Changes

*Occasionally true papillae and cyst-like structures with colloid-like material are identified.

*Occasionally true papillae and cyst-like structures with colloid-like material are identified.

*Epithelial cells are tall, may have nuclear grooves and intranuclear cytoplasmic inclusions.  

*Epithelial cells are tall, may have nuclear grooves and intranuclear cytoplasmic inclusions.  

*The most characteristic feature is the presence of nuclei in the apical rather than basal pole of the cells hence the “reverse polarity”.

*The most characteristic feature is the presence of nuclei in the apical rather than basal pole of the cells hence the “reverse polarity”.[[File:Tall Cell Carcinoma with Reversed Polarity Evin G picture Aug 2023.jpg|none|thumb|600x600px|Breast tissue specimen containing tall cell carcinoma with reversed polarity. This tumor features solid nests of tumor cells with fibrovascular cores including foamy histiocytes (H&E stain, original magnification x20). Courtesy of H. Evin Gulbahce, University of Utah.]]<br />

==Immunophenotype<ref name=":0">{{Cite journal|last=Alsadoun|first=Nadjla|last2=MacGrogan|first2=Gaëtan|last3=Truntzer|first3=Caroline|last4=Lacroix-Triki|first4=Magali|last5=Bedgedjian|first5=Isabelle|last6=Koeb|first6=Marie-Hélène|last7=El Alam|first7=Elsy|last8=Medioni|first8=Dan|last9=Parent|first9=Michel|date=2018-09|title=Solid papillary carcinoma with reverse polarity of the breast harbors specific morphologic, immunohistochemical and molecular profile in comparison with other benign or malignant papillary lesions of the breast: a comparative study of 9 additional cases|url=https://pubmed.ncbi.nlm.nih.gov/29785016|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=31|issue=9|pages=1367–1380|doi=10.1038/s41379-018-0047-1|issn=1530-0285|pmid=29785016}}</ref><ref name=":1">{{Cite journal|last=Chiang|first=Sarah|last2=Weigelt|first2=Britta|last3=Wen|first3=Huei-Chi|last4=Pareja|first4=Fresia|last5=Raghavendra|first5=Ashwini|last6=Martelotto|first6=Luciano G.|last7=Burke|first7=Kathleen A.|last8=Basili|first8=Thais|last9=Li|first9=Anqi|date=2016-12-15|title=IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity|url=https://pubmed.ncbi.nlm.nih.gov/27913435|journal=Cancer Research|volume=76|issue=24|pages=7118–7129|doi=10.1158/0008-5472.CAN-16-0298|issn=1538-7445|pmc=5502804|pmid=27913435}}</ref><ref name=":2">{{Cite journal|last=Lozada|first=John R.|last2=Basili|first2=Thais|last3=Pareja|first3=Fresia|last4=Alemar|first4=Barbara|last5=Paula|first5=Arnaud Da Cruz|last6=Gularte-Merida|first6=Rodrigo|last7=Giri|first7=Dilip D.|last8=Querzoli|first8=Patricia|last9=Cserni|first9=Gabor|date=2018-08|title=Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (solid papillary carcinomas with reverse polarity) harbour recurrent mutations affecting IDH2 and PIK3CA: a validation cohort|url=https://pubmed.ncbi.nlm.nih.gov/29603332|journal=Histopathology|volume=73|issue=2|pages=339–344|doi=10.1111/his.13522|issn=1365-2559|pmc=6783257|pmid=29603332}}</ref><ref name=":3">{{Cite journal|last=Pareja|first=Fresia|last2=da Silva|first2=Edaise M.|last3=Frosina|first3=Denise|last4=Geyer|first4=Felipe C.|last5=Lozada|first5=John R.|last6=Basili|first6=Thais|last7=Da Cruz Paula|first7=Arnaud|last8=Zhong|first8=Elaine|last9=Derakhshan|first9=Fatemeh|date=2020-06|title=Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity|url=https://pubmed.ncbi.nlm.nih.gov/31896809|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=33|issue=6|pages=1056–1064|doi=10.1038/s41379-019-0442-2|issn=1530-0285|pmc=7286791|pmid=31896809}}</ref><ref name=":4">{{Cite journal|last=Zhong|first=Elaine|last2=Scognamiglio|first2=Theresa|last3=D'Alfonso|first3=Timothy|last4=Song|first4=Wei|last5=Tran|first5=Hung|last6=Baek|first6=Inji|last7=Hoda|first7=Syed A.|date=2019-04|title=Breast Tumor Resembling the Tall Cell Variant of Papillary Thyroid Carcinoma: Molecular Characterization by Next-Generation Sequencing and Histopathological Comparison With Tall Cell Papillary Carcinoma of Thyroid|url=https://pubmed.ncbi.nlm.nih.gov/30227763|journal=International Journal of Surgical Pathology|volume=27|issue=2|pages=134–141|doi=10.1177/1066896918800779|issn=1940-2465|pmid=30227763}}</ref>==

==Immunophenotype==

*Most carcinomas do not express estrogen or progesterone receptors (ER, PR). Those that tend to show staining of only a small fraction of the cells.  

*Most carcinomas do not express estrogen or progesterone receptors (ER, PR). Those that tend to show staining of only a small fraction of the cells.  

|Positive (universal)||Cytokeratin 7, cytokeratin 5/6

|Positive (universal)||Cytokeratin 7, cytokeratin 5/6

|-

|-

|Positive (subset)||GCDFP-15, GATA3, IDH1/2 mutant, calretinin

|Positive (subset)||GCDFP-15, GATA3, IDH1/2 mutant<ref name=":3">{{Cite journal|last=Pareja|first=Fresia|last2=da Silva|first2=Edaise M.|last3=Frosina|first3=Denise|last4=Geyer|first4=Felipe C.|last5=Lozada|first5=John R.|last6=Basili|first6=Thais|last7=Da Cruz Paula|first7=Arnaud|last8=Zhong|first8=Elaine|last9=Derakhshan|first9=Fatemeh|date=2020-06|title=Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity|url=https://pubmed.ncbi.nlm.nih.gov/31896809|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=33|issue=6|pages=1056–1064|doi=10.1038/s41379-019-0442-2|issn=1530-0285|pmc=7286791|pmid=31896809}}</ref>, calretinin

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|Negative (universal)||HER2 (ERBB2) expression or amplification; TTF-1, thyroglobulin, myoepithelial markers (p63, myosin)

|Negative (universal)||HER2 (ERBB2) expression or amplification; TTF-1, thyroglobulin, myoepithelial markers (p63, myosin)

!Notes

!Notes

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==Characteristic Chromosomal Patterns==

==Characteristic Chromosomal Patterns==

!Notes

!Notes

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==Gene Mutations (SNV/INDEL)<ref name=":0" /><ref name=":1" /><ref name=":3" /><ref name=":2" /><ref name=":4" />==

==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

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|''IDH2'' codon 172 mutations

|''IDH2'' codon 172 mutations<ref name=":1">{{Cite journal|last=Chiang|first=Sarah|last2=Weigelt|first2=Britta|last3=Wen|first3=Huei-Chi|last4=Pareja|first4=Fresia|last5=Raghavendra|first5=Ashwini|last6=Martelotto|first6=Luciano G.|last7=Burke|first7=Kathleen A.|last8=Basili|first8=Thais|last9=Li|first9=Anqi|date=2016-12-15|title=IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity|url=https://pubmed.ncbi.nlm.nih.gov/27913435|journal=Cancer Research|volume=76|issue=24|pages=7118–7129|doi=10.1158/0008-5472.CAN-16-0298|issn=1538-7445|pmc=5502804|pmid=27913435}}</ref><ref name=":2">{{Cite journal|last=Lozada|first=John R.|last2=Basili|first2=Thais|last3=Pareja|first3=Fresia|last4=Alemar|first4=Barbara|last5=Paula|first5=Arnaud Da Cruz|last6=Gularte-Merida|first6=Rodrigo|last7=Giri|first7=Dilip D.|last8=Querzoli|first8=Patricia|last9=Cserni|first9=Gabor|date=2018-08|title=Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (solid papillary carcinomas with reverse polarity) harbour recurrent mutations affecting IDH2 and PIK3CA: a validation cohort|url=https://pubmed.ncbi.nlm.nih.gov/29603332|journal=Histopathology|volume=73|issue=2|pages=339–344|doi=10.1111/his.13522|issn=1365-2559|pmc=6783257|pmid=29603332}}</ref><ref name=":0">{{Cite journal|last=Alsadoun|first=Nadjla|last2=MacGrogan|first2=Gaëtan|last3=Truntzer|first3=Caroline|last4=Lacroix-Triki|first4=Magali|last5=Bedgedjian|first5=Isabelle|last6=Koeb|first6=Marie-Hélène|last7=El Alam|first7=Elsy|last8=Medioni|first8=Dan|last9=Parent|first9=Michel|date=2018-09|title=Solid papillary carcinoma with reverse polarity of the breast harbors specific morphologic, immunohistochemical and molecular profile in comparison with other benign or malignant papillary lesions of the breast: a comparative study of 9 additional cases|url=https://pubmed.ncbi.nlm.nih.gov/29785016|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=31|issue=9|pages=1367–1380|doi=10.1038/s41379-018-0047-1|issn=1530-0285|pmid=29785016}}</ref>

|Gain of function (Oncogene)

|Gain of function (Oncogene)

|<1 % (TCGA)  

|<1 % (TCGA)  

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

|-

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|''IDH2'' codon 172 mutations (majority are R172S, R172T; other mutations include R172G, R172W, R172I)

|''IDH2'' codon 172 mutations (majority are R172S, R172T; other mutations include R172G, R172W, R172I)<ref name=":4">{{Cite journal|last=Zhong|first=Elaine|last2=Scognamiglio|first2=Theresa|last3=D'Alfonso|first3=Timothy|last4=Song|first4=Wei|last5=Tran|first5=Hung|last6=Baek|first6=Inji|last7=Hoda|first7=Syed A.|date=2019-04|title=Breast Tumor Resembling the Tall Cell Variant of Papillary Thyroid Carcinoma: Molecular Characterization by Next-Generation Sequencing and Histopathological Comparison With Tall Cell Papillary Carcinoma of Thyroid|url=https://pubmed.ncbi.nlm.nih.gov/30227763|journal=International Journal of Surgical Pathology|volume=27|issue=2|pages=134–141|doi=10.1177/1066896918800779|issn=1940-2465|pmid=30227763}}</ref><ref name=":2" /><ref name=":1" /><ref name=":0" />

|Carbon metabolism: citrate cycle

|Carbon metabolism: citrate cycle

|Increased conversion of α-ketoglutarate (α-KG) to the oncometabolite R-2-hydroxylglutarate (R-2-HG). Increased levels of 2-HG result in hypermethylation of epigenetic targets and a subsequent block in cellular differentiation. Due to widespread hypermethylation, there is increased H3K27me3 nuclear immunoreactivity in tumors harboring ''IDH2'' R172 mutations.

|Increased conversion of α-ketoglutarate (α-KG) to the oncometabolite R-2-hydroxylglutarate (R-2-HG). Increased levels of 2-HG result in hypermethylation of epigenetic targets and a subsequent block in cellular differentiation. Due to widespread hypermethylation, there is increased H3K27me3 nuclear immunoreactivity in tumors harboring ''IDH2'' R172 mutations.

|-

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|''PIK3CA'' mutations: H1047R most common

|''PIK3CA'' mutations: H1047R most common<ref name=":2" />

|PI3K/AKT/mTOR pathway

|PI3K/AKT/mTOR pathway

|Three most common ''PIK3CA'' mutations are H1047R, E542K, and E545K; ''PIK3CA'' mutations induce hyperactivation of the alpha isoform of the catalytic subunit (p110α) of class IA PI3K kinase. Mutations are often co-occurring with other drivers in ER-positive breast cancers and are associated with endocrine resistance. ''PIK3CA'' mutations are targetable with the PI3K inhibitor alpelisib in ER positive breast cancers; however, tall cell carcinoma with reverse polarity is usually ER negative.

|Three most common ''PIK3CA'' mutations are H1047R, E542K, and E545K; ''PIK3CA'' mutations induce hyperactivation of the alpha isoform of the catalytic subunit (p110α) of class IA PI3K kinase. Mutations are often co-occurring with other drivers in ER-positive breast cancers and are associated with endocrine resistance. ''PIK3CA'' mutations are targetable with the PI3K inhibitor alpelisib in ER positive breast cancers; however, tall cell carcinoma with reverse polarity is usually ER negative.

==Additional Information==

==Additional Information==

==Links==

==Links==