Carcinoma renal cromofobo (variante eosinofila) vs. oncocitoma renal: dos tumores parecidos pero diferentes.
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Revisión de la literatura haciendo énfasis en las diferencias histopatologicas para distinguir estas entidades, una de ellas benigna y la otra maligna.
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Similar a Carcinoma renal cromofobo (variante eosinofila) vs. oncocitoma renal: dos tumores parecidos pero diferentes.
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Carcinoma renal cromofobo (variante eosinofila) vs. oncocitoma renal: dos tumores parecidos pero diferentes.
- 1. Carcinoma renal cromófobo vs. Oncotioma Revisión de la bibliografía. M. Mónica García Falcone
- 3. Definición, Epidemiología, Px Carcinoma renal Cromófobo Oncocitoma Carcinoma renal caracterizado por células grande pálidas (v. clásica) con membrana células prominente. Variante clásica, 40% eosinofila, Mal PX: cambio sarcomaoide, necrosis, estadio avanzado y angioinvasion. Neoplasia epitelial renal benigna compuesta por células de gran tamaño con citoplasma eosinófilo rico en mitocondrias, que se cree se origina a partir de cél intercaladas del colector. • 5% de tumores renales ep., • sexta década media de incidec., • H = M, • Esporádicos y hereditarios. • 5% de tumores renales epiteliales, • séptima década pico de incidencia, • 2:1 H:M, • Esporádicos. Hallazgo incidental. Imágenes grandes masas sin necrosis ni calcificaciones. Hallazgo incidental en Rx (la mayoría), Cicatriz central puede sugerir el Dx en imágenes. Menos de 10% de mortalidad. 4% infiltran vena renal. Buen Pronóstico!!! Benignos: solo hay caso documentado de mmts. Oxley JD, Sullivan J, Mitchelmore A, et al. Metastatic renal oncocytoma. J Clin Pathol 2007;60:720–2.
- 4. Diferencias macroscópicas Carcinoma renal Cromófobo Oncocitoma • Tx Sólido circunscripto con superficie ligeramente lobulada. • Puede tener áreas quísticas. • En fresco, la superficie de corte es homogénea marrón claro y luego en la fijación se torna grisácea. • Tx Bien-circunscripto, no- encapsulado que era clásicamente amarranoda y menos frecuentemente pálida amarillenta. • 33% cicatriz central stellate, mas frecuente en tumores grandes. • 20% hemorragia, • Necrosis es muy infrecuente.
- 5. Diferencias histológicas • Se comparó la morfología y morfometría nuclear de ca. cromófobo 24 CaCro clásicos, 6 CaCro-eosinofilos, 5 oncocitomas con histología dificultosa, y 25 oncocitomas clásicos. • Es posible diferenciar por características nucleares: • CaCro-C: rasinoid núcleo, halo perinuclear, membrana citoplasmática distintiva. • Oncocitoma: edema estromal o hialinizacion. • Pero no es posible distinguir con histología la variante eosinofila de los oncocitomas con histología dificultosa.
- 7. Diferencias IHQ Panel: vimentina, glutathione S-transferase (GST-alfa), CD10, CD117, CK 7, y epithelial cell adhesion molecule (EpCAM)
- 8. Diferencias IHQ • Se estudiaron 30 cromófobos (v. típica y eosinófila) y 10 oncocitomas: • CK 7, KAI1, epithelial-specific antigen (EMA), epithelial-related antigen (ERA), Claudin- 7, and Claudin-8 • Método automatizado.
- 9. Diferencias IHQ • Se estudia y propone otro panel de IHQ para diferenciar OR (n21), CaCrom- E (n16), y carcinoma renal papilar (n20) y de células claras (n16) con citoplasma eosinofilo. Ver siguiente diapositiva…
- 11. Diferencias IHQ • LMP2 es una subunidad de una proteasa que se sobreexpresa en lesiones oncociticas en la glándula tiroides. • Primer uso de este marcador para diferenciar su expresión en dos tumores renales oncociticos con curso clínico diferente: 56 OR, 38 CaCro-C y 7 CaCro-E, y 84 controles renales normales. • Se evaluó intensidad, localización y % comprometido. • Expresión citoplasmática: no concluyente. • Expresión nuclear: 7/7 (100%) CaCro-E positivos y 2/56 (4%) OR y 9/38 (24%) clásicos.
- 12. Diferencias citogenéticas • Objetivo: comparar alteraciones genéticas de CaCro-E vs. CaCro-c y OR. • 29 Tx renales: 9CaCro-E, 10 CaCro-c, 10 OR • FISH en muestras de parafina para cromosomas 1, 2, 6, 10, y 17. l • Perdidas de cromosomas 1, 2, 6, 10, and 17 are frequent in both eosinophilic and classic chromophobe renal cell carcinomas. • Loss of chromosome 1 occurs occasionally in oncocytoma but losses of chromosomes 2, 6, 10, and 17 are not found in oncocytomas. • When the differential diagnostic problem is oncocytoma vs eosinophilic chromophobe renal cell carcinoma, detection of losses of chromosomes 2, 6, 10, or 17 effectively excludes the diagnosis of oncocytoma and supports the diagnosis of chromophobe renal cell carcinoma.
- 13. Conclusión Carcinoma renal Cromófobo Oncocitoma • Crecimiento difuso, sólido, discohesivo; • Borde celular engrosado distintivo; • Núcleo “arrugado” con binucleacion y halo perinuclear, • Figuras mitóticas, • Hierro coloidal dif e int + • IHQ y FISH. • Crecimiento patrón organoide o en nidos, o tubular/solido/trabecular, • Citoplasma eosinofilico granular, • Núcleos redondos y monótonos, • Nucléolo pequeño o inscospicuo, • No binucleation, • Hiero coloidal negativo, • No pérdidas en chromosome 2, 6, 10 or 17, • No abundan microvesicles
- 15. Bibliografía consultada 1. Lina Liu, Junqi Qian, Harpreet Singh, Isabelle Meiers, Xiaoge Zhou, and David G. Bostwick (2007) Immunohistochemical Analysis of Chromophobe Renal Cell Carcinoma, Renal Oncocytoma, and Clear Cell Carcinoma: An Optimal and Practical Panel for Differential Diagnosis. Archives of Pathology & Laboratory Medicine: August 2007, Vol. 131, No. 8, pp. 1290-1297. 2. Carvalho J, Wasco MJ, Kunju LP, Thomas DG, Shah RB. Cluster analysis of immunohistochemical profiles delineates CK7, vimentin, S100A1 and C-kit (CD117) as an optimal panel in the differential diagnosis of renal oncocytoma from its mimics. Histopathology. 2011 Jan;58(2):169-79. doi: 10.1111/j.1365-2559.2011.03753.x. 3. Kim SS, Choi YD, Shim MK, Kim J, Cho YM, Jang JJ, Park RJ, Juhng SW, Choi C. Microscopic and nuclear morphometric findings of chromophobe renal cell carcinoma, renal oncocytoma, and tumor with overlapping histology. Ann Diagn Pathol. 2012 Dec;16(6):429-35. doi: 10.1016/j.anndiagpath.2012.03.002. Epub 2012 Apr 10. 4. Ohe C, Kuroda N, Takasu K, Senzaki H, Shikata N, Yamaguchi T, Miyasaka C, Nakano Y, Sakaida N, Uemura Y. Utility of immunohistochemical analysis of KAI1, epithelial-specific antigen, and epithelial- related antigen for distinction of chromophobe renal cell carcinoma, an eosinophilic variant from renal oncocytoma. Med Mol Morphol. 2012 Jun;45(2):98-104. doi: 10.1007/s00795-011-0546-3. Epub 2012 Jun 21. 5. Gang Zheng, M.D., Ph.D., Alcides Chaux, M.D., Rajni Sharma, Ph.D., George Netto, M.D., and Patrizio Caturegli, M.D. LMP2, a novel immunohistochemical marker to distinguish renal oncocytoma from the eosinophilic variant of chromophobe renal cell carcinoma. Exp Mol Pathol. 2013 February ; 94(1): 29– 32. 6. Matteo Brunelli, John N Eble, Shaobo Zhang, Guido Martignoni, Brett Delahunt and Liang Cheng. Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma. Modern Pathology (2005) 18, 161–169. 7. Keng Lim Ng,Retnagowri Rajandram, Christudas Morais,Ning Yi Yap, Hema Samaratunga, Glenda C Gobe, Simon T Wood. Differentiation of oncocytoma from chromophobe renal cell carcinoma (RCC): can novel molecular biomarkers help solve an old problem? Ng KL, et al. J Clin Pathol 2014;67:97–104.
Notas del editor
- Sarcomatoid change, microscopic necrosis, high stage, small vessel invasion
- Objective.—To determine a practical immunohisto- chemical panel for the differential diagnosis of chromo- phobe carcinoma. Design.—Vimentin, glutathione S-transferase (GST-), CD10, CD117, cytokeratin (CK) 7, and epithelial cell ad- hesion molecule (EpCAM) were investigated in 22 cases of chromophobe carcinoma, 17 cases of oncocytoma, and 45 cases of clear cell carcinoma. Results.—Vimentin and GST- expression were exclu- sively observed in clear cell carcinoma. CD10 staining was more frequently detected in clear cell carcinoma (91%) than in chromophobe carcinoma (45%) and oncocytoma (29%). CD117 was strongly expressed in chromophobe carcinoma (82%) and oncocytoma (100%), whereas none of the cases of clear cell carcinomas were immunoreactive. Cytokeratin 7 was positive in 18 (86%) of 22 cases of chro- mophobe carcinoma, whereas all oncocytomas were neg- ative for CK7. EpCAM protein was expressed in all 22 cases of chromophobe carcinoma in more than 90% of cells, whereas all EpCAM-positive oncocytomas (5/17; 29%) dis- played positivity in single cells or small cell clusters. Conclusions.—Using the combination of 3 markers (vi- mentin, GST-, and EpCAM), we achieved 100% sensitivity and 100% specificity for the differential diagnosis of chro- mophobe carcinoma, oncocytoma, and clear cell carcino- ma. The pattern of ‘‘vimentin/GST- ’’ effectively exclud- ed clear cell carcinoma, and homogeneous EpCAM ex- pression confirmed the diagnosis of chromophobe carci- noma rather than oncocytoma. CD117 and CK7 were also useful markers and could be used as second-line markers for the differential diagnosis, with high specificity (100%) and high sensitivity (90% and 86%, respectively).
- In our study, CK7 positivity with membrane accentua- tion was found in 85% (17/20) of ChRCCs, whereas 90% (9/10) of ROs were negative. These results suggest that CK7 immunohistochemistry could be a useful tool in differenti- ating ChRCC from RO, as previously described.4–8 Accord- ingly, CK7 is often used to distinguish between ChRCC and RO in practical pathological diagnosis. CKs are classes of intermediate filaments that form the major structural pro- teins in eukaryotic cells.21 ChRCCs have well-defined cell borders on H&E preparations.1–3 The strong peripheral membranous staining of CK7 may reflect the peripheral distribution of intermediate filaments within the tumor cells. Abundant cytoplasmic microvesicles in ChRCC-T may push the intermediate filaments aside in the peripheral area of the cytoplasm because ChRCC-T has more abundant cytoplasmic microvesicles than does ChRCC-E.2,3,18 Cyto- plasmic CK7 staining was observed more often in eosino- philic cells than in pale cells. Therefore, evaluation of the CK7 staining distribution may be useful for pathologists in determination of the tumor variant in some ChRCC cases. However, further large-scale studies are required to prove this hypothesis. In recent years, KAI1, which is a metastasis suppressor gene whose expression correlates inversely with the meta- static potential of most solid tumors,22 was found to be of value in diagnosing ChRCC. Kauffman et al.9 have shown that ChRCC, but not other common renal tumor histologi- cal subtypes, including RO, stained with KAI1. The overall percentage of ChRCC tumors that stained positive with KAI1 in their study was 87% (27/31). Recently, Yusenko et al.10 also demonstrated that KAI1 is an excellent marker for distinguishing between ChRCC and RO, using molecular methods such as reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In our study, 90% (18/20) of the ChRCCs stained positive for KAI1 whereas 90% (9/10) of ROs were negative. Therefore, our results are consistent with those of two independent large-scale studies. In particular, we showed that 100% (6/6) of ChRCC-E displayed diffuse KAI1 staining and that KAI1 was the most useful marker for distinguishing ChRCC-E from RO. The results of KAI1 staining in the present study indicated that 50% of ChRCC-Es showed stronger positive staining for KAI1 in the cytoplasm than in the cell membrane. Accord- ingly, high cytoplasmic expression of KAI1 may be sugges- tive of ChRCC-E. High KAI1 expression in ChRCC may reflect a favorable clinical course because KAI1 can sup- press metastasis. However, a large-scale study of KAI1 expression in ChRCC with aggressive clinical behavior will be needed to prove this hypothesis. In the present study, the percentage of ChRCC-T, ChRCC- E, and RO that stained positive for ESA (95% for total ChRCC; 10% for RO) was the same as the percentage that stained positive for ERA, and thus these two antigens may be other useful diagnostic markers. Both the VU-1D9 and MOC31 monoclonal antibodies used in the present study to detect ESA and ERA, respectively, react with one of the partially overlapping epitopes in the first epidermal growth factor (EGF)-like repeat of epithelial cell adhesion molecule (Ep-CAM).23,24 Ep-CAM is a 40-kDa epithelial transmem- brane glycoprotein that has four extracellular domains containing EGF-like repeats and which functions as an epithelial-specific Ca2+-independent intercellular adhesion molecule.23 The fact that these antibodies yielded similar immunohistochemical results is consistent with the fact that they recognize the same molecule.Went et al.11 have reported that the expression pattern of Ep-CAM (assessed using the VU-1D9 antibody clone) could be a helpful tool in the dis- crimination of ChRCC and RO. Thus, diffuse and strong membrane-associated Ep-CAM expression in more than 75% of tumor cells indicated ChRCC, whereas most ROs focally expressed Ep-CAM. Liu et al.12 reported that the Ep-CAM protein (assessed using the clone C10 antibody) was expressed in more than 90% of the cells in all 22 cases of ChRCC, whereas all the Ep-CAM-positive ROs (5/17; 29%) only showed positive staining of single cells or small cell clusters. In the present study, 95% (19/20) of the ChRCCs showed diffuse and strong membranous expression of Ep-CAM, assessed using both anti-ESA and anti-ERA anti- bodies, whereas 90% (9/10) of the ROs showed a lack of Ep-CAM expression that was similar to results of previous reports. Pan et al.13 found that 82% (23/28) of ChRCCs and 0% (0/7) of ROs had membranous immunoreactivity for Ep-CAM, assessed using the MOC31 antibody, and they demonstrated that MOC31 antibody staining is useful for distinguishing ChRCC from RO. In our study, 95% (19/20) of ChRCCs showed positive staining with membranous asso- ciation using the MOC31 antibody, whereas 90% (9/10) of ROs were negative. Our result supports the hypothesis of Pan et al. that MOC31 antibody staining is a useful marker for distinguishing ChRCC from RO. These results suggest that most ChRCCs may possess tighter cell-to-cell connec- tions than ROs. The combined results suggest that histo- chemical analysis of Ep-CAM is useful for distinguishing between ChRCC and RO regardless of the clone of anti-Ep- CAM antibody used for this analysis. Claudin-7 and Claudin-8 code for tight junction proteins that are expressed in the distal nephron.25 Recently, Lech- pammer et al.14 found that a combination of Claudin-7 posi- tivity and Claudin-8 negativity supports a diagnosis of ChRCC, and, inversely, that Claudin-8 positivity and Claudin-7 negativity strongly favors a diagnosis of RO. Moreover, Osunkoya et al.15 reported that membranous Claudin-7 expression was characteristic of ChRCC and cytoplasmic immunoreactivity for Claudin-8 was character- istic of RO. Kim et al.7 demonstrated that 96% (24/25) of ROs showed cytoplasmic staining of Claudin-8. In our study, membranous Claudin-7 expression was detected in 95% (19/20) of ChRCC, compared with 20% of ROs, and Claudin-7 staining was a useful marker for the discrimina- tion of both tumors. However, Claudin-8 staining did not appear to be useful for distinguishing between ChRCC and RO. Regarding the origin of these neoplastic cells, some investigators have suggested that both ChRCC and RO are derived from intercalated cells of the collecting duct system.3 CK7, KAI1, ESA, ERA, Claudin-7, and Claudin-8 are expressed in the collecting duct of the normal kidney, and the expression of all these molecules in ChRCC may provide further evidence that ChRCC originates from collecting ducts. However, we suggest that most of these antigens that are expressed in the collecting duct system may show decreased expression or disappear in many ROs because cell-to-cell interactions of the majority of ROs decreases during tumorigenesis. In conclusion, our results show that immunohistochemi- cal markers of CK7, KAI1, ESA, ERA, and Claudin-7 are useful for distinction of ChRCC from RO. Of these five available markers, we recommend KAI1, ESA, and ERA to especially distinguish ChRCC-E from RO. These markers appear to be more useful than CK7, used as the current practical marker.
- The cytoplasmic expression of LMP2 was similar among the renal lesions, being present in 44 of 56 (79%) ROs, 27 of 38 (71%) CHRCCs, and 7 of 7 (100%) CHRCC-EO cases. The nuclear expression of LMP2, however, was more informative. All CHRCC-EO cases (7 of 7, 100%) strongly showed nuclear LMP2 staining, as opposed to only 2 of 56 (4%, P<0.0001) ROs and 9 of 38 (24%, P=0.0001) classic CHRCCs. These results suggest that the nuclear LMP2 expression can be used in clinical scenarios where histological distinction between RO and CHRCC-EO remains challenging
- Chromophobe renal cell carcinomas frequently showed loss of chromosomes 1 (70% of classic, 67% of eosinophilic), 2 (90% classic, 56% eosinophilic), 6 (80% classic, 56% eosinophilic), 10 (60% classic, 44% eosinophilic), and 17 (90% classic, 78% eosinophilic); Among the classic chromophobe renal cell carcinomas, only one had no loss of any of the chromosomes, while 50% had loss of all five chromosomes. Among the eosinophilic chromophobe renal cell carcinomas, one of nine had no loss and 44% had loss of all five chromosomes. One oncocytoma had loss of chromosome 1. No other chromosomal loss was detected in the oncocytomas. losses of chromosomes 1, 2, 6, 10, and 17 are frequent in both eosinophilic and classic chromophobe renal cell carcinomas. Loss of chromosome 1 occurs occasionally in oncocytoma but losses of chromosomes 2, 6, 10, and 17 are not found in oncocytomas. When the differential diagnostic problem is oncocytoma vs eosinophilic chromophobe renal cell carcinoma, detection of losses of chromosomes 2, 6, 10, or 17 effectively excludes the diagnosis of oncocytoma and supports the diagnosis of chromophobe renal cell carcinoma.