A National Quality Assurance program for breast immunohistochemistry: an Italian perspective.

A national project for the quality assessment of breast immunohistochemistry, involving 155 pathology laboratories distributed all over the Italian territory ( 19 regions), was carried out. The Project lasted one year from December 2014 to December 2015 and it was strongly supported by the Italian Society of Anatomic Pathology (SIAPEC/IAP). Proficiency tests were carried out by the Nordic Immunohistochemical Quality Control (NordiQC) organization. The main aim of the project was to investigate on the general performance of immunohistochemistry (ER, PR and HER2) in the field of breast cancer in the Italian territory, in order to emphasize any difference and give practical support to laboratories in daily practice.The present review article focused on the description of this extraordinary pioneer Italian experience. Besides NordiQC results, further analysis concerning epidemiology and geographical distribution were done.Aim of the study was to analyze the general results and to discuss on the benefits that a national quality control program may have if it became a mandatory service provided by the National Health Care System.In general, the Italian data were in accordance with the general results obtained from the "official" NordiQC HER2, PR and ER assessments. A HER2 scoring consensus between labs and assessor group was achieved in 80% of cases.Interestingly, what emerges from our study is that no substantial differences exist among the three Italian macro-areas (North, Center and South) in the quality of Immunohistochemistry performed for breast cancer. No statistically significant difference was even found between laboratories that perform more or less than 100 tests/year.

High CXCR4 expression correlates with sunitinib poor response in metastatic renal cancer.

BACKGROUND: Almost 30% of the sunitinib-treated patients for metastatic renal carcinoma (mRCC) do not receive a clinical benefit. Convincing evidences demonstrated a cross talk between the VEGF and CXCR4 pathways. It was hypothesized that CXCR4 expression in primary renal cancer could predict sunitinib responsiveness. PATIENTS AND METHODS: In this exploratory study sixty-two mRCC patients receiving sunitinib as first-line treatment were evaluated for CXCR4 expression through immunohistochemistry (IHC). Correlations between CXCR4 expression, baseline patients and tumour characteristics were studied by contingency tables and the chi-square test. Univariable analysis was performed with the log-rank test, and the Cox model was applied for multivariable analysis. RESULTS: The objective response rate of sunitinib first-line therapy was 35.5% (22/62) with a disease control rate (response and stable disease) of 62.9% (39/62). CXCR4 expression was absent/low in 30 (48.4%), moderate in 17 (27.4%), and high in 15 (24.2%) tumors respectively. Low or absent CXCR4 expression predicted response to sunitinib therapy. Moreover, Fuhrman grading and concomitant, CXCR4 and Fuhrman grading, strongly predicted sunitinib first line therapy responsiveness on progression-free survival and overall survival. CONCLUSIONS: High CXCR4 expression correlates with sunitinib poor response in metastatic renal cancer.

Neuroendocrine tumors diagnosed at the Antonio Cardarelli hospital (Naples, Italy) between 2006-2009: a single-institution analysis.

Neuroendocrine tumors (NETs) are rare, with an incidence of about 5 per 100,000 inhabitants. As no study on NETs has ever been specifically conducted on the population of Campania, we performed a retrospective analysis of all newly diagnosed NETs at the Antonio Cardarelli hospital between 2006-2009. A search of the registry of the Pathology Department of the Antonio Cardarelli hospital was carried out to retrieve available data on all newly diagnosed NET cases. Two hundred and ninety-nine NET tumors were diagnosed at our Institution from January, 2006 to December, 2009. Globally, 121 patients (40% of the population) had a lung NET, while 92 patients (30% of the population) presented a GEP-NET. The most common primary tumor site varied by sex, with female patients being more likely to have a primary NET in the lung, breast or colon, and male patients being more likely to have a primary tumor in the lung. Also, twenty-three cases of breast NETs were identified, and clinical information regarding therapy and response was available for 22 patients. Our study represents a pioneering effort to provide the medical community in Campania with basic information on a large number of patients with different types of NETs. The Antonio Cardarelli hospital could greatly benefit from cooperation with other hospitals in order to become a highly specialized center for NETs in the region and Southern Italy.

Unknown primary tumors.

An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity. Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming "algorithmic process" it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.

[Hepatic splenosis diagnosed by fine-needle cytology]. / Splenosi epatica diagnosticata con citologia con ago sottile.

A case of hepatic splenosis, diagnosed by FNA cytology, in a 56 years old cirrhotic man is reported. The cytologic material, aspirated from a 4.8 cm "suspicious for hepatocarcinoma" nodule, showed, within a hematic background, small-medium sized lymphoid cells, neutrophils and eosinophils granulocytes, histiocytes with large cytoplasm, plasma cells; mixtures of these cells, within a reticular network, were often aggregated in large structures, in which endothelial cells organized in vascular-like structures were also visible. The cell block, showed sinusoidal structures, lymphoid follicular aggregates and fibrous septa, strongly suggesting the micromorphology of the normal spleen. Splenosis is an autotransplant of splenic tissue, morphologically organized in non-capsulated, functioning, self-limited nodules, secondary to a post-traumatic splenectomy. Usual presentation of this condition is the presence of several bluish nodules on the peritoneal surface. Nevertheless, sporadic cases in other organs have been reported. To the best of our review of the Medical Literature, a hepatic splenosis is an exceptional even and the present is the first case in this location diagnosed by FNA cytology. The present one is also the case with the largest latency between the splenectomy and the splenosis detection (43 years).

[Pleomorphic adenoma in unusual anatomic sites: case reports and review of literature]. / Adenoma pleomorfo in sedi atipiche: casi clinici e revisione della letteratura.

Pleomorphic adenoma is the most common neoplasm of the major salivary glands, in particular of the parotid gland. Only occasionally can it be found in the cervicofacial area outside the major and minor salivary glands of the oral cavity. The present article describes three cases of pleomorphic adenoma, respectively of the external auditory canal, the nose, and the larynx. The three tumors showed no clinical or radiological signs of malignancy and were surgically excised with a suitable margin of healthy tissue. Histologically, the typical features of pleomorphic adenoma were observed in the larynx case alone. The pleomorphic adenoma of the external auditory canal evidenced an extensive apocrine glandular component; the neoplasm of the nose was itself characterized by ample proliferation of fused cells. Immunohistochemical findings revealed focal or widespread positivity to cytokeratin, S100 protein and muscle-specific actin in both the epithelial and mesenchymal components of the neoplasm. Cases of pleomorphic adenoma in sites other than the major salivary glands show clinical and radiological signs of benignity. Their histopathological identification is, however, not always straightforward; immunohistochemistry can contribute significantly to the formulation of a definitive diagnosis and to the realization of an appropriate follow-up.

[Abdominal lymphoma with abscess and thoracic perforation: en-bloc resection]. / Linfoma addominale ascessualizzato e perforato in torace: resezione "en-bloc".

The authors compare a rare case of acute onset Gastric Lymphoma with that present in the literature. The patient, a white 67 year-old man, was admitted to hospital in severe general condition. On CT scan an opacity of the pleura and a subtotal collapse of the left lung associated with a mass infiltrating the diaphragm, the gastric fundus and pancreas were seen. After 48 hours from the admission an operation was performed. The abdominal mass infiltrating the stomach, the spleen and the left thorax was resected en-bloc by laparotomy. A Boulau drainage was inserted. The histology showed an high malignant, diffused, big cell lymphoma. The patient was discharged 23 days later after a regular postoperative course. Surgery can be necessary, sometime curative in gastric lymphomas while long term result and quality of life could be improved by chemotherapy.

Renal cell carcinoma with rhabdoid features.

Neoplasms with rhabdoid features have been reported at many anatomic sites. In the kidney, rhabdoid tumors are typically found in children, whereas only rare examples have been reported in adults. Little is known of renal cell carcinomas (RCCs) that exhibit rhabdoid features. The objective of this study was to determine the incidence of RCC with rhabdoid attributes and characterize the histologic, immunophenotypic, and ultrastructural features by retrospective analysis of 480 consecutively identified cases of RCC in radical nephrectomy specimens. Immunohistochemical evaluation was performed in cases with rhabdoid foci using a panel of antibodies to pancytokeratin (pan-CK), CK7, CK20, epithelial membrane antigen (EMA), S-100 protein, desmin, vimentin, neuron-specific enolase (NSE), muscle-specific actin (MSA), smooth muscle actin (SMA), human melanoma, black-45 (HMB-45), and glial fibrillary acidic protein (GFAP). Electron microscopy was also performed in selected cases. The presence and extent of rhabdoid foci in relation to pathologic stage and grade were assessed. Twenty-three of 480 cases of RCC (4.7%) exhibited rhabdoid features. The 23 patients were all adults with a mean age of 61.8 years (age range, 33-84 yrs). Fifteen of the patients were men and eight were women. Histologically, the rhabdoid foci were typified by sheets and clusters of variably cohesive, large epithelioid cells with vesicular and often eccentric nuclei, prominent nucleoli, and large, paranuclear intracytoplasmic hyaline globules (inclusions). The presence of these rhabdoid features was related to high histologic Fuhrman grade of the nonrhabdoid carcinoma component, with an incidence of 0 of 84 grade I cases, eight of 300 grade 2 cases (2.6%), six of 70 grade 3 cases (8.9%), and nine of 26 grade 4 cases (34.6%; p = 3 x 10(-9)). The rhabdoid foci were all high grade. The presence of rhabdoid foci was also found in higher stage carcinomas. A total of 52% (12 of 23) of RCC cases with rhabdoid features exhibited extrarenal extension compared with 28% (24 of 92) of contemporary RCCs without rhabdoid features (p = 0.03). The size of the rhabdoid component ranged from 1 mm to more than 2 cm and comprised 1% to 50% of the renal mass. Immunoreactivity for vimentin (100%), NSE (79%), and panCK (56%) was present in the majority of cases. Substantial percentages of cases were immunopositive for EMA (47%) and S-100 protein (37%), with minimal to no immunohistochemical reactivity for CK7 (5%), SMA (5%), CK20 (0%), desmin (0%), MSA (0%), HMB-45 (0%), and GFAP (O%). A distinctive globular, paranuclear reaction pattern was found for the cytokeratin, EMA, and vimentin immunostains. Ultrastructurally, the rhabdoid cells had paranuclear intermediate filament aggregates or paranuclear condensation of organelles, often associated with peripheral vacuolization. Adult RCCs may harbor a rhabdoid component, and these neoplasms can be regarded as "composite" tumors. Rhabdoid elements are important to identify because of their high-grade nature, and association with high stage. Adult RCC with rhabdoid elements should be distinguished from pure rhabdoid tumors of kidney, in light of their clinicopathologic differences. Rhabdoid differentiation in adult renal cell carcinoma may represent clonal divergence and/ or evolution, and emergence of a particularly aggressive element.

Neoplasms composed of eosinophilic polygonal cells: an overview with consideration of different cytomorphologic patterns.

Neoplasms that are composed of large eosinophilic cells present a distinctive and challenging image to the diagnostic pathologist. Potential lineages for such lesions include several types of epithelial tissue, as well as melanocytic, lymphoid, germ-cell, and mesenchymal proliferations. Attention to morphological details represents a useful first step in the further evaluation of eosinophilic large-cell tumors. These tumors can usually be segregated into one of four cytological categories, including granular eosinophilic (oncocytic and oncocytoid), fibrillary eosinophilic (myoid), globular eosinophilic (rhabdoid and gemistocytic), and diffusely eosinophilic (hyaline-cell and deeply eosinophilic, not further specified). Correlation with anatomic locations, nuances of clinical presentation, and results of electron microscopic and immunohistochemical studies provides additional data that can be used for a specific interpretation, especially if it is applied in an algorithmic fashion.

Oxyphilic proliferations of the respiratory tract and paranasal sinuses.

Neoplasms of the upper respiratory comprised primarily of eosinophilic cells are, in general, rare, and they include a diverse group of lesions. Low-grade oncocytic neuroendocrine neoplasms (so-called oncocytic carcinoids) can be encountered in several locations throughout the respiratory tract. The oncocytoma and related entities, lesions that presumably arise from minor gland tissue, can likewise be seen from the nasal cavity to the lung; differences in clinical significance may relate to the location of such lesions, and are discussed herein. Granular cell tumor is another entity that can involve both the upper respiratory tract and lungs, and specific features of this lesion in different anatomic sites are highlighted. The oncocytic variant of Schneiderian papilloma is an important nasal lesion to recognize, because of important therapeutic and prognostic implications of that diagnosis. Finally, unique oncocytic variants of glomus tumor and pulmonary alveolar adenoma are discussed, as well as eosinophilic varieties of pulmonary carcinomas and mesotheliomas.

Nested polymerase chain reaction on vaginal smears of tuberculous cervicitis. A case report.

BACKGROUND: Tuberculous cervicitis (TC) is a rare disease the diagnosis of which is based on the microscopic and/or cultural recognition of mycobacteria. In recent years, the polymerase chain reaction (PCR), especially with double-round amplification ("nested" PCR [nPCR]), has been increasingly used for rapid detection of mycobacteria in clinical samples. CASE: The present case is the first example of tuberculosis diagnosed with the aid of nPCR amplification of mycobacterial DNA fragments on smeared and Papanicolaou-stained cytologic material. First detected on vaginal smears, the amplicon IS6110 was subsequently identified also on paraffin-embedded tissue sections. CONCLUSION: The technique described here could also be applied to aspiration cytology smears to give rapid and accurate information on mycobacterial infections.

Fine-needle aspiration cytology and immunohistology of low-grade adenosquamous carcinoma of the breast.

Low-grade adenosquamous carcinoma of the breast (LASCB) is a relatively recently-described, rare histotype of breast cancer that has a favorable prognosis. Its principal microscopic features are the presence of "syringoid" ("tadpole"-shaped) ductal profiles of tumor cells, a bland and modestly cellular stromal background, and the variable presence of keratinizing ("epidermoid") cell groups. As such, the basic image of LASCB is quite similar to that of microcystic adnexal or adenosquamous carcinoma of the skin or "syringomatous adenoma" of the nipple. We report the fine-needle aspiration cytologic (FNA) attributes of this neoplasm, as well as its immunohistochemical characteristics and differential diagnosis.

[Flow cytometry in prostate cancer. Evaluation of its feasibility for biopsy specimens and correlation with grading]. / La citometria a flusso nel carcinoma della prostata. Valutazione della praticabilità su campioni bioptici e correlazione con il grading.

BACKGROUND: Pathologic staging and grading are the most important prognostic factors in prostatic cancer. Unfortunately, pathologic staging needs to be evaluated by surgical procedures; moreover, the proposed grading systems are largely based upon subjective histopathologic evaluations. In recent years, these problems have been approached with flow cytometry (FCM). The present study evaluates the significance of DNA ploidy of prostatic carcinoma assessed by FCM. MATERIALS AND METHODS: Microscopic slides from 132 core needle biopsies and 22 surgical specimens of prostatic carcinoma were reviewed and classified according to Gleason's score modified by Epstein et al. Formalin-fixed, paraffin-embedded tissue samples were prepared for FCM evaluation using standard techniques. Adequate histograms were obtained from 113 biopsies (85.6%) and from all the surgical specimens (100%). RESULTS: Among the 113 biopsy specimens, a statistically significant correlation was found between DNA ploidy and Epstein's grading, since high-grade neoplasms accounted for 40.38% of non-diploid cases and only for 21.33% of diploid cases (chi square = 5.8; p = 0.05). Moreover, tetraploid tumors were defined as a separate FCM category with an absolute prevalence (65.52%) of non-high grade neoplasms (chi square = 5.9; p = 0.05). Although not submitted to statistical analysis, data collected from surgical specimens showed similar distribution. CONCLUSIONS: DNA ploidy assessment by FCM is a viable procedure in the majority of needle biopsy tissue samples of prostatic carcinoma; it may produce prognostic parameters with greater objectivity than conventional histologic grading.

Clear cell tumors of unknown nature and origin: a systematic approach to diagnosis.

Not infrequently, surgical pathologists encounter malignant neoplasms composed of clear cells, the sources and natures of which are indeterminate on the basis of conventional morphological study. In this context, it is frustrating that tumors of completely dissimilar lineage can show strikingly similar microscopic appearances; moreover, anatomic location provides few if any definitive clues to the likely final diagnosis in many cases of clear cell neoplasia. Because of these factors, it is necessary to systematically pursue the same approach to the pathological assessment of clear cell tumors, routinely considering not only clinical and radiologic details but also the possible application of immunohistology, electron microscopy, and cytogenetics. This review provides algorithmic schemes by which such techniques can be applied, as well as their potential drawbacks and limitations.

Clear cell neoplasms of the endocrine system and thymus.

Clear cell tumors of the endocrine system and thymus are rare lesions with which surgical pathologists have only infrequent contact. As a result, these neoplasms may be misinterpreted and incorrectly classified. This review considers the histological, immunohistochemical, and ultrastructural features of clear cell pituitary adenomas, parathyroid tumors, pancreatic endocrine neoplasms, adrenocortical proliferations, and thymic malignancies. Emphasis is placed throughout on differential diagnosis with microscopically-similar lesions. Clear cell endocrine tumors and thymic lesions manifest a variety of potential lineages, including examples with epithelial, neural, germ cell, and lymphoid differentiation. Because of the wide differences in behavior and recommended treatment in this group, accuracy in diagnosis is essential.