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'''Bone''' occasionally crosses the desk of the pathologist.  Primary bone tumours are rare; the most common bone tumour is metastases.<ref>WMSP P.632</ref>
[[Image:Osteosarcoma - very high mag.jpg|thumb|250px|right|A chondro-osseous tumour ([[osteosarcoma]]). [[H&E stain]].]]
'''Chondro-osseous tumours''' occasionally cross the desk of the pathologist.  They are grouped together as [[bone]] may develop from [[cartilage]].  


==Normal==
Primary bone tumours are rare; the most common bone tumour is [[metastases]].<ref name=Ref_WMSP632>{{Ref WMSP|632}}</ref> 
*Normal bone has osteocytes.
**If the osteocytes are missing... the bone is dead.


*Osteoblasts - make bone.
Bone tumours occasionally are lumped with soft tissue tumours.  Soft tissue tumours are dealt with in the ''[[soft tissue lesions]]'' article.  An introduction to bone is found in the ''[[bone]]'' article. An introduction to cartilage is found in the ''[[cartilage]]'' article.
*Osteoclasts - destroy bone.


Memory device: 'b' before 'c'.
==General==
==Diagnosing bone tumours==
*Diagnosis of a primary bone tumour should not be made without radiologic & clinical information!
*Diagnosis should not be made without radiologic & clinical information.
*Metastasis:primary bone tumours = >20:1.<ref name=Ref_WMSP632>{{Ref WMSP|632}}</ref>


===Bone marrow===
===Common malignant===
*Fat content (%) ~= age (in years)<ref>IAV 26 Feb 09</ref>
*[[Osteosarcoma]].
**e.g. 60 year old will have 60% fatty replacement.
*[[Chondrosarcoma]].
*[[Ewing's sarcoma]].
*[[Multiple myeloma]].
*[[Metastases]].
**Most common tumours metastatic to bone (mnemonic: ''BLT with Ketchup & Pickles''):
***[[Breast]].
***[[Liver tumours|Liver]].
***[[Thyroid gland|Thyroid gland]].
***[[Kidney tumours|Kidney]].
***[[Prostate gland]].
 
Epidemiology:<ref name=Ref_TN2005_OR42>{{Ref TN2005 |OR42}}</ref>
*Osteosarcoma -> 2nd decade.
*Ewing's ->5-20 yrs.
*Chondrosarcoma -> from enchondroma or osteochrondroma -- patients over 40 yrs.
*[[Multiple myeloma]] -> most common primary bone tumour in adults.


*Should see three cell lines.
===Malignant bone tumours by age===
**The cell lines:<ref>[http://emedicine.medscape.com/article/199003-overview http://emedicine.medscape.com/article/199003-overview]</ref>
Most common by age:<ref name=Ref_TN2005_OR42>{{Ref TN2005 |OR42}}</ref>
***Erythroid (red cells),  
*<1 year old - [[neuroblastoma]].
***Myeloid (white blood cells),  
*1-10 years old - [[Ewing sarcoma|Ewing's]] of tubular bones.
***Megakaryocytic (platelets).
*10-30 years old - osteosarcoma, Ewing's of flat bones.
*30-40 years old - [[reticulum cell sarcoma]], [[fibrosarcoma]], parosteal osteosarcoma, [[malignant giant cell tumour]], [[lymphoma]].
*>40 years old - mets, [[multiple myeloma]], [[chondrosarcoma]].


Note: Lymphocytes are considered separately and typically spared in bone marrow failure.<ref>[http://emedicine.medscape.com/article/199003-overview http://emedicine.medscape.com/article/199003-overview]</ref>
===Benign aggressive bone tumours===
*[[Giant cell tumour of bone]].
*[[Osteoblastoma]].
**Thought to be related to [[osteoid osteoma]].
**If in long bones often diaphyseal.


Identifying the lines:<ref>[http://upload.wikimedia.org/wikipedia/commons/6/69/Hematopoiesis_%28human%29_diagram.png http://upload.wikimedia.org/wikipedia/commons/6/69/Hematopoiesis_%28human%29_diagram.png]</ref>
Ref.:<ref name=Ref_TN2005_OR41>{{Ref TN2005 |OR41}}</ref><ref>URL: [http://www.emedicine.com/RADIO/topic494.htm http://www.emedicine.com/RADIO/topic494.htm].</ref>
#Megakaryocytes:
#*Big cells ~ 3x the size of a RBC.
===Summary tables===
#Normoblasts (RBC precursors):
====Bone tumours====
#*Hyperchromatic, i.e. blue, nucleus.
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
#Myeloid line:
! Entity
#*Granules.
! Key feature
#*Reniform nucleus, i.e. kidney bean shaped nucleus.
! Other features
! Radiology / gross
! Clinical
! Stains / other
! Image
|-
| [[Osteoma]]
| normal bone (???)
| other features (???)
| radiology / gross (???)
| ?
| no stains / may be assoc. with [[FAP]]
| [[Image:Osteoma -- intermed mag.jpg |thumb|center|150px| Osteoma. (WC)]]
|-
| [[Osteoid osteoma]]
| osteoblastic rimming
| anastomosing bony trabeculae
| must be <2 cm,<ref name=pmid25224389>{{Cite journal  | last1 = Yalcinkaya | first1 = U. | last2 = Doganavsargil | first2 = B. | last3 = Sezak | first3 = M. | last4 = Kececi | first4 = B. | last5 = Argin | first5 = M. | last6 = Basdemir | first6 = G. | last7 = Oztop | first7 = F. | title = Clinical and morphological characteristics of osteoid osteoma and osteoblastoma: a retrospective single-center analysis of 204 patients. | journal = Ann Diagn Pathol | volume = 18 | issue = 6 | pages = 319-25 | month = Dec | year = 2014 | doi = 10.1016/j.anndiagpath.2014.08.006 | PMID = 25224389 }}</ref> metaphysis
| painful, NSAIDs remove pain, young
| IHC / other
| [[Image:Osteoid_osteoma_-_high_mag.jpg |thumb|center|150px| Osteoid osteoma. (WC)]]
|-
| [[Osteoblastoma]]
| osteoblastic rimming
| anastomosing bony trabeculae
| must be >1 cm,<ref name=pmid25224389/> often >=2 cm, metaphysis
| not painful
| IHC / other
| [[Image:Osteoblastoma_-_high_mag.jpg|thumb|center|150px|Osteoblastoma. (WC)]]
|-
| [[Ewing sarcoma]]
| [[small round blue cell tumour]]
| cytoplasmic clearing (due to glycogen)
| usu. diaphysis
| pediatric, typically 1-10 years
| PAS+, PASD-, [[chromosomal translocations]] (usually t(11;22)(q24;q12)) 
| [[Image:Ewing_sarcoma_-_PAS_-_high_mag.jpg |thumb|center|150px| Ewing sarcoma. [[PAS stain]]. (WC)]]
|-
| [[Osteosarcoma]]
| osteoid
| +/-hemorrhage, +/-cartilage
| distal femur, prox. tibia, prox. humerous
| typically 10-30 years, pain, swelling
| no stains; many subtypes
| [[Image:Osteosarcoma_-_very_high_mag.jpg |thumb|center|150px|Osteosarcoma. (WC)]]
|-
| [[Giant cell tumour of bone]]
| abundant giant cells
| nuclei of surrounding cells similar to those in giant cells
| growth plate of long bones
| 20-45 years old, +/-joint pain, +/-immobility
| IHC / other
| [[Image:Giant_cell_tumour_of_bone_-_high_mag.jpg|thumb|center|150px|Giant cell tumour. (WC)]]
|-
|}


Images:
====Cartilage tumours====
*[http://commons.wikimedia.org/wiki/File:Bone_marrow_WBC.JPG Myeloid line (WC)].
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
! Entity
! Key feature
! Other features
! Radiology / gross
! Clinical
! Stains / other
! Image
|-
| [[Chondroma]]
| ctyologically benign cells
| equally spaced nests
| usu. diaphysis
| benign / DDx: chondroma, well-diff. chondrosarcoma
| IHC / bone marrow cavity chondroma = ''enchondroma''
| [[Image:Enchondroma_-_very_high_mag.jpg |thumb|center|150px| Enchondroma. (WC)]]
|-
| [[Chondroblastoma]]
| abundant extracellular material, abundant eosinophilic cytoplasm
| calcifications surround cells nests ("chickenwire" appearance) - '''classic'''
| epiphysis
| DDx: [[giant cell tumour of bone]]
| S100+ve, vimentin +ve
| [[Image:Chondroblastoma_-_very_high_mag.jpg |thumb|center|150px| Chondroblastoma. (WC)]]
|-
| [[Chondrosarcoma]]
| cartilaginous appearance +/- nuclear atypia
| lack osteoid, if present -> osteosarcoma
| usu. diaphysis, classically hip; almost never distal extremity
| >40 years old
| IHC / may be histologically benign looking
| [[Image:Chondrosarcoma_%282%29.jpg |thumb|center|150px|Chondrosarcoma. (WC)]]
|-
|}


====Organization====
====Other====
*Mature hematopoeitic cells at the centre (distant from bone).
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
*Immature hematopoeitic cells adjacent to the bone.
! Entity
! Key feature
! Other features
! Radiology / gross
! Clinical
! Stains / other
! Image
|-
| [[Osteochondroma]]
| benign bone and cartilage
| Other features
| metaphyseal lesions
| Clinical
| IHC / other
| Image
|-
| [[Adamantinoma]]
| bisphasic - stroma & epithelium
| Other features
| tibia, fibula, intracortical, radiolucent
| Clinical
| IHC / other
| [[Image:Adamantinoma_-_intermed_mag.jpg |thumb|center|150px|Adamantinoma. (WC)]]
|-
| [[Diffuse tenosynovial giant-cell tumour]] ([[AKA]] [[PVNS]])
| pigmented giant cells
| nodules
| Radiology / gross
| Clinical
| IHC / other
| [[Image:Pigmented_villonodular_synovitis_low_mag.jpg |thumb|center|150px| PVNS. (WC)]]
|-
| [[Brown tumour]]
| fibrosis, +/-giant cells
| unaffected bone incr. osteoblasts and osteoclasts
| Radiology / gross
| due to hypercalcemia; not a neoplasm
| IHC / other
| [[Image:Brown_tumour_-_low_mag.jpg |thumb|center|150px| Brown tumour. (WC)]]
|-
|}


==Infectious==
====Radiology====
===Osteomyelitis===
=====Radiologic features=====
General
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
*Hematogenous - often in children.
! Features
*Direct entry (skin defect) - adults with diabetes.
! Benign
! Malignant
|-
| Bone changes
| sclerotic rim
| tumour perforation
|-
| Circumscription
| pushing margins
| ill-defined/moth-eaten
|-
| Soft tissue involvement
| no
| common
|-
| Periosteal reaction
| no
| "hair-on-end" or "sunburst",<br> "onion skin", Codman's triangle
|}


Micro.
=====Location=====
*PMNs.
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
! Diagnosis
! [[Epiphysis]]
! [[Metaphysis]]
! [[Diaphysis]]
! Type of lesion
|-
| [[Aneurysmal bone cyst]]
| common
| most common
| rare
| [[bone]]
|-
| [[Chondroblastoma]]
| most common
| rare
| extremely rare
| [[cartilage]]
|-
| [[Chondrosarcoma]]
| uncommon
| common
| most common
| [[cartilage]]
|-
| [[Chondromyxoid fibroma]]
| rare
| most common
| common
| other
|-
| [[Enchondroma]]
| rare
| common
| common
| [[cartilage]]
|-
| [[Ewing sarcoma]]
| rare
| common
| most common
| [[bone]]
|-
| [[Giant cell tumour of bone|Giant cell tumour]]
| most common
| rare
| extremely rare
| [[bone]]
|-
| Metastatic carcinoma
| rare
| common
| most common
| other
|-
| Non-ossifying fibroma
| extremely rare
| most common
| common
| other
|-
| [[Osteoblastoma]]
| rare
| most common
| uncommon
| [[bone]]
|-
| [[Osteochondroma]]
| extremely rare{{fact}} <!-- PMID 12873205 questions this -->
| most common
| common
| [[bone]]/[[cartilage]]
|-
| [[Osteoid osteoma]]
| uncommon
| common
| common<ref name=wheelessonline>URL: [http://www.wheelessonline.com/ortho/osteoid_osteoma http://www.wheelessonline.com/ortho/osteoid_osteoma]. Accessed on: 7 May 2012</ref>
| [[bone]]
|-
| [[Osteosarcoma]]
| rare
| most common
| uncommon
| [[bone]]
|}


===Chronic osteomyelitis===
How to remember the primary bone lesions:
*Plasma cells.
#''Ewing sarcoma'' is the only malignant primary bone tumour of the diaphysis.
**May be sterile, i.e. no organisms.
#''Giant cell tumour of bone'' is the only primary bone lesion of the epiphysis.
#The rest of the primary bone lesions are metaphyseal.
#*''Osteochondroma'' is bone first and cartilage second. It behaves like most primary bone lesions; it is usually metaphyseal.


==Bone tumours==
How to remember the primary cartilaginous lesions:
General:
#''Chondroblastoma'' is epiphyseal.  The chicken wire goes around the chicken coop.
*Metastasis:primary bone tumours = >20:1.<ref>WMSP P.632</ref>
#The others are diaphyseal.


==Giant cell tumour==
=Cartilage=
General<ref>WMSP P.648</ref>
==Chondroma==
*Approx. 5% of primary bone tumours.
{{Main|Chondroma}}
*Age 20-45 years.


Clinical
==Chondroblastoma==
*May present with joint pain, immobility.
{{Main|Chondroblastoma}}


Micro.
==Chondromyxoid fibroma==
*Mononuclear cells '''key feature'''.
{{Main|Chondromyxoid fibroma}}
*Giant cells.


==Chondrosarcoma==
==Chondrosarcoma==
===Micro===
{{Main|Chondrosarcoma}}
Features:<ref>IAV 26 Feb 09</ref>
*Abnormal cartilage.
*Nuclear atypia.
**Nuclear clearing.
**Nucleoli.


==Ewing sarcoma==
=Bone=
===General===
==Osteoma==
*AKA EWS/PNET:
{{Main|Osteoma}}
**EWS = Ewing sarcoma.
**PNET = Primative neuroectodermal tumour.
*EWS and PNET were once thought to be different tumours.


Clinical
==Osteoid osteoma==
*Painful.
{{Main|Osteoid osteoma}}
*Usually younger than 20 years.


===Radiology===
==Osteoblastoma==
Features:<ref>WMSP P.650</ref>
{{Main|Osteoblastoma}}
*Long bones, diaphyses.
*Destructive.
*"Onion-skin" periosteal reaction.


===Microscopic===
==Ewing sarcoma==
Classification:
{{Main|Ewing sarcoma}}
*Small blue cell tumour.


Features:<ref>PST. 22 February 2010.</ref>
==Osteosarcoma==
*Scant clear cytoplasm (contain glycogen - PAS +ve, PAS-D -ve).
{{Main|Osteosarcoma}}
*Lack nucleoli.
*Round small nucleus.


===[[IHC]]===
==Giant cell tumour of bone==
Features:<ref>WMSP P.651</ref>
{{Main|Giant cell tumour of bone}}
*CD99 +ve (plasma membrane staining).
*CD45 -ve.
**Done to r/o lymphoma.
*+/-Neural markers (NSE, synaptophysin, CD57 (??? CD56 ???), S100).
*+/-Cytokeratins.
*Caveolin-1<ref>PST. 22 February 2010.</ref>
**New kid on the block.


Notes:<ref>PST. 22 February 2010.</ref>
=Other=
*CD99 +ve (plasma membrane) tumours:
This section collects stuff that doesn't neatly fit into the ''bone'' or ''cartilage'' category.
**Lymphoblastic lymphoma/leukemia.
**Angiomatoid fibrous histiocytoma.
**Desmoplastic small round cell tumour.


===Molecular diagnostics===
==Notochordal tumors==
Common features:
Notochordal tumors arise from notochordal remnants and thus are seen in the clivus or sacrum.
*''EWS/FLI-1 fusion gene'' formation due to translocation: ''t(11;22)(q24;q12)''.<ref>URL: [http://atlasgeneticsoncology.org/Tumors/Ewing5010.html http://atlasgeneticsoncology.org/Tumors/Ewing5010.html]. Accessed on: 23 February 2010.</ref><ref name=pmid3163261>PMID: 3163261</ref>
{{Main|Chordoma}}
**Often detected by RT-PCR (with EWS 5' and FLI-1 3' primers).


Notes:
==Osteochondroma==
*The ''t(11;22)(q24;q12)'' is seen in ~90% of EWS/PNET... but also in:
{{Main|Osteochondroma}}
**Olfactory neuroblastoma.
**Small cell osteogenic sarcoma.
**Polyphenotypic tumours.
**Rhbdomyosarcoma.
**Neuroblastoma (possibly).
*Several other translocations exist.


==Pigmented villonodular synovitis==
==Diffuse tenosynovial giant-cell tumour==  
*Commonly abbreviated: ''PVNS''.
*[[AKA]] ''tenosynovial giant-cell tumour, diffuse type''.
*Course: benign.
*Previously known as ''pigmented villonodular synovitis'' (PVNS).<ref>{{Ref PBoD8|1247}}</ref>
{{Main|Diffuse tenosynovial giant-cell tumour}}


===Microscopy===
==Giant cell tumour of tendon sheath==
Features:<ref>[http://www.wheelessonline.com/ortho/pigmented_villonodular_synovitis http://www.wheelessonline.com/ortho/pigmented_villonodular_synovitis]</ref>
*Abbreviated ''GCT of tendon sheath''.
*Subsynovial nodules composed of cells with:
{{Main|Giant cell tumour of tendon sheath}}
**Abundant cytoplasm.
**Pale nuclei.
*Multinucleated giant cells.
*Hemosiderin-laden macrophages.
*Foam cells.


==Osteosarcoma==
==Adamantinoma==
===General===
{{Main|Adamantinoma}}
*Terry Fox was afflicited by this tumour.
 
===Definition===
*Tumour that makes osteoid.
**Osteoid = (extracellular) organic component of bone, normally produced by osteoblasts (cells which make bone matrix).


===Histology===
==Brown tumour==
*Spindle cells with malignant features (e.g. nuclear membrane irregularies, marked nuclear
 
size differences, mitoses) surrounded by delicate strands of osteoid.
**Osteoid on H&E: pink, homogenous, "glassy".
**Tumours typically very cellular - when compared to normal bone.
*Large (multinucleated) osteoclast-like giant cells may be seen.<ref>{{cite journal |author=Papalas JA, Balmer NN, Wallace C, Sangueeza OP |title=Ossifying dermatofibroma with osteoclast-like giant cells: report of a case and literature review |journal=Am J Dermatopathol |volume=31 |issue=4 |pages=379-83 |year=2009 |month=June |pmid=19461244 |doi=10.1097/DAD.0b013e3181966747 |url=}}</ref>
 
==Adamantinoma==
===General===
===General===
Features:<ref>WMSP P.650.</ref>
*''Not'' a true neoplasm.<ref name=pmid16775919>{{cite journal |author=Meydan N, Barutca S, Guney E, ''et al.'' |title=Brown tumors mimicking bone metastases |journal=J Natl Med Assoc |volume=98 |issue=6 |pages=950–3 |year=2006 |month=June |pmid=16775919 |pmc=2569361 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569361/?page=1 }}</ref>  
*Rare: < 1% of bone tumours.
**If ''tumour'' is understood as a synonym for ''neoplasm'', the name is a misnomer.
*25-35 years old.
**May (clinically) mimic a true neoplasm.
*Tibia, fibula.
*Due to hyperparathyroidism - usually [[parathyroid adenoma]].
*Benign, may be locally aggressive.
**Usually secondary to chronic renal failure.
*Cousin of [[ameloblastoma]].<ref>NEED REF.</ref>


===Radiology===
====Hypercalcemia DDx====
*Intracortical, radiolucent.
Mnemonic ''GRIMED'':<ref>{{Ref TN2006 |Emerg.}}</ref>
*Granulomatous disease (tuberculosis, [[sarcoidosis]]).
*Renal disease.
*Immobility.
*Malignancy (esp. [[squamous cell carcinoma]], [[plasmacytoma]]).
*Endocrine ([[parathyroid gland|primary hyperparathyroidism]] - leads to [[brown tumour]]).
*Drugs (thiazides ... others).


Micro.
===Microscopic===
*Fibrous tumour.
Features:
*Fibrosis.
*+/-Giant cells with round to oval nuclei and nucleoli.<ref>URL: [http://path.upmc.edu/cases/case139/micro.html http://path.upmc.edu/cases/case139/micro.html]. Accessed on: 6 January 2012.</ref>
*Bone unaffected by tumour - increased numbers of the following:
**Multinucleated cells (osteoclasts).
**Mononuclear cells around the bony trabeculae (osteoblasts).


==Common malignant==
DDx:
*Osteosarcoma.
*[[Giant cell tumour of bone]] and other [[giant cell lesions]].
*Chondrosarcoma.
*Ewing's sarcoma.
*Multiple myeloma.
*Metastases.
**Most common tumours metastatic to bone (mnemonic: ''BLT with Ketchup & Pickles''):
***Breast,
***Liver,
***Thyroid,
***Kidney,
***Prostate.  


Epi.<ref>TN05 OR42</ref>
====Images====
*Osteosarcoma -> 2nd decade.  
<gallery>
*Ewing's ->5-20 yrs.
Image:Brown_tumour_-_low_mag.jpg | Brown tumour - low mag. (WC)
*Chondrosarcoma -> from enchondroma or osteochrondroma -- patients over 40 yrs.
Image:Brown_tumour_-_intermed_mag.jpg | Brown tumour - intermed. mag. (WC)
*Multiple myeloma -> most common primary bone tumour in adults.
Image:Brown_tumour_-_high_mag.jpg | Brown tumour - high mag. (WC)
</gallery>
www:
*[http://wwwold.path.utah.edu/classes/webpath/bonehtml/bone053.htm Brown tumour (utah.edu)].
*[http://www.mda-sy.com/pathology/BONEHTML/BONE054.HTM Brown tumour (mda-sy.com)].
*[http://path.upmc.edu/cases/case139/micro.html Brown tumour - several images (upmc.edu)].


==Malignant bone tumours by age==
=See also=
Most common by age:<ref>TN05 OR42</ref>
*[[Hematopathology]].
*<1 year old - neuroblastoma.
*[[Soft tissue lesions]].
*1-10 years old - Ewing's of tubular bones.
*[[Small round cell tumours]].
*10-30 years old - osteosarcoma, Ewing's of flat bones.
*30-40 years old - reticulum cell sarcoma, fibrosarcoma, parosteal osteosarcoma, malignant giant cell tumour, lymphoma.
*>40 years old - mets, multiple myeloma, chondrosarcoma.
 
==Benign aggressive bone tumours==
*Giant cell tumours.
*Osteoblastoma.
**Thought to be related to osteoid osteoma.
**If in long bones often diaphyseal.
Ref.:<ref>TN05 OR41</ref><ref>[http://www.emedicine.com/RADIO/topic494.htm http://www.emedicine.com/RADIO/topic494.htm]</ref>
 
==Brown cell tumour==
===Etiology===
*Due to hyperparathyroidism - usually parathyroid adenoma.
 
===Microscopy===
*Fibrosis.


===Hypercalcemia DDx===
=References=
Mnemonic ''GRIMED'':<ref>TN06 Emerg</ref>
*Granulomatous disease (tuberculosis, sarcoidosis).
*Renal disease.
*Immobility.
*Malignancy (esp. squamous cell carcinoma, [[plasmacytoma]]).
*Endocrine (primary hyperparathyroidism - leads to brown cell tumour).
*Drugs (thiazides ... others).
 
==References==
{{reflist|2}}
{{reflist|2}}


==See also==
=External links=
*[[Hematopathology]].
*[http://www.medpath.info/MainContent/Skeletal/Bone_07.html Bone lesions (medpath.info)].
*[http://www.radiologyassistant.nl/en/494e15cbf0d8d Bone radiology (radiologyassistant.nl)].


[[Category:Chondro-osseous tumours]]
[[Category:Weird stuff]]
[[Category:Weird stuff]]
Michael
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