Lymphomatoid granulomatosis pathophysiology: Difference between revisions

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{{Lymphomatoid granulomatosis}}
{{Lymphomatoid granulomatosis}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{kakbar}}
==Overview==
==Overview==
 
[[Lymphomatoid granulomatosis]] arises from [[T cell|T cells]] infused with [[Epstein Barr virus|EBV]], which are lymphoid cells that are normally involved in [[Immunity (medical)|Immunity]].As a result patients typically resent with pulmonary symptoms (cough, dyspnea, chest tightness).Patients with lymphomatoid granulomatosis tend to have low CD4 counts usually due to infection (EBV, hep c, and hiv) and/or immunospression( immunosuppressive drugs, and Inherited immunodeficiency diseases).On microscopic pathology inflammation of micro vessels are seen or angitis is seen and t cells containing EBV.On gross pathology nodules are seen mostly in the lung.
[[Lymphomatoid granulomatosis]] arises from [[T cell|T cells]] infused with EBV, which are [[Lymphoid cells]] that are normally involved in [[Immunity (medical)|Immunity]].
 
 
==Pathophysiology==
==Pathophysiology==
===Physiology===
===Physiology===
The normal physiology of cell mediated immunity can be understood as follows: Historically, the immune system was divided into two branches: humoral immunity, for which the defending function of immunization could be seen in the humor (cell-free bodily fluid or serum) and cellular immunity, for which the defending function of immunization was associated with cells. CD4 cells or helper T cells provide defense against varying  pathogenic organisms. Naive T cells, mature T cells that have yet to come upon an antigen, are transformed into activated effector T cells after coming across an antigen-presenting cells (APCs). These APCs, such as macrophages, dendritic cells, and B cells in some cases, pack antigenic peptides onto the MHC of the cell, in turn introducing the peptide to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens.<ref name="pmid21297689">{{cite journal |vauthors=Denburg JA, Bienenstock J |title=Physiology of the immune response |journal=Can Fam Physician |volume=25 |issue= |pages=301–7 |date=March 1979 |pmid=21297689 |pmc=2382958 |doi= |url=}}</ref>
*The normal physiology of [[cell mediated immunity]] can be understood as follows:  
*Historically, the [[immune system]] was divided into two branches:
**[[Humoral immunity]], for which the defending function of [[immunization]] could be seen in the humor (cell-free bodily fluid or serum)
**[[Cell-mediated immunity|Cellular immunity]] or [[Cell-mediated immunity|Cell mediated immunity]] , for which the defending function of immunization was associated with cells. The cell involved in cell mediated immunity are the following:
***[[CD4|CD4 cells]] or [[T helper cell|Helper T cells]] provide defense against varying  pathogenic organisms.  
***[[T cell|Naive T cells]]
*Mature T cells that have yet to come upon an antigen, and are transformed into activated effector T cells after coming across an [[Antigen-presenting cell|antigen-presenting cells]] (APCs)
**These APCs, are the following 
***[[Macrophage|Macrophages]]
***[[Dendritic cell|Dendritic cells]]
***[[B cell|B cells]]
*The cells listed above in some cases, pack antigenic [[Peptide|peptides]] onto the [[MHC]] of the cell, in turn introducing the peptide to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens.<ref name="pmid21297689">{{cite journal |vauthors=Denburg JA, Bienenstock J |title=Physiology of the immune response |journal=Can Fam Physician |volume=25 |issue= |pages=301–7 |date=March 1979 |pmid=21297689 |pmc=2382958 |doi= |url=}}</ref>
===Pathogenesis===
===Pathogenesis===


*It is understood that Lymphomatoid granulomatosis is seen in extranodal sites, most commonly the lung. Other recurrent sites of involvement include kidney, skin, central nervous system and liver. The pattern of necrosis in both Lymphomatoid granulomatosis and T/Natural killer cell lymphoma is very similar, accentuating the probable importance of EBV in interceding the vascular damage. Recent studies shows that the chemokines IP-10 and Monoclonal immunoglobilins in the pathogenesis of the vascular damage. Although the most common infiltrating cells are T cells, the T cell receptor genes are not clonally rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases contain clonal rearrangements. EBV sequences can be confined to B cells and are clonal in most cases. Most patients with Lymphomatoid granulomatosis carefully evaluated clinically have irregularities in there cytotoxic T cell function and low levels of CD8+ T cells<ref name="pmid9547995">{{cite journal| author=Jaffe ES, Wilson WH| title=Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. | journal=Cancer Surv | year= 1997 | volume= 30 | issue=  | pages= 233-48 | pmid=9547995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9547995  }} </ref><ref name="pmidhttps://doi.org/10.1016/S0046-8177(72)80005-4">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=https://doi.org/10.1016/S0046-8177(72)80005-4 | doi= | pmc=5922622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
*It is understood that [[Lymphomatoid granulomatosis]] is seen in extranodal sites, most commonly the lung
Other systems of the body which are affected in Lymphomatoid granulomatosis include:<ref name="pmid23547864">{{cite journal| author=Hussein MR| title=Atypical lymphoid proliferations: the pathologist's viewpoint. | journal=Expert Rev Hematol | year= 2013 | volume= 6 | issue= 2 | pages= 139-53 | pmid=23547864 | doi=10.1586/ehm.13.4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23547864  }} </ref>
*Other recurrent sites of involvement include the following:
**Kidney
**Skin
**Central nervous system
**Liver
*The pattern of necrosis in both [[Lymphomatoid granulomatosis]] and T/Natural killer cell lymphoma are very similar, accentuating the probable importance of [[Epstein Barr virus|EBV]] in interceding the vascular damage
*Recent studies shows that the [[Chemokine|chemokines]] IP-10 and [[Monoclonal antibodies|monoclonal immunoglobilins]] are indicated in the pathogenesis of the vascular damage
*Although the most common infiltrating cells are [[T cell|T cells]], the T cell receptor genes are not clonally rearranged. However, by [[VDJ polymerase chain reaction]], approximately 60% of cases contain clonal rearrangements
*EBV sequences can be confined to B cells and are clonal in most cases  
*Most patients with [[Lymphomatoid granulomatosis]] carefully evaluated clinically have irregularities in there cytotoxic T cell function and low levels of [[Cytotoxic T cell|CD8+ T cells]]<ref name="pmid9547995">{{cite journal| author=Jaffe ES, Wilson WH| title=Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. | journal=Cancer Surv | year= 1997 | volume= 30 | issue=  | pages= 233-48 | pmid=9547995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9547995  }} </ref><ref name="pmidhttps://doi.org/10.1016/S0046-8177(72)80005-4">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=https://doi.org/10.1016/S0046-8177(72)80005-4 | doi= | pmc=5922622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
Other systems of the body which are affected in [[Lymphomatoid granulomatosis]] include:<ref name="pmid23547864">{{cite journal| author=Hussein MR| title=Atypical lymphoid proliferations: the pathologist's viewpoint. | journal=Expert Rev Hematol | year= 2013 | volume= 6 | issue= 2 | pages= 139-53 | pmid=23547864 | doi=10.1586/ehm.13.4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23547864  }} </ref>
*Pulmonary<ref name="pmid27872542">{{cite journal| author=Ankita G, Shashi D| title=Pulmonary Lymphomatoid Granulomatosis- a Case Report with Review of Literature. | journal=Indian J Surg Oncol | year= 2016 | volume= 7 | issue= 4 | pages= 484-487 | pmid=27872542 | doi=10.1007/s13193-016-0525-1 | pmc=5097759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27872542  }} </ref> <ref name="pmid26452211">{{cite journal| author=Piña-Oviedo S, Weissferdt A, Kalhor N, Moran CA| title=Primary Pulmonary Lymphomas. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 6 | pages= 355-75 | pmid=26452211 | doi=10.1097/PAP.0000000000000090 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26452211  }} </ref>
*Pulmonary<ref name="pmid27872542">{{cite journal| author=Ankita G, Shashi D| title=Pulmonary Lymphomatoid Granulomatosis- a Case Report with Review of Literature. | journal=Indian J Surg Oncol | year= 2016 | volume= 7 | issue= 4 | pages= 484-487 | pmid=27872542 | doi=10.1007/s13193-016-0525-1 | pmc=5097759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27872542  }} </ref> <ref name="pmid26452211">{{cite journal| author=Piña-Oviedo S, Weissferdt A, Kalhor N, Moran CA| title=Primary Pulmonary Lymphomas. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 6 | pages= 355-75 | pmid=26452211 | doi=10.1097/PAP.0000000000000090 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26452211  }} </ref>
*CNS<ref name="pmid26607855">{{cite journal| author=Sugita Y, Muta H, Ohshima K, Morioka M, Tsukamoto Y, Takahashi H et al.| title=Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis. | journal=Neuropathology | year= 2016 | volume= 36 | issue= 4 | pages= 313-24 | pmid=26607855 | doi=10.1111/neup.12276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26607855  }} </ref><ref name="pmid28451478">{{cite journal| author=Kubota M, Taniguchi M, Tobisawa S, Nakata Y, Nakaya M, Tamogami H et al.| title=T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System. | journal=Cureus | year= 2017 | volume= 9 | issue= 3 | pages= e1119 | pmid=28451478 | doi=10.7759/cureus.1119 | pmc=5406172 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28451478  }} </ref>
*CNS<ref name="pmid26607855">{{cite journal| author=Sugita Y, Muta H, Ohshima K, Morioka M, Tsukamoto Y, Takahashi H et al.| title=Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis. | journal=Neuropathology | year= 2016 | volume= 36 | issue= 4 | pages= 313-24 | pmid=26607855 | doi=10.1111/neup.12276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26607855  }} </ref><ref name="pmid28451478">{{cite journal| author=Kubota M, Taniguchi M, Tobisawa S, Nakata Y, Nakaya M, Tamogami H et al.| title=T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System. | journal=Cureus | year= 2017 | volume= 9 | issue= 3 | pages= e1119 | pmid=28451478 | doi=10.7759/cureus.1119 | pmc=5406172 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28451478  }} </ref>
*Skin
*Skin<ref name="pmid11688570">{{cite journal| author=Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M et al.| title=Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. | journal=Am J Surg Pathol | year= 2001 | volume= 25 | issue= 9 | pages= 1111-20 | pmid=11688570 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688570  }} </ref><ref name="pmid25355540">{{cite journal| author=Rysgaard CD, Stone MS| title=Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature. | journal=J Cutan Pathol | year= 2015 | volume= 42 | issue= 3 | pages= 188-93 | pmid=25355540 | doi=10.1111/cup.12402 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25355540  }} </ref>


==Gross Pathology==
==Gross Pathology==
On gross pathology, the following is seen:<ref name="pmid11688570">{{cite journal| author=Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M et al.| title=Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. | journal=Am J Surg Pathol | year= 2001 | volume= 25 | issue= 9 | pages= 1111-20 | pmid=11688570 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688570  }} </ref>
On gross pathology, the following is seen:<ref name="pmid11688570">{{cite journal| author=Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M et al.| title=Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. | journal=Am J Surg Pathol | year= 2001 | volume= 25 | issue= 9 | pages= 1111-20 | pmid=11688570 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688570  }} </ref>
*Lung nodules up to 10 cm with central necrosis and cavitation
*[[Lung nodules]] up to 10 cm with central [[necrosis]] and cavitation<ref name="pmid22361129">{{cite journal| author=Bartosik W, Raza A, Kalimuthu S, Fabre A| title=Pulmonary lymphomatoid granulomatosis mimicking lung cancer. | journal=Interact Cardiovasc Thorac Surg | year= 2012 | volume= 14 | issue= 5 | pages= 662-4 | pmid=22361129 | doi=10.1093/icvts/ivr083 | pmc=3329320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22361129  }} </ref><ref name="pmid22214969">{{cite journal| author=Colby TV| title=Current histological diagnosis of lymphomatoid granulomatosis. | journal=Mod Pathol | year= 2012 | volume= 25 Suppl 1 | issue=  | pages= S39-42 | pmid=22214969 | doi=10.1038/modpathol.2011.149 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22214969  }} </ref>
*15% of patients with skin lesions have indurated and atrophic plaques
*15% of patients with skin lesions have indurated and [[Atrophy|atrophic]] plaques<ref name="pmid25419752">{{cite journal| author=Fischer R, Shaath T, Meade C, Fraga GR, Rajpara A| title=An eschar and violaceous nodules as the presenting signs of lymphomatoid granulomatosis. | journal=Dermatol Online J | year= 2014 | volume= 20 | issue= 11 | pages=  | pmid=25419752 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25419752  }} </ref><ref name="pmid27051739">{{cite journal| author=Shaigany S, Weitz NA, Husain S, Geskin L, Grossman ME| title=A case of lymphomatoid granulomatosis presenting with cutaneous lesions. | journal=JAAD Case Rep | year= 2015 | volume= 1 | issue= 4 | pages= 234-7 | pmid=27051739 | doi=10.1016/j.jdcr.2015.05.008 | pmc=4808726 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27051739  }} </ref>


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis,  the presence of an angiocentric and angiodestructive accumulation of differing numbers of T cells with varying numbers of atypical clonal EBV-positive B cells in a polymorphous inflammatory background is seen in Lymphomatoid granulomatosis. This is what is seen in the different organ systems that Lympahtoid granulomatosis affects:<ref name="pmid9737242">{{cite journal| author=Guinee DG, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN| title=Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells. | journal=Am J Surg Pathol | year= 1998 | volume= 22 | issue= 9 | pages= 1093-100 | pmid=9737242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9737242  }} </ref>
On microscopic histopathological analysis,  the presence of an angiocentric and angiodestructive accumulation of differing numbers of [[T cell|T cells]] with varying numbers of atypical clonal EBV-positive B cells in a polymorphous inflammatory background is seen in [[Lymphomatoid granulomatosis]]. This is what is seen in the different organ systems that [[Lympahtoid granulomatosis|Lymphomatoid granulomatosis]] affects:<ref name="pmid9737242">{{cite journal| author=Guinee DG, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN| title=Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells. | journal=Am J Surg Pathol | year= 1998 | volume= 22 | issue= 9 | pages= 1093-100 | pmid=9737242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9737242 }} </ref><ref name="pmid22214969">{{cite journal| author=Colby TV| title=Current histological diagnosis of lymphomatoid granulomatosis. | journal=Mod Pathol | year= 2012 | volume= 25 Suppl 1 | issue=  | pages= S39-42 | pmid=22214969 | doi=10.1038/modpathol.2011.149 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22214969 }} </ref>
*Lung:
*Lung:
**Nodular and disseminated lymphoid infiltrates alongside lymphatics and bronchovascular bundles
**Nodular and disseminated lymphoid infiltrates alongside lymphatics and bronchovascular bundles<ref name="pmid22745203">{{cite journal| author=Hare SS, Souza CA, Bain G, Seely JM, Gomes MM et al.| title=The radiological spectrum of pulmonary lymphoproliferative disease. | journal=Br J Radiol | year= 2012 | volume= 85 | issue= 1015 | pages= 848-64 | pmid=22745203 | doi=10.1259/bjr/16420165 | pmc=3474050 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22745203  }} </ref>
**Centers of nodules have large vessels with lymphatic infiltration
**Centers of [[Nodule (medicine)|nodules]] have large vessels with lymphatic infiltration<ref name="pmid22745203">{{cite journal| author=Hare SS, Souza CA, Bain G, Seely JM, Gomes MM et al.| title=The radiological spectrum of pulmonary lymphoproliferative disease. | journal=Br J Radiol | year= 2012 | volume= 85 | issue= 1015 | pages= 848-64 | pmid=22745203 | doi=10.1259/bjr/16420165 | pmc=3474050 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22745203  }} </ref>
**Typically high grade
**Typically high grade
**Small lymphocytes, plasma cells and histiocytes are also present, seldomly accompanied by neutrophils, granulomas are mostly seen with cutaneous involvement
**Small [[Lymphocyte|lymphocytes]], [[Plasma cell|plasma cells]] and [[Histiocyte|histiocytes]] are also present, seldomly accompanied by [[Neutrophil|neutrophils]], [[Granuloma|granulomas]] are mostly seen with cutaneous involvement<ref name="pmid20441499">{{cite journal| author=Mukhopadhyay S, Gal AA| title=Granulomatous lung disease: an approach to the differential diagnosis. | journal=Arch Pathol Lab Med | year= 2010 | volume= 134 | issue= 5 | pages= 667-90 | pmid=20441499 | doi=10.1043/1543-2165-134.5.667 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20441499  }} </ref>
 
*Skin:
*Skin:
**Usually multiple erythematous dermal papules or subcutaneous nodules with an angiocentric lymphohistiocytic infiltrate of CD4+ T cells and angiodestruction, necrosis,  
**Usually multiple erythematous dermal [[Papule|papules]] or subcutaneous [[Nodule (medicine)|nodules]] with an angiocentric [[lymphohistiocytic]] infiltrate of [[T helper cell|CD4+ T cells]] and angiodestruction, [[necrosis]], [[panniculitis]], atypia<ref name="pmiddoi:10.1001/archderm.1996.03890360054010">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=doi:10.1001/archderm.1996.03890360054010 | doi= | pmc=5922622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
  panniculitis, atypia
*Grading:<ref name="pmid11688570">{{cite journal| author=Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M et al.| title=Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. | journal=Am J Surg Pathol | year= 2001 | volume= 25 | issue= 9 | pages= 1111-20 | pmid=11688570 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688570  }} </ref><ref name="pmid9737242">{{cite journal| author=Guinee DG, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN| title=Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells. | journal=Am J Surg Pathol | year= 1998 | volume= 22 | issue= 9 | pages= 1093-100 | pmid=9737242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9737242  }} </ref> Relates to the proportion of EBV+ B cells relative to the reactive background lymphocytes
**Grade 1:
***infrequent [[Epstein Barr virus|EBV]] positive cells (< 5/HPF)
***No large [[atypical cells]]
***Small amount of [[necrosis]]
***Some cases  resolve immediately 
**Grade 2:
***EBV positive large lymphoid cells or immunoblasts (5 - 50/HPF)
***Intermittent large atypical cells
***Modest amount of [[necrosis]]
***Some cases spontaneously resolve
**Grade 3:
***large atypical CD20+ B cells with extensive necrosis and > 50/HPF EBV positive cells
***Prevalent population of large atypical cells
***May be coalescent
***Diffuse [[necrosis]]


*Grading:
==References==
**Relates to the proportion of EBV+ B cells relative to the reactive background lymphocytes
**Grade 1 - infrequent EBV positive cells (< 5/HPF)
**Grade 2 - EBV positive large lymphoid cells or immunoblasts (5 - 50/HPF)
**Grade 3 - large atypical CD20+ B cells with extensive necrosis and > 50/HPF EBV positive cells
=References==
{{Reflist|2}}
{{Reflist|2}}


Latest revision as of 21:08, 18 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kamal Akbar, M.D.[2]

Overview

Lymphomatoid granulomatosis arises from T cells infused with EBV, which are lymphoid cells that are normally involved in Immunity.As a result patients typically resent with pulmonary symptoms (cough, dyspnea, chest tightness).Patients with lymphomatoid granulomatosis tend to have low CD4 counts usually due to infection (EBV, hep c, and hiv) and/or immunospression( immunosuppressive drugs, and Inherited immunodeficiency diseases).On microscopic pathology inflammation of micro vessels are seen or angitis is seen and t cells containing EBV.On gross pathology nodules are seen mostly in the lung.

Pathophysiology

Physiology

  • The normal physiology of cell mediated immunity can be understood as follows:
  • Historically, the immune system was divided into two branches:
  • Mature T cells that have yet to come upon an antigen, and are transformed into activated effector T cells after coming across an antigen-presenting cells (APCs)
  • The cells listed above in some cases, pack antigenic peptides onto the MHC of the cell, in turn introducing the peptide to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens.[1]

Pathogenesis

  • It is understood that Lymphomatoid granulomatosis is seen in extranodal sites, most commonly the lung
  • Other recurrent sites of involvement include the following:
    • Kidney
    • Skin
    • Central nervous system
    • Liver
  • The pattern of necrosis in both Lymphomatoid granulomatosis and T/Natural killer cell lymphoma are very similar, accentuating the probable importance of EBV in interceding the vascular damage
  • Recent studies shows that the chemokines IP-10 and monoclonal immunoglobilins are indicated in the pathogenesis of the vascular damage
  • Although the most common infiltrating cells are T cells, the T cell receptor genes are not clonally rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases contain clonal rearrangements
  • EBV sequences can be confined to B cells and are clonal in most cases
  • Most patients with Lymphomatoid granulomatosis carefully evaluated clinically have irregularities in there cytotoxic T cell function and low levels of CD8+ T cells[2][3]

Other systems of the body which are affected in Lymphomatoid granulomatosis include:[4]

Gross Pathology

On gross pathology, the following is seen:[9]

Microscopic Pathology

On microscopic histopathological analysis, the presence of an angiocentric and angiodestructive accumulation of differing numbers of T cells with varying numbers of atypical clonal EBV-positive B cells in a polymorphous inflammatory background is seen in Lymphomatoid granulomatosis. This is what is seen in the different organ systems that Lymphomatoid granulomatosis affects:[15][12]

  • Lung:
  • Skin:
  • Grading:[9][15] Relates to the proportion of EBV+ B cells relative to the reactive background lymphocytes
    • Grade 1:
    • Grade 2:
      • EBV positive large lymphoid cells or immunoblasts (5 - 50/HPF)
      • Intermittent large atypical cells
      • Modest amount of necrosis
      • Some cases spontaneously resolve
    • Grade 3:
      • large atypical CD20+ B cells with extensive necrosis and > 50/HPF EBV positive cells
      • Prevalent population of large atypical cells
      • May be coalescent
      • Diffuse necrosis

References

  1. ↑ Denburg JA, Bienenstock J (March 1979). "Physiology of the immune response". Can Fam Physician. 25: 301–7. PMC 2382958. PMID 21297689.
  2. ↑ Jaffe ES, Wilson WH (1997). "Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications". Cancer Surv. 30: 233–48. PMID 9547995.
  3. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMC 5922622. PMID https://doi.org/10.1016/S0046-8177(72)80005-4 Check |pmid= value (help).
  4. ↑ Hussein MR (2013). "Atypical lymphoid proliferations: the pathologist's viewpoint". Expert Rev Hematol. 6 (2): 139–53. doi:10.1586/ehm.13.4. PMID 23547864.
  5. ↑ Ankita G, Shashi D (2016). "Pulmonary Lymphomatoid Granulomatosis- a Case Report with Review of Literature". Indian J Surg Oncol. 7 (4): 484–487. doi:10.1007/s13193-016-0525-1. PMC 5097759. PMID 27872542.
  6. ↑ Piña-Oviedo S, Weissferdt A, Kalhor N, Moran CA (2015). "Primary Pulmonary Lymphomas". Adv Anat Pathol. 22 (6): 355–75. doi:10.1097/PAP.0000000000000090. PMID 26452211.
  7. ↑ Sugita Y, Muta H, Ohshima K, Morioka M, Tsukamoto Y, Takahashi H; et al. (2016). "Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis". Neuropathology. 36 (4): 313–24. doi:10.1111/neup.12276. PMID 26607855.
  8. ↑ Kubota M, Taniguchi M, Tobisawa S, Nakata Y, Nakaya M, Tamogami H; et al. (2017). "T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System". Cureus. 9 (3): e1119. doi:10.7759/cureus.1119. PMC 5406172. PMID 28451478.
  9. ↑ 9.0 9.1 9.2 Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M; et al. (2001). "Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features". Am J Surg Pathol. 25 (9): 1111–20. PMID 11688570.
  10. ↑ Rysgaard CD, Stone MS (2015). "Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature". J Cutan Pathol. 42 (3): 188–93. doi:10.1111/cup.12402. PMID 25355540.
  11. ↑ Bartosik W, Raza A, Kalimuthu S, Fabre A (2012). "Pulmonary lymphomatoid granulomatosis mimicking lung cancer". Interact Cardiovasc Thorac Surg. 14 (5): 662–4. doi:10.1093/icvts/ivr083. PMC 3329320. PMID 22361129.
  12. ↑ 12.0 12.1 Colby TV (2012). "Current histological diagnosis of lymphomatoid granulomatosis". Mod Pathol. 25 Suppl 1: S39–42. doi:10.1038/modpathol.2011.149. PMID 22214969.
  13. ↑ Fischer R, Shaath T, Meade C, Fraga GR, Rajpara A (2014). "An eschar and violaceous nodules as the presenting signs of lymphomatoid granulomatosis". Dermatol Online J. 20 (11). PMID 25419752.
  14. ↑ Shaigany S, Weitz NA, Husain S, Geskin L, Grossman ME (2015). "A case of lymphomatoid granulomatosis presenting with cutaneous lesions". JAAD Case Rep. 1 (4): 234–7. doi:10.1016/j.jdcr.2015.05.008. PMC 4808726. PMID 27051739.
  15. ↑ 15.0 15.1 Guinee DG, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN (1998). "Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells". Am J Surg Pathol. 22 (9): 1093–100. PMID 9737242.
  16. ↑ 16.0 16.1 Hare SS, Souza CA, Bain G, Seely JM, Gomes MM; et al. (2012). "The radiological spectrum of pulmonary lymphoproliferative disease". Br J Radiol. 85 (1015): 848–64. doi:10.1259/bjr/16420165. PMC 3474050. PMID 22745203.
  17. ↑ Mukhopadhyay S, Gal AA (2010). "Granulomatous lung disease: an approach to the differential diagnosis". Arch Pathol Lab Med. 134 (5): 667–90. doi:10.1043/1543-2165-134.5.667. PMID 20441499.
  18. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMC 5922622. PMID doi:10.1001/archderm.1996.03890360054010 Check |pmid= value (help).

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