Se presenta un estudio histológico, inmunohistoquímico (IHQ) y molecular de un liposarcoma desdiferenciado paratesticular remitido a nuestro centro, con hallazgos histológicos similares a un tumor miofibroblástico inflamatorio. Las células tumorales fueron positivas para actina músculo liso (AML) y focalmente positivas para CD56, CD99, Bcl2 y EMA. La expresión de WT1, calretinina, miogenina, CK(AE1/AE3), desmina, H-caldesmona, CD34, ALK, CKIT, DOG1, MUC4 y STAT6 fue negativa. MDM2 mostró positividad nuclear intensa y difusa por IHQ y alto nivel de amplificación génica mediante hibridación fluorescente in situ (FISH). La FISH no reveló reordenamiento del gen SYT. En el estudio histológico del corte remitido no encontramos evidencias de componente liposarcomatoso bien diferenciado, aunque el aspecto macroscópico de la pieza lo sugería. El liposarcoma desdiferenciado puede presentar hallazgos histológicos que recuerdan a un tumor miofibroblástico inflamatorio y que expanden el espectro histológico de esta variante de liposarcoma. El conocimiento de la existencia de esta variante de liposarcoma es de crucial importancia para no confundirla con otras neoplasias que, aunque histológicamente similares, difieren en la evolución clínica y/o tratamiento.(AU)
We report the histological, immunohistochemical, and molecular findings of a dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features occurring in the paratesticular region. Histologically, the dedifferentiated component closely resembled an inflammatory myofibroblastic tumor. The neoplastic cells were positive for smooth muscle actin with focal CD56, CD99, Bcl2 and EMA expression. WT1, calretinin, myogenin, CK(AE1/AE3), desmin, H-caldesmon, CD34, ALK, CKIT, DOG1, MUC4 and STAT6 were negative. MDM2 showed diffuse and strong nuclear positivity in neoplastic cells and fluorescence in situ hybridization (FISH) revealed amplified MDM2 (high level) but no SYT rearrangement. Although a lipomatous component was evident macroscopically, well-differentiated liposarcomatous components were not evident in the section examined. Dedifferentiated liposarcoma can have prominent inflammatory myofibroblastic tumor-like features. Pathologists should be aware of this histological variant in order to avoid misdiagnosing dedifferentiated liposarcoma as inflammatory myofibroblastic tumor or other spindle cell tumors which have different behavioral patterns and treatment requirements.(AU)
Humans , Liposarcoma , Histology , Immunohistochemistry , Antigens, CD34 , In Situ Hybridization, Fluorescence
Las histiocitosis de células no Langerhans, como la enfermedad de Rosai-Dorfman (ERD) y el xantogranuloma, son trastornos raros que pueden mostrar solapamiento de los hallazgos histopatológicos e inmunohistoquímicos. En el presente estudio describimos un caso clínico de una paciente femenina de 53años con placas eritematoso-violáceas en las mejillas y edema en los pabellones auriculares. Se realizó una biopsia y en el examen histopatológico se observó una proliferación de histiocitos con emperipolesis característica de la ERD junto con un infiltrado linfoplasmocítico. El estudio inmunohistoquímico mostró que la mayoría de los histiocitos fueron positivos para S100 y CD68, y negativos para CD1a, lo que confirmó el diagnóstico de ERD. El análisis molecular no detectó la mutación BRAF-V600, NRAS ni KRAS. Se discute el diagnóstico diferencial entre las histiocitosis no de células de Langerhans con presentación cutánea. El patólogo debe estar al tanto de las presentaciones clínicas o patológicas inusuales de la ERD, y en los pacientes con enfermedad no resecable/escasamente resecable o resistentes al tratamiento clásico de la ERD deberían explorarse otras opciones terapéuticas basadas en los resultados de los estudios moleculares.(AU)
Non-Langerhans cell histiocytosis, including Rosai-Dorfman disease (RDD) and xanthogranuloma are rare disorders with occasional overlapping in the histopathological and immunohistochemical (IHC) findings. We report the case of a 53-year-old woman with erythematous-violaceous plaques on the cheeks and edema in the auricular pavilions. A biopsy was performed and the histopathological examination revealed a histiocytic proliferation with emperipolesis characteristic of RDD and lymphoplasmocitic infiltrate. IHC analysis showed S100 and CD68 positivity in the histiocytes but was negative for CD1a, supporting the diagnosis of RDD. Molecular analysis failed to detect BRAF-V600, NRAS or KRAS mutation. We discuss the differential diagnosis of cutaneous non-Langerhans cell histiocytosis. Pathologist must be aware of unusual presentations of RDD and further treatment options must be explored for patients with unresectable lesions and/or resistance to the classical management of RDD.(AU)
Humans , Female , Middle Aged , Histiocytosis, Sinus , Skin Diseases , Necrobiotic Xanthogranuloma
Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR-mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors. SIGNIFICANCE: EDNR antagonists can be repurposed to improve drug delivery in VEGFA-secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , Endothelin-1/metabolism , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Biological Availability , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Endothelin-1/genetics , ErbB Receptors/genetics , Erlotinib Hydrochloride/pharmacology , Gefitinib/pharmacokinetics , Humans , Lung Neoplasms/genetics , Mice , Mutation , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Vasoconstriction/drug effects , Vasoconstriction/physiology , Xenograft Model Antitumor Assays
