Expression of p63 in Reactive Hyperplasias and Malignant Lymphomas

Park, Chan-Kum; Oh, Yu Whan

doi:10.3346/jkms.2005.20.5.752

Cited by 30 publications

(36 citation statements)

References 32 publications

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“…19,20,[22][23][24]28,45 Furthermore, several prior studies have noted that this reactivity was attributable to TAp63 rather than DNp63 isoform at mRNA level 22,28 and by immunohistochemistry, 45,46 and our findings confirm these observations. The functional significance of frequent p63 reactivity in lymphomas is unclear, but it may be related to p63 (but not p40) occasionally labeling germinal center lymphocytes.…”

Section: Discussionsupporting

confidence: 82%

“…9,12,14,16 Another important limitation of p63 as a 'squamous marker' is its unexpected expression in several other tumor types, particularly lymphomas, where reactivity has been reported in up to half of the cases. [19][20][21][22][23][24] This is a particularly treacherous pitfall with drastic treatment implications, as large cell lymphoma may present as a solitary thoracic mass, and its epithelioid morphology may closely mimic nonsmall cell carcinoma. [25][26][27] In this setting, strong expression of p63 could misclassify an unsuspected lymphoma as squamous cell carcinoma.…”

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confidence: 99%

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p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma

et al. 2012

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Immunohistochemistry has recently emerged as a powerful ancillary tool for differentiating lung adenocarcinoma and squamous cell carcinoma-a distinction with important therapeutic implications. Although the most frequently recommended squamous marker p63 is extremely sensitive, it suffers from low specificity due to its reactivity in a substantial proportion of lung adenocarcinomas and other tumor types, particularly lymphomas. p40 is a relatively unknown antibody that recognizes DNp63-a p63 isoform suggested to be highly specific for squamous/basal cells. Here we compared the standard p63 antibody (4A4) and p40 in a series of 470 tumors from the archives of Memorial Sloan-Kettering Cancer Center and The Johns Hopkins Hospital, which included lung squamous cell carcinomas (n ¼ 81), adenocarcinomas (n ¼ 237), and large cell lymphomas (n ¼ 152). The p63 was positive in 100% of squamous cell carcinomas, 31% of adenocarcinomas, and 54% of large cell lymphomas (sensitivity 100%, specificity 60%). In contrast, although p40 was also positive in 100% of squamous cell carcinomas, only 3% of adenocarcinomas, and none of large cell lymphomas had p40 labeling (sensitivity 100%, specificity 98%). The mean percentage of p63 versus p40-immunoreactive cells in squamous cell carcinomas was equivalent (97 vs 96%, respectively, P ¼ 0.73). Rare adenocarcinomas with p40 labeling had reactivity in no more than 5% of tumor cells, whereas the mean (range) of p63-positive cells in adenocarcinomas and lymphomas was 26% (1-90%) and 48% (2-100%), respectively. In summary, p40 is equivalent to p63 in sensitivity for squamous cell carcinoma, but it is markedly superior to p63 in specificity, which eliminates a potential pitfall of misinterpreting a p63-positive adenocarcinoma or unsuspected lymphoma as squamous cell carcinoma. These findings strongly support the routine use of p40 in place of p63 for the diagnosis of pulmonary squamous cell carcinoma.

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma

et al. 2012

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“…30 Of particular note, overexpression of p63 TA isoforms is frequently detected in B-cell malignancies, such as diffuse large B-cell lymphoma 31,32 and follicular lymphoma. 33 Moreover, high levels of TAp63 RNA and protein were found to correlate with higher grade, more aggressive disease, and a higher proliferative index.…”

Section: Discussionmentioning

confidence: 99%

CD74 induces TAp63 expression leading to B-cell survival

Lantner¹,

Starlets²,

Gore³

et al. 2007

Blood

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Most mature follicular B cells circulate within the periphery in a quiescent state, without actively contributing to an acute immune response. Lasting B-cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. We recently demonstrated that cell surface CD74 controls mature B-cell survival. Stimulation of cell surface CD74 leads to NF-B activation, which enables entry of the stimulated B cells into the S phase, induction of DNA synthesis, and cell division, and augments the expression of survival genes. In the present study, we investigated CD74 target genes to determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B-cell survival. We report that CD74 activates the p65 member of the NF-B family, which in turn up-regulates the expression of p53-related TAp63 proteins. IntroductionIn healthy individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival, and proliferation. Survival factors have been shown to play a critical role in maintaining lymphocyte homeostasis.Recently, we demonstrated that CD74 (invariant chain, Ii) controls mature B-cell survival. CD74 is a nonpolymorphic type II integral membrane protein, containing a short N-terminal cytoplasmic tail of 28 amino acids (aa's), followed by a single 24-aa transmembrane region, and an approximately 150-aa lumenal domain. The CD74 chain was originally thought to function mainly as an MHC class II chaperone, promoting the exit of MHC class II molecules from the endoplasmic reticulum (ER), directing them to endocytic compartments, preventing peptide binding within the ER, and contributing to peptide editing in the MHC class II compartment. 1 However, CD74 was recently found to play an additional role as an accessory signaling molecule. A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the surface of antigen-presenting cells together with CD44. 2,3 In macrophages, CD74 was recently reported to demonstrate high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74, and this interaction is required for MIF-mediated cell proliferation. 4 In a previous series of studies, we showed that CD74 is directly involved in shaping the B-cell repertoire 5 through a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105. 6 NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which is liberated from the membrane. 7 We demonstrated that following the removal of the CD74 lumenal domain, an intramembranal cleavage event at amino acid 42 occurs, resulting in the release of the CD74 cytosolic fragment (CD74-ICD; aa's 1-42). CD74-ICD, which has no NLS motif, then translocates to the nucleus and activates NF-B. 8 Thus, fol...

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“…However, p63 has proven surprisingly unhelpful in distinguishing between PLGA, adenoid cystic carcinoma, and pleomorphic adenoma, as it often shows strong and diffuse positivity in PLGA despite its lack of myoepithelial differentiation [23,25,26]. Similar aberrant p63 immunolabeling has been seen in lung adenocarcinomas, soft tissue neoplasms, and lymphomas [27][28][29][30]. Recently, the antibody to p40, an isotype of p63, has emerged as a more specific marker of basal and myoepithelial cell differentiation [29][30][31][32].…”

Section: Introductionmentioning

confidence: 94%

Polymorphous Low Grade Adenocarcinoma has a Consistent p63+/p40− Immunophenotype that Helps Distinguish it from Adenoid Cystic Carcinoma and Cellular Pleomorphic Adenoma

Rooper

Sharma

Bishop

2014

Head and Neck Pathol

107

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Polymorphous low grade adenocarcinoma (PLGA) is a tumor of minor salivary glands that exhibits considerable morphologic overlap with adenoid cystic carcinoma and cellular pleomorphic adenoma, especially in small biopsy specimens. Unlike these other tumor types. PLGAs do not harbor a myoepithelial component, yet their frequent positivity for p63 diminishes the usefulness of this particular myoepithelial marker as a discriminating immunostain. p40 is an antibody that recognizes DNp63, a p63 isoform that is more specific for true myoepithelial differentiation. As such, p40 immunostaining could help distinguish PLGAs from adenoid cystic carcinomas and pleomorphic adenomas. In this study, p63 and p40 immunohistochemistry was performed on paraffin embedded, formalin fixed tissue from 11 PLGAs, 101 adenoid cystic carcinomas, and 31 pleomorphic adenomas. All 11 PLGAs (100 %) were positive for p63 but completely negative for p40. Among adenoid cystic carcinomas, 91 of 101 (90 %) were positive for p63 and 90/101 (89 %) were positive for p40. The single discordant p63?/p40-adenoid cystic carcinoma exhibited solid architecture and high grade features not typically seen in PLGA. Among pleomorphic adenomas, 21/31 (68 %) were positive for p63 and 13/31 (42 %) were positive for p40. For the pleomorphic adenomas, the discordant p63?/p40-staining pattern was seen only in the overtly mesenchymal chondromyxoid stroma. The cellular epithelial component of the pleomorphic adenomas demonstrated concordant p63?/p40? or p63-/p40-immunophenotypes. PLGA consistently exhibits a p63?/p40-immunophenotype that can help distinguish it from adenoid cystic carcinoma and cellular pleomorphic adenoma, tumors that characteristically demonstrate concordant p63 and p40 immunostaining patterns. A p63/p40 immunohistochemical panel can provide a valuable tool for making the distinction between these morphologically similar but clinically divergent entities.

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Expression of p63 in Reactive Hyperplasias and Malignant Lymphomas

Cited by 30 publications

References 32 publications

p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma

p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma

CD74 induces TAp63 expression leading to B-cell survival

Polymorphous Low Grade Adenocarcinoma has a Consistent p63+/p40− Immunophenotype that Helps Distinguish it from Adenoid Cystic Carcinoma and Cellular Pleomorphic Adenoma

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