No abstract

IntroductionAdrenocortical carcinoma is a rare tumor of the adrenal cortex which accounts for no more than 0.2% of all malignancies, with two peaks of incidence in early childhood and adults over age 60. It represents an aggressive disease with up to two thirds of cases having distant metastases at the time of diagnosis and a mean survival of less than 30 months, 1-3 although combined treatment modalities, with special reference to mitotane-based therapy, seems to improve its outcome. 4The differential diagnosis of carcinomas from adenomas has been based on several microscopic features, none of them being alone absolutely indicative of malignancy. 5,6 Despite the majority of adrenocortical carcinomas do not represent a diagnostic pitfall in the clinical practice, there are several other cases in which the distinction from their benign counterparts is not straightforward.These cases are a challenge for the pathologist, since the therapeutic strategy in adrenocortical carcinomas is radically different from that of adenomas and an accurate diagnosis is mandatory.This issue is also relevant because adrenal tumors are increasingly recognized in clinical practice:the widespread use of imaging techniques has resulted in the clinical dilemma of the adrenal incidentaloma, 7 and although the vast majority of adrenal incidentalomas are benign lesions, in up to 12% of cases an incidental adrenocortical carcinoma may be discovered. 8Different scoring systems for adrenocortical carcinoma have therefore been developed, using mathematical models or numerical scores based on the association of a given threshold for each considered parameter to malignancy. [9][10][11] The most widely employed scoring system was proposed 11 and revisited in a subsequent report 12 by Weiss, and includes nine parameters related to tumor structure (loss of clear cytoplasm, presence of diffuse architecture and of necrosis), cytological features (atypia, mitotic count, atypical mitotic figures) and invasive properties (sinusoidal, venous and capsular invasion).Unfortunately, Weiss and other scoring systems are sometimes difficult to apply, subjective and/or time consuming, despite several re-visitations and implementations occurred along years to

Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, lowto-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P!0.001), at variance with phosphorylated 4EBP1

Cav-1 immunoreactivity in lung carcinoma is histotype-dependent and acquired de novo in brain metastases, suggesting a site-specific phenotypic shift in secondary lesions.