Micropapillary Adenocarcinoma Research Articles

Differential expression of CRKL and AXL genes in lung adenocarcinoma subtypes according to the epidermal growth factor receptor and anaplastic lymphoma kinase gene status.

Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related mortality. Adenocarcinoma (AC) is the predominant histological type of NSCLC; however, AC consists of several subtypes. It has not yet been determined whether there is a correlation of CRKL and AXL expression with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene status in lung AC. We assayed exons 18 through 21 of the EGFR gene by direct sequencing; ALK rearrangement and the expression of CRKL and AXL were detected by immunostaining. A total of 212 cases of AC were included in this study, diagnosed using the novel classification system established by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society in 2011, including 69 acinar ACs, 17 lepidic predominant ACs (LPAs), 63 papillary, 14 mucinous, 17 micropapillary and 32 solid ACs. Of the 212 cases, 101 harbored EGFR mutations. The most common subtypes carrying delK745-S753 were papillary and acinar ACs. ALK rearrangement was found in 23 cases (11%) of lung ACs. Acinar and solid ACs were the most frequent subtypes with ALK aberrance, particularly in acinar ACs with cribriform structure (4/5 cases, 80%). The expression of CRKL was significantly different among the AC subtypes (P=0.01), with the highest and lowest expression levels of CRKL protein in papillary ACs and LPAs, respectively (P<0.05). AXL expression was also significantly different among the AC subtypes (P=0.002) and was correlated with lymph node infiltration in acinar ACs. ACs with EGFR mutations exhibited high levels of AXL protein expression compared to those without mutations (P<0.001). Acinar AC with cribriform structure is a distinct subtype that frequently harbors ALK rearrangement. The activation of AXL may be one of the factors contributing to the invasion of acinar and micropapillary ACs.

Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma?—reply

Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma?—reply

Micropapillary Adenocarcinoma of the Colon: An Uncommon Variant and Location

Micropapillary Adenocarcinoma of the Colon: An Uncommon Variant and Location

Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma?

Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma?

Abstract 11: Arginine deprivation therapy using ADI-PEG20 as a novel therapeutic modality in the treatment of bladder cancer.

Abstract Background: Argininosuccinate synthetase (ASS1) catalyzes the rate limiting step in the biosynthesis of arginine. ASS1-deficient tumors are therefore candidates for arginine deprivation therapy, utilizing ADI-PEG20 as it degrades circulating arginine. We therefore evaluated 187 patients with bladder cancer, who underwent radical cystectomy between 1988 and 2008 at our institution for ASS1 expression. ASS1 was evaluated as a predictor of disease outcome, while in-vitro studies were conducted to assess the therapeutic efficacy of ADI-PEG20 in representative cell lines. Design: ASS-1 expression was assessed by immunostaining and stratified based on moderate to strong expression (2+, 3+) versus absent to weak expression (0 or 1+). Both univariate and multivariate statistical analysis of ASS1 expression, along with various clinical parameters, was carried out to determine the effect on overall (OS) and progression-free (PFS) survival. In addition, multiple bladder cancer cell-lines were screened for ASS1 expression and utilized as an in-vitro model. Downstream signaling changes in these cells, in response to arginine deprivation, were assessed by quantitative PCRs and immunoblotting and this was correlated with changes in cell viability, proliferation and cell death. The latter was assessed by a combination of clonogenic and MTT assays in addition to propidium iodide (PI) staining alone or PI /Annexin V double staining followed by flow cytometry. Results: 63% had conventional urothelial carcinoma (UCa), while the rest had rarer variants such as squamous cell carcinoma (SCC: 18%), the micropapillary variant (9%), adenocarcinoma (5%) and small cell carcinomas (4%). Micropapillary variants (71%) and adenocarcinomas (90%) tended to show moderate to strong ASS1 expression, while UCa (42%) and small cell carcinomas (38%) demonstrated intermediate ASS1 expression (2+, 3+). In contrast, patients with SCC tended to have weak ASS1 expression (91%, 0 or 1+). In univariate analysis, increased ASS1 expression was associated with poorer OS (p≤.10 in all cases for OS) and PFS (p=.03 for PFS (2+, 3+ vs 0, 1+)). In multivariate analysis, ASS1 expression (3+ vs 0, 1+ or 2+), p=.04, along with positive nodes (p=.0005), surgical margins (p=.007), and higher pT-stage (p=.02) were all seen to be independent predictors of poorer OS. In-vitro studies with UCa derived J82 cells (that were found to be ASS1 deficient) following ADI-PEG20 treatment revealed an activation of GCN2, a kinase known to be activated by amino acid deprivation. Downstream changes included induction of the pro-apoptotic gene CHOP. This was correlated with a reduction in cell viability (IC50=0.24ug/ml) that was attributed to increased apoptosis. Conclusion: High ASS1 expression is an independent predictor of poor OS and PFS in bladder cancer. Furthermore, ADI-PEG20 represents a promising new therapy for ASS1-deficient bladder cancers. Citation Format: Sounak Gupta, Mir Maria, John Bomalaski, Paul J. Elson, Kamini Singh, Jyoti Harwalkar, Paula Carver, Alex Almasan, Donna E. Hansel. Arginine deprivation therapy using ADI-PEG20 as a novel therapeutic modality in the treatment of bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 11. doi:10.1158/1538-7445.AM2013-11

Current Readings: Pathology, Prognosis, and Lung Cancer

The 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma introduced the new categories of adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive mucinous adenocarcinoma, and replaced the category of mixed subtype adenocarcinoma with lepidic, acinar, papillary, micropapillary, and solid predominant adenocarcinoma. The aim of this manuscript is to evaluate whether the new classification can be applied successfully in determining prognosis of surgically resected patients. Six consecutive clinicopathologic studies using the new classification that were published between spring 2011 and fall 2012 were reviewed. Overall, they demonstrated excellent outcome for adenocarcinoma in situ and minimally invasive adenocarcinoma; intermediate outcome for lepidic, acinar, and papillary predominant adenocarcinoma; and poor outcome for solid and micropapillary predominant adenocarcinoma and invasive mucinous adenocarcinoma. As the new classification remains a proposal at this time, it is hoped that thoracic surgeons will play a leading role in its worldwide dissemination for clinical care and research.

Prognostic Patterns in the Histopathology of Pulmonary Adenocarcinoma

Prognostic Patterns in the Histopathology of Pulmonary Adenocarcinoma

Cervical adenocarcinoma presenting as a cardiac tamponade in a 57-year-old woman: a case report

IntroductionPericardial effusion as a complication of malignant gynecological disorders is rare. Few cases of endometrial cancer, squamous cell carcinoma of the cervix, ovarian cancer and uterine carcinosarcoma have been previously reported. We report the first case of cardiac tamponade secondary to a cervical adenocarcinoma.Case presentationA 54-year-old Caucasian woman, without any relevant medical history and no gynecological aftercare, was admitted to our hospital emergency room with severe dyspnea. Echocardiography revealed severe pericardial effusion with a swinging heart. An emergency pericardial drainage was performed through a pericardial window, which permitted the draining of 700 mL of bloody fluid and a pericardial biopsy. Cytological examination of the fluid revealed atypical cells, and the biopsy specimen showed tumor emboli suggestive of adenocarcinoma. Magnetic resonance imaging showed a 35 mm cervical lesion indicative of an endocervical tumor. Exploratory laparoscopy revealed diffuse peritoneal lesions and histological examination of cervical curettage showed a poorly differentiated micropapillary adenocarcinoma of the cervix.ConclusionCarcinomatous pericarditis as the first symptom of a malignant gynecological adenocarcinoma has not, to the best of our knowledge, been documented before. This case highlights the extreme severity of pericardial effusion secondary to cervical adenocarcinoma, a sign of advanced disease. Gynecological malignancies have to be considered in cases of neoplastic pericardial effusion.

Patient selection in non-small cell lung cancer: Histologic versus molecular subtypes?

Until recently, the selection of systemic therapy has not varied according to histologic subtypes of non-small cell lung cancer (NSCLC) and is largely empirical. Thus, the diagnosis of “non-smallcell lung cancer not otherwise specified” (NSCLC-NOS) has been a frequently-used, acceptable term for clinical decision-making, despite the fact that it is not recognized by the World Health Organization Classification of Lung Tumors (1). This paradigm has been challenged by new generation of rational cancer therapeutics. The first emphasis on histology in treatment decision in NSCLC came from safety concerns about the first-in-class angiogenesis inhibitor bevacizumab. A randomized Phase II trial of carboplatin and paclitaxel alone or with lowor high-dose bevacizumab revealed a severe (and even fatal) occurrence of pulmonary hemorrhage in NSCLC patients with squamous histology receiving bevacizumab (2). Thus, patients with squamous histology were subsequently excluded from Phase III trials of bevacizumab and most of anti-angiogenesis inhibitors in advanced NSCLC (3-6). The identification of molecularly-defined cohorts of NSCLC patients who demonstrate dramatic clinical response to targeted agents has changed the landscape of lung cancer therapy. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), gefinitb or gefitinib, was the first targeted therapy used for the treatment of NSCLC patients (7,8). Initial clinical experiences suggested that high tumor responses were observed among patients with adenocarcinoma and a light or never smoking history (9-11). These clinical observations led to the development of a Phase III trial of gefinitb compared with first-line chemotherapy doublets in this clinically selected patient population (12). Surprisingly, correlative molecular analyses in this Phase III study reveals that the key driver of response to EGFR TKIs is the presence of TK-activating EGFR mutations rather than histology, Asian ethnicity or clinical characteristics (13). The higher clinical responses observed in never or light smokers and NSCLC patients with adenocarcinoma rather than squamous histology are due to the higher prevalence of TK-activating EGFR mutations present in these patients. These results led to world-wide clinical testing for EGFR mutations for selecting those NSCLC patients for first-line therapy of an EGFR TKI in 2009 (14). Of note, papillary and micropapillary adenocarcinoma subtypes have been correlated with lung adenocarcinomas with EGFR mutations (15). However, the clinical value of subtyping histologic-genetic correlations in NSCLC remains to be determined as the genetic features for the majority of NSCLC have yet to be characterized and the histologic diagnosis of lung adenocarcinoma or squamous carcinoma could vary significantly between pathologists. Nevertheless, the cancer armentarium that might be selected by molecular biomarker status is quickly increasing. The echinoderm microtubule-

Pathological classification of intrahepatic cholangiocarcinoma based on a new concept

Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic differentiation. To date, ICC was largely classified into adenocarcinoma and rare variants. Herein, we propose to subclassify the former, based on recent progress in the study of ICC including the gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is, ICC is classifiable into the conventional (bile duct) type, the bile ductular type, the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic parenchyma. Hepatic progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites, IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB, particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma, mucinous/signet ring cell carcinoma, clear cell type, undifferentiated type, neuroendocrine carcinoma and so on. This classification of ICC may open up a new field of research of ICC and contribute to the clinical approach to ICC.

Lung adenocarcinomas with micropapillary components

Micropapillary adenocarcinoma is becoming increasingly recognized as a prognostically important histological subtype of carcinoma in various organs. This report presents the clinicopathological findings of lung adenocarcinomas with micropapillary components. A total of 15 patients with micropapillary components were selected between April 2005 and December 2008. The results of their clinical presentation, metastasis to lymph nodes, pleural invasion, pathological stage, and clinical outcomes were evaluated. In all, 12 patients underwent a lobectomy or bilobectomy with a regional lymph node dissection; 8 showed metastases to the regional lymph nodes at the time of the operation. Altogether, 14 of 15 cases showed lymphovascular invasion; 10 cases were up-staged after the operation because of lymph node metastases or pleural invasion. The duration of follow-up ranged from 1 to 42 months (median 16 months). Seven patients are alive without disease, whereas seven are alive with disease and one patient died of disease. These results suggest that the micropapillary components are a manifestation of aggressive behavior, as shown by the frequent lymph node metastases and pleural invasion. Surgeons should search more carefully for metastases and conduct a closer follow-up on these patients when this feature is present with lung adenocarcinoma.

Cytologic diagnosis of pulmonary adenocarcinoma with micropapillary pattern: Does it correlate with the histologic findings?

Micropapillary adenocarcinoma is associated with poor-prognosis in several organs including the lung. The presence of small tight balls of neoplastic cells devoid of fibrovascular core in cytological preparations (micropapillary tufts) has been described as characteristic of micropapillary adenocarcinoma. In the lung, however, this criterion has not been validated. The cytological material of 46 cases of histologically proven pulmonary adenocarcinoma with a micropapillary component was compared to 33 cases with no micropapillary component to determine the specificity of micropapillary tufts for the histologic diagnosis of micropapillary adenocarcinoma. Other histologic patterns of invasive pulmonary adenocarcinomas (acinar, papillary, and solid) were also compared with patterns of neoplastic cell aggregates in cytological preparations. There were no significant differences in the distribution of micropapillary clusters between the two groups. The positive predictive value for the cytologic diagnosis of a micropapillary component in lung adenocarcinomas was of 64%. Similar findings were observed for other invasive patterns. Therefore, the detection of micropapillary tufts in cytology is not specific for the diagnosis of a pulmonary micropapillary adenocarcinoma in the lung.

Lung adenocarcinoma with micropapillary component presenting with metastatic scrotum tumor and cancer-to-cancer metastasis: A case report

A 54-year-old man was admitted to the hospital presenting with a 3-month history of sclerosing dermal lesion in the external genitalia. A scrotal skin biopsy revealed a poorly-differentiated adenocarcinoma, immunohistochemically positive for cytokeratin 7 (CK7) and for thyroid transcription factor 1 (TTF-1), and negative for CK20. One month after admission, he died of respiratory failure. At autopsy, a consolidating lesion with vague margin was noted in the left lung as well as a well-circumscribed nodule in the right lobe of the thyroid. Histopathologically, pulmonary lesion was adenocarcinoma with a micropapillary component. On the other hand, thyroid tumor was diagnosed as a follicular variant of papillary carcinoma with foci of micropapillary adenocarcinoma. Positive immunohistochemistry for surfactant protein on micoropapillary component was useful to confirm that micropapillary component was of lung adenocarcinoma origin.

Lung Adenocarcinoma: Modification of the 2004 WHO Mixed Subtype to Include the Major Histologic Subtype Suggests Correlations Between Papillary and Micropapillary Adenocarcinoma Subtypes, EGFR Mutations and Gene Expression Analysis

The histologic heterogeneity of lung adenocarcinoma creates a variety of complex challenges to pathologists in analyzing the various subtypes. Current classification schemas do not take into account the major subtype. We analyzed 100 cases for clinical, pathologic, and molecular features using a modification of the 2004 World Health Organization (WHO) classification to record the major component in the mixed subtype tumors. The tumors were analyzed for KRAS mutation and epidermal growth factor receptor (EGFR) by mutation, chromogenic in situ hybridization, and immunohistochemistry for EGFR and phosphorylated EGFR. Gene expression analysis was performed using HG-U133A Affymetrix oligonucleotide microarrays revealing 3 gene clusters. The most common major histologic subtype was papillary (37%) followed by acinar (30%), solid (25%) and bronchioloalveolar (7%) carcinoma (BAC), although no pure BACs were seen. Sixteen tumors harbored EGFR mutations and 14 KRAS mutations. Papillary adenocarcinoma strongly correlated with EGFR mutation (P<0.001) and gene profile Cluster 1 (P=0.006) with weaker correlations with low grade (P=0.038) and favorable behavior in Stage 1 patients (P=0.047). Micropapillary subtype correlated strongly with EGFR mutation (P<0.001) and weakly with Cluster 1 (P=0.030). Solid adenocarcinoma strongly correlated with gene profile Cluster 3 (P=0.001) and worse survival (P=0.001). BAC as a major component strongly correlated with gene Cluster 2 (P=0.001). Cluster 1 correlated strongly with less smoking (P<0.001), papillary histology (P<0.001), and EGFR mutations (P<0.001). Cluster 3 strongly correlated with heavier smoking (P<0.001), larger tumor size (P<0.001), solid subtype (P<0.001), and poor grade (P=0.004); weak correlations were found with KRAS mutation (P=0.025). No correlation was found with BAC and EGFR by mutation, chromogenic in situ hybridization or immunohistochemistry. Higher stage (P<0.001), grade (P<0.001), and solid subtype (P=0.001) correlated with shorter survival. Our data suggest that EGFR mutations are associated with papillary adenocarcinoma and gene profile Cluster 1. We discovered this only because we used a comprehensive approach examining in detail all histologic subtypes and we modified the 2004 WHO mixed subtype to include the major histologic subtype. As we do not know the major genetic pathways of 30% to 70% of lung adenocarcinomas, the comprehensive histologic subtyping we propose gives advantage for recognition of unanticipated histologic-genetic correlations that might not be detected using classification systems that focus primarily on specific aspects of adenocarcinomas such as BAC or EGFR mutations. Such an approach should be considered in future studies for validation in other datasets.

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast. Are WT1, CA125, and GCDFP-15 useful in differential diagnosis?

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast have close histologic similarities. Thus, when these cancers occur synchronously or metachronously in the same patient, it is difficult to determine the primary site. We examined 23 serous papillary adenocarcinomas (16 ovarian, 5 endometrial, and 2 peritoneal) and 37 invasive micropapillary carcinomas of the breast (12 pure and 25 mixed types) on immunohistochemical expression of Wilm's tumor antigen-1 (WT1), CA125, and gross cystic disease fluid protein-15 (GCDFP-15), which have been reported to be useful in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. The positive rates of WT1, CA125, and GCDFP-15 in serous papillary adenocarcinomas were 78%, 78%, and 0%, respectively, and the corresponding rates in invasive micropapillary carcinomas were 3%, 40%, and 38%. The CA125-positive rate of invasive micropapillary carcinoma was higher than the rate reported for other types of breast carcinomas. We consider CA125 to be not always useful in the differential diagnosis of serous papillary adenocarcinoma and invasive micropapillary carcinoma. Although the positive rate of WT1 was significantly higher in serous papillary adenocarcinoma than in invasive micropapillary carcinoma, WT1 expression in endometrial serous papillary adenocarcinoma was infrequent (20%). WT1 and GCDFP-15 could be useful markers for the differential diagnosis of ovarian and peritoneal serous papillary adenocarcinoma versus breast invasive micropapillary adenocarcinoma. However, the availability of GCDFP-15 is limited because of the low positive rate of GCDFP-15 in invasive micropapillary carcinomas.

Lung adenocarcinoma with a micropapillary pattern: a clinicopathological study of 25 cases

Lung adenocarcinoma with a micropapillary pattern has recently been described, but its biological behavior is as yet uncertain. In this article we present a clinicopathological study of lung adenocarcinoma with micropapillary morphology. We selected 25 patients with lung adenocarcinoma with micropapillary morphology from the 2001-2004 pathology files (age range 54 to 81 years; mean 64.5 years). Micropapillary carcinoma is predominantly located at the periphery of the tumor nodule or mass and occurs irrespective of the subtype of the adenocarcinoma. A micropapillary component was seen against a mucinous background in three cases and microcalcifications resembling psammoma bodies were seen in one case. Four cases showed intensive invasive growth such as micropapillary adenocarcinoma of the breast and 21 showed alveolar type morphology with piling-up of the neoplastic cells with or without stromal invasion. Seven of twenty-three (30.4%) showed lymph node metastases at time of operation. Twelve of twenty-five (48%) showed pleural invasion. Regarding clinical outcome, 14 patients were alive without disease, 5 were alive with disease, and 5 died of the lung adenocarcinoma. No significant relationship was found between the extent of the micropapillary component and prognosis. However, the carcinoma seen in the five patients who died showed breast type histology with intensive invasive growth in three cases and alveolar type histology with intensive stromal invasion in two. Lung micropapillary carcinoma of breast type may behave more aggressively than the alveolar type.

Intrahepatic cholangiocarcinoma with multicystic, mucinous appearance and oncocytic change

A case is reported herein of intrahepatic cholangiocarcinoma (ICC) with multicystic, mucinous appearance and oncocytic change. Because of liver dysfunction, a 73-year-old woman was hospitalized in early October 2003. She was diagnosed as having ICC of the right hepatic lobe with occlusion of the hilar and perihilar bile ducts by imaging examination. Extended right lobectomy was performed but the patient died of liver failure on the next day. In surgically resected specimens, the tumor (3 x 3 cm) was mainly located in the right lobe, and tumors infiltrated along the biliary tree as well as invading into the adjacent hepatic parenchyma. The tumor mass had a sponge or honeycomb appearance. Microscopically, these tumors were composed of multiple microcysts filled by abundant mucin and lined by micropapillary adenocarcinoma cells. Their cytoplasm was acidophilic, appearing as an oncocyte, and carcinoma cells were positive for mitochondrial antigen in addition to biliary cytokeratins. There were no ovarian-like stromas around these cystic tumors, and communication of the biliary lumen with these carcinomatous cysts was not evident, thus different from biliary mucinous cystadenocarcinoma and intraductal papillary neoplasm of the liver. This is the third case of multicystic mucinous ICC and the present case might have been derived from intrahepatic peribiliary glands.

Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice.

Members of the signal transducers and activators of transcription (Stat) family regulate essential cellular growth and survival functions in normal cells and have also been implicated in tumorigenesis. We have studied the potential role of Stat5 in mammary tumorigenesis by targeting Stat5 variants to the mammary gland of transgenic mice using regulatory sequences of the beta-lactoglobulin gene. Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8-12 months. Undifferentiated carcinomas most frequently occurred in mice expressing the carboxyl-terminally truncated Stat5. The more differentiated papillary and micropapillary adenocarcinomas were primarily found in mice overexpressing the native and constitutively active transgenes. Higher levels of translation initiation factor 4E (eIF4E) and cyclin D1 expression but lower levels of activated Stat3 were found in tumors of mice expressing the constitutively active Stat5 when compared to mice expressing the wild-type or truncated forms. A higher expression of the estrogen receptor (ERalpha) was observed in carcinomas compared to other phenotypes. The ability of both forms of Stat5, the transactivating form and the dominant negative form, to participate in oncogenesis indicates that there is more than one mechanism by which Stat5 contributes to this process. The transactivation function of Stat5 is involved in the determination of tumors with a more differentiated phenotype.