dependent on stage
| Other      =
| ClinDDx    =
}}
'''Hodgkin [[lymphoma]]''', abbreviated '''HL''', is a haematological [[malignancy]]. If not otherwise specified, Hodgkin lymphoma generally refers to classical Hodgkin lymphoma (CHL) rather than [[nodular lymphocyte-predominant Hodgkin lymphoma]] (NLPHL). The latter accounts for only about 5% of the loose label of Hodgkin lymphoma<ref name=Ref_WMSP567/> and shows a sufficiently different biology and immunophenotype that is essentially a different disease (see [[nodular lymphocyte-predominant Hodgkin lymphoma|main article on NLPHL]]). The common feature is large atypical cells: Hodgkin/Reed-Sternberg cells in the case of classical Hodgkin lymphoma and "popcorn"/lymphohistiocytic/L&H cells in NLPHL. However, at least in typical cases, there are morphological and immunophenotypic differences.


==Clinical==
Classical Hodgkin lymphoma has a bi-modal distribution, afflicting young adults and with a further peak in incidence in middle-age. Fortunately, it usually has a good prognosis.
Sx:<ref name=Ref_WMSP567>{{Ref WMSP|567}}</ref>
 
*Fever, night sweats, weight loss.
Pathologists say "... it is both the easiest and hardest diagnosis to make." The reason for this is: the diagnosis depends on finding Reed-Sternberg cells (or Popcorn cells); if they are obvious the diagnosis is easy... if you can't find 'em and an alternative diagnosis is not apparent -- you wonder whether you're missing them.
*Infections (due to immune dysfunction).
 
==General==
===Clinical===
Symptoms:<ref name=Ref_WMSP567>{{Ref WMSP|567}}</ref>
*"[[B symptoms]]" - all required:<ref>URL: [http://lymphoma.about.com/od/symptoms/f/bsymptoms.htm http://lymphoma.about.com/od/symptoms/f/bsymptoms.htm]. Accessed on: 11 August 2010.</ref> weight loss, night sweats and fever.
*Infections due to immune dysfunction.


Diagnosis:
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>
*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>
 
==Microscopic==
Features:
*Reed-Sternberg cell (by definition).
**Large binucleated cell.
**Macronucleolus - approximately the size of a RBC (~8 micrometers).
**Well-defined cell border.


==HL subtypes==
Prognosis:
Types:<ref name=Ref_WMSP567/>
*Usually good.
*Classical HL (CHL) - ~95% of HL.
*Unlike non-Hodgkin lymphomas, it spreads in a predictable pattern; thus, staging plays an important role in determining the therapy.<ref name=PCPBoD8_315>{{Ref PCPBoD8|315}}</ref>
*Nodular lymphocyte-predominant HL (NLPHL) - ~5% of HL.
*Clinically classified into early favourable, early unfavourable and late/advanced disease.


==Classical HL==
===Classic HL sub-types===
====Subtypes of classic HL====
There are four CHL subtypes:<ref name=Ref_WMSP567/>
There are four CHL subtypes:<ref name=Ref_WMSP567/>
#Nodular sclerosis CHL - ~70% of CHL.
#Nodular sclerosis CHL - ~70% of CHL.
Line 28: Line 57:
#Mixed cellularity CHL - ~20-25% of CHL.
#Mixed cellularity CHL - ~20-25% of CHL.
#*Like nodular sclerosis - but no fibrosis.
#*Like nodular sclerosis - but no fibrosis.
#*May be associated with [[HIV]] infection.<ref name=pmid20138008>{{cite journal |author=Sissolak G, Sissolak D, Jacobs P |title=Human immunodeficiency and Hodgkin lymphoma |journal=Transfus. Apher. Sci. |volume=42 |issue=2 |pages=131–9 |year=2010 |month=April |pmid=20138008 |doi=10.1016/j.transci.2010.01.008 |url=}}</ref>
#Lymphocyte-rich CHL - rare.
#Lymphocyte-rich CHL - rare.
#*T lymphocytes only (no mix of cells).
#*T lymphocytes only (no mix of cells).
#Lymphocyte-depleted CHL - rare.
#Lymphocyte-depleted CHL - rare.
#*Assoc. with HIV infection.
#*May be associated with HIV infection.<ref name=pmid20138008/>


Memory device:  
Memory device:  
*The subtypes prevalence is in reverse alphabetical order.
*The subtypes prevalence is in reverse alphabetical order.


==Nodular lymphocyte-predominant HL==
==Gross==
*AKA ''lympho-histiocytic variant''.
Location:
*Almost always arises from a [[lymph node]] - classically in the neck, but may be in the axilla and mediastinum
*Spleen may be involved
*Bone marrow involvement is unusual (~5% of cases, higher in HIV-associated cases), so bone marrow assessment is usually not performed
*''Extranodal Hodgkin lymphoma'' is (case report) rare.<ref name=pmid11100066>{{Cite journal  | last1 = Vadmal | first1 = MS. | last2 = LaValle | first2 = GP. | last3 = DeYoung | first3 = BR. | last4 = Frankel | first4 = WL. | last5 = Marsh | first5 = WL. | title = Primary localized extranodal hodgkin disease of the transverse colon. | journal = Arch Pathol Lab Med | volume = 124 | issue = 12 | pages = 1824-7 | month = Dec | year = 2000 | doi = 10.1043/0003-9985(2000)1241824:PLEHDO2.0.CO;2 | PMID = 11100066 }}</ref>


Features:
==Microscopic==
*The diagnostic cells in this variant: relatively small, lobulated nucleus, small nucleoli.
Defined by ''Reed-Sternberg cells'' (RSCs). Morphologically similar mononuclear cells are known as Hodgkin cells. RSCs are:
*Large binucleated cell (>= 45 micrometres).<ref name=Ref_PCPBoD8_329>{{Ref PCPBoD8|329}}</ref>
**May be multinucleated.
**May have a horseshoe-like shape.
*[[Macronucleolus]] - approximately the size of a RBC (~8 micrometers).
*Well-defined cell border.
*Abundant cytoplasm.


Image:  
RSC may show peri-cellular clearing, making the cells appear within a space. These are called lacunar cells (as they are in a "lake"). Apoptotic RSC may show pyknotic nuclei and scant eosinophilic cytoplasm and are sometimes known as "mummified" cells.
*[http://webpathology.com/image.asp?case=388&n=16 Popcorn cell (webpathology.com)].
 
===Images (classic HL)===
<gallery>
Image:CHL mummified cell x40.jpg | "Mummified" RSC. (WC)
Image:CHL lacunar cell x40.jpg | "Lacunar cell". (WC)
Image:16S14098 cHL multinucleate HRS cell x40c.jpg | Multinucleate RSC. (WC)
Image:Hodgkin_lymphoma_cytology_large.jpg | HL mixed cellularity - cytology. (WC)
Image:Hodgkin_lymphoma_cytology_small.jpg | HL mixed cellularity - cytology. (WC)
Image:Hodgkin_lymphoma_%281%29_mixed_cellulary_type.jpg | HL mixed cellularity. (WC)
</gallery>
 
===DDx both CHL & NLPHL===
*CHL/NLPHL.
*[[Diffuse large B cell lymphoma]] (DLBCL), esp. ''T-cell/histiocytic-rich LBCL''.
*[[Anaplastic large cell lymphoma]] (ALCL).
*B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.<ref name=pmid22222636>{{Cite journal  | last1 = Gualco | first1 = G. | last2 = Natkunam | first2 = Y. | last3 = Bacchi | first3 = CE. | title = The spectrum of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases. | journal = Mod Pathol | volume =  | issue =  | pages =  | month = Jan | year = 2012 | doi = 10.1038/modpathol.2011.200 | PMID = 22222636 | URL = http://www.nature.com/modpathol/journal/vaop/ncurrent/full/modpathol2011200a.html }}</ref> (typically in cases of numerous large atypical cells where the morphology and immunophenotype do not neatly fit into either DLBCL or CHL).


==IHC==
==IHC==
Abbreviated panel:<ref name=Ref_WMSP568>{{Ref_WMSP|568}}</ref>
Abbreviated panel:<ref name=Ref_WMSP568>{{Ref_WMSP|568}}</ref>
*CD30 Reed-Sternberg cells (RSCs) +ve ~98%  
*CD30 Reed-Sternberg cells (RSCs) +ve ~98% (beware of mis-interpreting CD30+ activated lymphoid cells)
*CD15 Reed-Sternberg cells +ve ~80%, stains neutrophils.
*CD15 Reed-Sternberg cells +ve ~80%, stains neutrophils.
*Both CD30 and CD15 are classically positive in a membranous and Golgi pattern
*MUM1 +ve
*CD45 '''often negative''' in RSCs.
*CD45 '''often negative''' in RSCs.
*CD20 may stain RSCs.
*CD20 may stain RSCs (usually negative, but can be weak).
*PAX5 +ve.<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>
*PAX5 +ve, though said to be weaker than background normal B-cells<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>


Additional - for completeness:
Additional - for completeness:
*CD3 (T lymphocytes)
*CD3 (T lymphocytes) - negative in RSCs
*OCT2/BOB1 negative (co-transcription factors for immunoglobulin production, one or the other is usually negative)
*40% are EBV positive.


NLPHL IHC '''differs''' from the classical HL:<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>
NLPHL IHC '''differs''' from the classical HL:<ref name=Ref_APBR683>{{Ref APBR|683}}</ref>
Line 61: Line 120:
*CD10 +ve.
*CD10 +ve.
*Bcl-6 +ve.
*Bcl-6 +ve.
*EMA +ve.
*[[EMA]] +ve (40-50%)
*CD30 -ve
*CD30 -ve
*CD15 -ve.
*CD15 -ve.
===A panel===
{| class="wikitable"
|Antibody || NLPHL || CHL
|-
|CD45 || +ve || -ve
|-
|CD20 || +ve || -ve
|-
|BCL6 || +ve || -ve
|-
|MUM1<ref>URL: [http://www.ncbi.nlm.nih.gov/omim/601900 http://www.ncbi.nlm.nih.gov/omim/601900]. Accessed on: 10 August 2010.</ref> || -ve || +ve
|-
|CD30 || -ve || +ve (most sensitive).
|-
|CD15 || -ve || +ve
|-
|CD21 || networks present || no networks
|-
|[[CD23]] || networks present || no networks
|-
|OCT-2 || +ve || -ve
|-
|PAX5 || +ve || +ve (proves B cell linage)
|-
|CD3 || usu. < benign B cell || usu. > benign B cell component
|-
|CD57 || rosettes around malign. cells || -
|-
|EBER || -ve || +ve/-ve
|-
|EMA || +ve/-ve || -ve
|-
|4 unstained || ||
|}
==Sign out==
===Suggestive FNA===
<pre>
Lymph Node, Right Neck, FNA:
- Large binucleated and multinucleated cells with macronucleoli in
  a background of abundant lymphocytes, histiocytes, rare eosinophils.
Comment:
A cell block is not available for further work-up. The findings raise the possibility of Hodgkin's lymphoma.
A further biopsy is required for the diagnosis.
</pre>


==See also==
==See also==
*[[Lymph nodes]].
*[[Lymph nodes]].
*[[Lymph node pathology]]/
*[[Lymph node pathology]].
*[[Haematopathology]].
*[[Haematopathology]].


Latest revision as of 22:01, 4 December 2018

Classical Hodgkin lymphoma
Diagnosis in short

HL mixed cellularity - cytology.
LM Reed-Sternberg cell (large binucleated cell (>= 45 micrometres), +/-multinucleated, +/-horseshoe-like shape, macronucleolus - approximately the size of a RBC (~8 micrometers)), well-defined cell border, abundant cytoplasm.
Subtypes nodular sclerosis CHL, mixed cellularity CHL, lymphocyte-rich CHL, lymphocyte-depleted CHL
LM DDx

diffuse large B cell lymphoma (esp. T-cell/histiocytic-rich LBCL), anaplastic large cell lymphoma,

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma
IHC CD30 Reed-Sternberg cells (RSCs) +ve ~98%, CD15 Reed-Sternberg cells +ve ~80% (also stains neutrophils), CD45 often negative in RSCs, CD20 -ve/+ve, PAX5 +ve
Site usu. lymph node - classically in the neck
Clinical history young adults, older adults (bimodal distribution)
Signs lymphadenopathy - usu. neck, +/-B symptoms (fever, night sweats, weight loss)
Prevalence common
Prognosis usu. good, dependent on stage

Hodgkin lymphoma, abbreviated HL, is a haematological malignancy. If not otherwise specified, Hodgkin lymphoma generally refers to classical Hodgkin lymphoma (CHL) rather than nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The latter accounts for only about 5% of the loose label of Hodgkin lymphoma[1] and shows a sufficiently different biology and immunophenotype that is essentially a different disease (see main article on NLPHL). The common feature is large atypical cells: Hodgkin/Reed-Sternberg cells in the case of classical Hodgkin lymphoma and "popcorn"/lymphohistiocytic/L&H cells in NLPHL. However, at least in typical cases, there are morphological and immunophenotypic differences.

Classical Hodgkin lymphoma has a bi-modal distribution, afflicting young adults and with a further peak in incidence in middle-age. Fortunately, it usually has a good prognosis.

Pathologists say "... it is both the easiest and hardest diagnosis to make." The reason for this is: the diagnosis depends on finding Reed-Sternberg cells (or Popcorn cells); if they are obvious the diagnosis is easy... if you can't find 'em and an alternative diagnosis is not apparent -- you wonder whether you're missing them.

General

Clinical

Symptoms:[1]

  • "B symptoms" - all required:[2] weight loss, night sweats and fever.
  • Infections due to immune dysfunction.

Diagnosis:

  • HL cannot be diagnosed with standard flow cytometry (FC) - but has been diagnosed with specialized FC.[3]

Prognosis:

  • Usually good.
  • Unlike non-Hodgkin lymphomas, it spreads in a predictable pattern; thus, staging plays an important role in determining the therapy.[4]
  • Clinically classified into early favourable, early unfavourable and late/advanced disease.

Classic HL sub-types

Subtypes of classic HL

There are four CHL subtypes:[1]

  1. Nodular sclerosis CHL - ~70% of CHL.
    • Mixed cellular background - T cell, plasma cells, eosinophils, neutrophils and histiocytes.
    • Nodular sclerosing fibrosis - thick strands fibrosis.
  2. Mixed cellularity CHL - ~20-25% of CHL.
    • Like nodular sclerosis - but no fibrosis.
    • May be associated with HIV infection.[5]
  3. Lymphocyte-rich CHL - rare.
    • T lymphocytes only (no mix of cells).
  4. Lymphocyte-depleted CHL - rare.
    • May be associated with HIV infection.[5]

Memory device:

  • The subtypes prevalence is in reverse alphabetical order.

Gross

Location:

  • Almost always arises from a lymph node - classically in the neck, but may be in the axilla and mediastinum
  • Spleen may be involved
  • Bone marrow involvement is unusual (~5% of cases, higher in HIV-associated cases), so bone marrow assessment is usually not performed
  • Extranodal Hodgkin lymphoma is (case report) rare.[6]

Microscopic

Defined by Reed-Sternberg cells (RSCs). Morphologically similar mononuclear cells are known as Hodgkin cells. RSCs are:

  • Large binucleated cell (>= 45 micrometres).[7]
    • May be multinucleated.
    • May have a horseshoe-like shape.
  • Macronucleolus - approximately the size of a RBC (~8 micrometers).
  • Well-defined cell border.
  • Abundant cytoplasm.

RSC may show peri-cellular clearing, making the cells appear within a space. These are called lacunar cells (as they are in a "lake"). Apoptotic RSC may show pyknotic nuclei and scant eosinophilic cytoplasm and are sometimes known as "mummified" cells.

Images (classic HL)

  • "Mummified" RSC. (WC)
    "Mummified" RSC. (WC)
  • "Lacunar cell". (WC)
    "Lacunar cell". (WC)
  • Multinucleate RSC. (WC)
    Multinucleate RSC. (WC)
  • HL mixed cellularity - cytology. (WC)
    HL mixed cellularity - cytology. (WC)
  • HL mixed cellularity - cytology. (WC)
    HL mixed cellularity - cytology. (WC)
  • HL mixed cellularity. (WC)
    HL mixed cellularity. (WC)

DDx both CHL & NLPHL

  • CHL/NLPHL.
  • Diffuse large B cell lymphoma (DLBCL), esp. T-cell/histiocytic-rich LBCL.
  • Anaplastic large cell lymphoma (ALCL).
  • B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.[8] (typically in cases of numerous large atypical cells where the morphology and immunophenotype do not neatly fit into either DLBCL or CHL).

IHC

Abbreviated panel:[9]

  • CD30 Reed-Sternberg cells (RSCs) +ve ~98% (beware of mis-interpreting CD30+ activated lymphoid cells)
  • CD15 Reed-Sternberg cells +ve ~80%, stains neutrophils.
  • Both CD30 and CD15 are classically positive in a membranous and Golgi pattern
  • MUM1 +ve
  • CD45 often negative in RSCs.
  • CD20 may stain RSCs (usually negative, but can be weak).
  • PAX5 +ve, though said to be weaker than background normal B-cells[10]

Additional - for completeness:

  • CD3 (T lymphocytes) - negative in RSCs
  • OCT2/BOB1 negative (co-transcription factors for immunoglobulin production, one or the other is usually negative)
  • 40% are EBV positive.

NLPHL IHC differs from the classical HL:[10]

  • LCA +ve.
  • CD20 +ve.
  • CD10 +ve.
  • Bcl-6 +ve.
  • EMA +ve (40-50%)
  • CD30 -ve
  • CD15 -ve.

A panel

Antibody NLPHL CHL
CD45 +ve -ve
CD20 +ve -ve
BCL6 +ve -ve
MUM1[11] -ve +ve
CD30 -ve +ve (most sensitive).
CD15 -ve +ve
CD21 networks present no networks
CD23 networks present no networks
OCT-2 +ve -ve
PAX5 +ve +ve (proves B cell linage)
CD3 usu. < benign B cell usu. > benign B cell component
CD57 rosettes around malign. cells -
EBER -ve +ve/-ve
EMA +ve/-ve -ve
4 unstained

Sign out

Suggestive FNA

Lymph Node, Right Neck, FNA:
	- Large binucleated and multinucleated cells with macronucleoli in 
	  a background of abundant lymphocytes, histiocytes, rare eosinophils. 

Comment:
A cell block is not available for further work-up. The findings raise the possibility of Hodgkin's lymphoma. 

A further biopsy is required for the diagnosis.

See also

References

  1. ↑ 1.0 1.1 1.2 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 567. ISBN 978-0781765275.
  2. ↑ URL: http://lymphoma.about.com/od/symptoms/f/bsymptoms.htm. Accessed on: 11 August 2010.
  3. ↑ Fromm JR, Thomas A, Wood BL (March 2009). "Flow cytometry can diagnose classical hodgkin lymphoma in lymph nodes with high sensitivity and specificity". Am. J. Clin. Pathol. 131 (3): 322–32. doi:10.1309/AJCPW3UN9DYLDSPB. PMID 19228638.
  4. ↑ 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. 315. ISBN 978-1416054542.
  5. ↑ 5.0 5.1 Sissolak G, Sissolak D, Jacobs P (April 2010). "Human immunodeficiency and Hodgkin lymphoma". Transfus. Apher. Sci. 42 (2): 131–9. doi:10.1016/j.transci.2010.01.008. PMID 20138008.
  6. ↑ Vadmal, MS.; LaValle, GP.; DeYoung, BR.; Frankel, WL.; Marsh, WL. (Dec 2000). "Primary localized extranodal hodgkin disease of the transverse colon.". Arch Pathol Lab Med 124 (12): 1824-7. doi:10.1043/0003-9985(2000)1241824:PLEHDO2.0.CO;2. PMID 11100066.
  7. ↑ 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. 329. ISBN 978-1416054542.
  8. ↑ Gualco, G.; Natkunam, Y.; Bacchi, CE. (Jan 2012). "The spectrum of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases.". Mod Pathol. doi:10.1038/modpathol.2011.200. PMID 22222636.
  9. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 568. ISBN 978-0781765275.
  10. ↑ 10.0 10.1 Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 683. ISBN 978-1416025887.
  11. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/601900. Accessed on: 10 August 2010.
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