Antonio Maiorana

Pulmonary carcinomas with pleomorphic sarcomatoid or sarcomatous elements. A clinicopathologic and immunohistochemical study of 75 cases

We collected 75 primary pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements to better define their clinical, histologic, and immunohistochemical profile. The patients age ranged from 42 to 81 years (mean 65 years), and the male-to-female ratio was 9.7:1. Sixty-nine patients (92%) were smokers. Cough and hemoptysis were the most frequent presenting symptoms. Fifty-nine patients (65%) died of disease: only stage significantly predicts overall survival (p = 0.0273). Microscopically, based on the WHO criteria, 58 cases were classified as pleomorphic carcinoma (51 with an epithelial component, 7 composed exclusively of spindle and giant cells), 10 as spindle cell carcinoma, 3 as giant cell carcinoma, 3 as carcinosarcoma, and 1 as pulmonary blastoma. Immunohistochemically, in the tumors composed exclusively of spindle and/or giant cells, thyroid transcription factor-1 (TTF-1) and cytokeratin 7 were positive in 55% and 70% of the cases, respectively, whereas surfactant protein-A was always negative. In pleomorphic carcinomas with an epithelial component, cytokeratin 7, TTF-1, and surfactant protein-A were positive in the sarcomatoid component in 62.7%, 43.1%, and 5.9% of the cases, respectively, whereas they were always negative in the sarcomatous part of carcinosarcomas and blastoma. In the epithelial component of pleomorphic carcinomas, cytokeratin 7, TTF-1, and surfactant protein-A were positive in 76.4%, 58.8%, and 39.2% of the cases, respectively, whereas the same antibodies did not react with the epithelial component of carcinosarcomas; in the case of blastoma, the epithelial part of the tumor was positive for cytokeratin 7 and TTF-1, whereas it was negative for surfactant protein-A. Cytokeratin 20 was always negative. In our opinion, this study: 1) supports the metaplastic histogenetic theory for this group of tumors; 2) shows that cytokeratin 7 and TTF-1, but not surfactant protein-A, are useful immunohistochemical markers in this setting; 3) confirms that stage is at the moment the only significant prognostic parameter, as in conventional non-small cell lung carcinomas; and 4) shows that this group of tumors has a worse prognosis than conventional non-small cell lung carcinoma at surgically curable stages I, justifying their segregation as an independent histologic type in the WHO classification.

Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFRα, PDGFRβ, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung

Purpose Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets. Patients and Methods We reviewed 83 patients with pure pulmonary LCNEC to investigate their clinicopathologic features, therapeutic strategy, and immunohistochemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFRα, PDGFRβ, and Met. Results LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRα in 60.2%, PDGFRβ in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (≥ 3 cm)...

Mr of Benign Peripheral Nerve Sheath Tumors

Seventeen benign peripheral nerve sheath tumors were studied using MR. In all cases T2 relaxation time, signal intensity on T1-weighted images (lesion/muscle ratio), detectability of nerve of origin, nerve-lesion relationship, and presence of a capsule were assessed. Sixteen tumors showed marked hyperintensity on T2-weighted images with T2 relaxation times values greater than 95 ms. One schwannoma was almost isointense with fat (T2 60 ms). All lesions were isointense with muscle on T1-weighted images. In schwannomas the nerve was usually situated at the periphery of the lesion and only in one case was it obliterated by the mass. In neurofibromas the nerve was either visible in a central position within the mass (two cases) or no longer visible (five cases). A capsule could be detected in 70% of the schwannomas and in 30% of the neurofibromas. In patients with soft tissue masses, MR may contribute to recognition of nerve sheath tumors by showing the nerve of origin and typical signal hyperintensity on T2-weighted images. It can also be helpful in distinguishing between schwannomas and neurofibromas by the location of the nerve of origin and the presence of a capsule.

Synchronous occurrence of epithelial and stromal tumors in the stomach: a report of 6 cases.

OBJECTIVE The synchronous development of epithelial and stromal tumors in the stomach has been reported rarely in the literature. A series of 6 such cases is described in this article. METHODS Clinical and pathologic data were recorded and the literature was reviewed. RESULTS Five cases featured the simultaneous occurrence of stromal tumors (1 benign, 3 borderline, 1 malignant) and adenocarcinomas, whereas the stromal tumor in the sixth case was found in association with a carcinoid. No collision tumors were observed. In 2 cases, tumors arose from the same site and were closely juxtaposed, but in 4 patients they developed from different areas of the stomach. A preoperative histologic diagnosis of both tumors was not achieved in any case. Two patients harbored occult infiltrative epithelial lesions (1 diffuse-type adenocarcinoma, 1 carcinoid), which were detected only at pathologic examination of the gastric mucosa adjacent to the stromal tumor. CONCLUSIONS The simultaneous occurrence of epithelial and stromal tumors in the stomach can be less rare than usually expected. Coincidence alone could account for such an association, particularly in areas with high incidence rates of gastric cancer. The hypothesis that a single carcinogenic agent might interact with two neighboring tissues in the stomach inducing the development of tumors of different histotype cannot be theoretically discarded.

Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer

BACKGROUND Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. PATIENTS AND METHODS We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworaks tumor regression grade (TRG) was evaluated on surgical specimens. RESULTS Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). CONCLUSIONS In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

Immunohistochemical markers of sweat gland tumors

Using immunoperoxidase methods, normal sweat glands, 44 benign and 4 malignant sweat gland tumors were tested for the presence of carcinoembryonic antigen (CEA), pregnancy‐specific‐B1‐glycoprotein (SPI) and actin (ACT). CEA and SP1 stained the secretory and duct‐lining cells of normal eccrine glands. Among benign tumors, 74% were positive for CEA and 44% for SPI. The staining reaction was found mainly in luminal secretions and surrounding cells. Staining by SPI was reduced, but not suppressed, after absorption with the purified antigen. ACT was found in myoepithelial cells of the secretory tract of normal glands and in basal cells of all cases of hidradenoma papilliferum. Only 3 sweat gland carcinomas reacted for CEA. In a malignant chondroid syringoma, no ACT‐positive cells were seen in the myxochondroid stroma. The potential value of CEA, SP1 and ACT in the diagnosis of sweat gland tumors is discussed.

Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis

BACKGROUND Identification of the clinical behavior of atypical Spitzoid tumors with conflicting histopathologic features remains controversial. OBJECTIVE We sought to assess whether molecular findings may be helpful in the diagnostic and prognostic assessment of atypical Spitzoid tumors. METHODS A total of 38 controversial, atypical Spitzoid lesions (≥ 1 mm in thickness) were analyzed for clinicopathological features, chromosomal alterations by fluorescence in situ hybridization (FISH) analysis (RREB1/MYB/CCND1/CEP6), BRAF(V600E) mutation by allele-specific real-time polymerase chain reaction confirmed by sequencing, and H-RAS gene mutation by direct sequencing. RESULTS Atypical Spitzoid lesions developed in 21 female and 17 male patients (mean age 22 years). Nine patients underwent sentinel lymph node biopsy and a sentinel lymph node micrometastasis was detected in 4 of these 9 cases. Four additional patients, who did not receive a sentinel lymph node biopsy, experienced bulky lymph node metastases and one experienced visceral metastases and death. Lesions from patients with lymph node involvement showed more deep mitoses (P < .01), less inflammation (P = .05), and more plasma cells (P = .04). FISH analysis demonstrated the presence of chromosomal alterations in 6 of 25 cases. Correlation with follow-up data showed that the only case with fatal outcome showed multiple chromosomal alterations by FISH analysis. BRAF(V600E) mutation was detected in 12 of 16 cases (75%) and H-RAS mutation on exon 3 was found in 3 of 11 cases (27%). LIMITATIONS Our results require validation in a larger series with longer follow-up information. CONCLUSIONS FISH assay may be of help in the prognostic evaluation of atypical Spitzoid tumors. Diagnostic significance of BRAF(V600E) and H-RAS mutations in this setting remains unclear.

Frequency and Distribution of Herpesvirus-like DNA Sequences (KSHV) in Different Stages of Classic Kaposi's Sarcoma and in Normal Tissues from an Italian Population

The frequency and distribution of herpesvirus‐like DNA sequences (KSHV) were investigated by PCR in the pathologic skin lesions of a series of 22 HIV‐negative elderly patients with classic Kaposis sarcoma (KS) from Italy, one of the few regions of the world where classic KS is prevalent. Viral sequences were clearly identifiable in 15 cases, in particular in 2 of 5 patch, in 3 of 6 plaque and in 10 of 11 nodular lesions. Our findings confirm the association of these herpesvirus‐like DNA sequences with KS in unrelated populations, providing evidence of the putative KS‐associated agent in all different histologic lesions of the disease, mainly in the nodular stage. The search for other herpesviruses by PCR showed that Epstein‐Barr virus (EBV) sequences were present in 7 of 22 pathologic skin lesions. In 4 cases, both EBV and KSHV were present. On the contrary, all 22 classic KS specimens were negative for human herpesvirus‐6 sequences. Two of 3 patch and the 1 nodular lesions from AIDS‐related KS patients examined were positive for KSHV but negative for both EBV and HHV‐6 sequences. Furthermore, we evaluated the prevalence of KSHV sequences in the normal population of the same geographical area. Thirteen peripheral blood mononuclear cell samples, 9 salivary gland tissues and 6 saliva samples from healthy subjects were invariably found negative for KSHV, using the same PCR technique. Of interest, 2 of 11 hyperplastic tonsils harboured these herpesvirus‐like sequences, suggesting that, like other herpesviruses, the KS‐associated agent may be harboured in a proportion of normal individuals and tonsils may represent at least one of the possible reservoirs of this putative lymphotropic γ‐herpesvirus in vivo.

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

Prostate cancer, the most frequently diagnosed cancer in Western men, can display a high variability in term of clinical aggressiveness and prognosis and none of the available markers is able to accurately predict its clinical course. Dystroglycan (DG), a non‐integrin adhesion molecule, is a complex formed by two subunits, α‐ and β‐DG, which bind to extracellular matrix molecules and cytoskeleton, respectively. DG expression is frequently reduced in human cancers and has been related to tumor grade and aggressiveness. This study investigated the role of DG in human prostate tumorigenesis and its suitability as a prognostic marker. The expression level of extracellular α‐DG subunit was frequently reduced in human prostate cancer cell lines and primary tumors and the percentage of positive tumor cells was significantly further decreased in vivo following androgen ablation therapy (median = 1%) compared to pre‐treatment samples (median = 28%). A significant relationship was observed between α‐DG staining on the post‐treatment samples and tumor recurrence. A dose‐ and time‐dependent decrease of DG expression also occurred in human prostate cancer cells following treatment with the anti‐androgen flutamide. Stable expression of an exogenous DG cDNA in the LNCaP human prostate carcinoma cell line resulted in a marked inhibition of both anchorage‐dependent and independent growth and of the in vivo tumorigenicity. These findings confirm and extend previous evidence that disturbances in the function of the DG complex might contribute to the definition of the malignant behavior of prostate cancer cells and suggest that androgens might regulate DG expression in these cells. J. Cell. Physiol. 213: 528–539, 2007.

Superficial papillary urothelial carcinomas in young and elderly patients: a comparative study

To compare the clinicopathological and immunohistochemical findings of superficial papillary transitional cell carcinomas in ‘young’ and ‘elderly’ patients, as the natural history and prognosis of bladder tumours in young patients remains a matter of debate.