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Key words: atheroembolic disease; necrotizing glomerulitis; vasculitis [ABSTRACT FROM PUBLISHER]

Neuroendocrine tumors (NETs) are frequently associated with second primary malignancies (SPMs). Earlier studies have demonstrated that NETs are highly associated with synchronous or metachronous gastrointestinal and genitourinary SPMs. We report, for the first time, a case of pure NE breast carcinoma (NEBC) exhibiting all of the World Health Organization (WHO)-categorized morphological and phenotypic NE features (i.e., round solid nests of spindle cells, plasmacytoid cells, large clear or mucinous signet-ring cells with a peripheral palisading tendency and immunohistochemical positivity for the NE markers synaptophysin and chromogranin in more than 50% of the tumor cell population) along with synchronous abdominal non-Hodgkin's lymphoma. In the present study, we review the diagnosis, clinicopathological features and histogenetic profiling of NEBC and discuss the literature relevant to the clinical and anatomopathological management of this case. This previously unreported case of synchronous solid NEBC and abdominal lymphoma, together with earlier studies showing that primary symptoms are caused by SPMs in a significant subgroup of NET patients, strongly supports the notion that NETs should be cautiously considered to be index tumors. Therefore, risk-adapted clinicopathological follow-up with systematic investigation is strongly recommended.

KRAS mutation status is being used as the sole biomarker to predict therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A significant number of mCRC patients with KRAS wild-type (WT) tumors, however, do not benefit from cetuximab. We are also lacking efficacy predictors in head and neck squamous cell carcinomas with an intact KRAS signaling and in non-small cell lung cancer in which KRAS mutations do not predict cetuximab efficacy. We recently established pre-clinical models of EGFR gene-amplified KRAS WT A431 squamous carcinoma cells chronically adapted to grow in the presence of cetuximab. We employed the ingenuity pathway analysis software to functionally interpret data from Agilent's whole human genome arrays in the context of biological processes, networks, and pathways. Cetuximab-induced activation of the interferon (IFN)/STAT1 appeared to switch from 'growth inhibitory' in acutely-treated cells to 'pro-survival' in chronically-adapted cells. Cetuximab treatment appeared to negatively select initially dominant IFN-sensitive clones and promoted selection of IFN- and cetuximab-refractory tumor clones constitutively bearing an up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR ligands amphiregulin (AREG), epiregulin (EREG), and neuregulin-1/heregulin (NRG1) predicted for acute cetuximab's functioning. Chronic cetuximab, however, appeared to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote selection of cetuximab-refractory clones exhibiting a knocked-down neuregulin signaling. Our current evolutionary mapping of the transcriptomic changes that occur during cetuximab-induced chronic blockade of EGFR/KRAS WT signaling strongly suggests that mRNAs coding for IFN/STAT1- and EGFR ligands-related genes can be evaluated as novel predictors of efficacy in KRAS WT squamous cancer patients being treated with cetuximab.

The prognostic abilities of breast cancer gene expression signatures are due mostly to the detection of proliferation activity. One of the strongest, yet simple and well-reproducible proliferation-associated prognostic factors is the mitotic activity index (MAI). However: a) counting mitotic figures is regarded by many histopathologists as cumbersome and time-consuming, and b) most available immunohistochemical markers are much weaker predictors than the MAI. We have investigated the spatio-temporal sub-cellular distribution of the Serine 2481-autophosphorylated form of mTOR (PP-mTOR(Ser2481)) during the G(1)/S-to-M-phase transition both in cultured cancer cells and in cancer tissue specimens. Using a high-resolution, automated confocal high-content imaging system, we observed that mitotic cells notably accumulated a distinct pattern of nuclear and cytoplasmic immunolabelings of PP-mTOR(Ser2481). Parallel experiments examining site-specific phosphorylation (i.e., Serine 10 and Serine 28) of the G(2)/M marker Histone H3 (PP-H3) revealed that PP-H3(Ser10/Ser28) staining efficiently detected mitotic cells from prophase until the beginning of anaphase, but not during late anaphase, telophase and cytokinesis. PP-mTOR(Ser2481) staining associated near and between separating chromosomes not only during early mitotic stages but also to the midzone and to midbody at ana/telophase through cytokinesis. We then evaluated the usefulness of PP-mTOR(Ser2481) immunostaining for improving the efficiency of mitotic counting using. Anti-PP-mTOR(Ser2481)-labeled mitotic figures (MFs) were easily seen and permitted a quick identification of mitotic hotspots in formalin-fixed cancer tissues, even at low magnification. Importantly, average mitotic counts were significantly higher when using PP-mTOR(Ser2481) staining than with the hematoxylin and eosin (H&E) protocol in breast cancer core biopsies. Mitotic count based on PP-mTOR(Ser2481) immunostaining increased tumor grade by one grade in 2 of 9 breast carcinomas. These findings warrant forthcoming studies to confirm both the accuracy and the prognostic value of PP-mTOR(Ser2481) as a novel high-contrast immunohistochemical mitosis marker in larger populations of human breast carcinomas.

Using a high-resolution, automated confocal high-content imaging system, we investigated the sub-cellular localization of the Serine 2481-autophosphorylated form of mTOR (PP-mTOR(Ser2481)) during mitosis and cytokinesis in human cancer cells. PP-mTOR(Ser2481) exhibited a punctate nuclear distribution in interphase cancer cells, with the number of PP-mTOR(Ser2481) nuclear speckles positively relating with the proliferative capacity of cancer cells. PP-mTOR(Ser2481) expression dynamically rearranged within the cytoplasm in a close association near and between separating chromosomes during early stages of mitosis. Towards the end of anaphase and in telophase, PP-mTOR(Ser2481) drastically focused on the midzone and ultimately in the centre of the midbody at the presumptive cleavage furrow. In cells at cytokinesis, PP-mTOR(Ser2481) appeared as a doublet facing each other at the apical ends of two daughter cells. Three-dimensional analysis confirmed that PP-mTOR(Ser2481) positioned at a ring structure wrapped round by microtubule bundles to connect daughter cells. These results reveal for the first time that PP-mTOR(Ser2481) may be unexpectedly involved in the terminal stages of cytokinesis.

Primary pure neuroendocrine breast carcinomas (NEBC) have been considered special features within conventional breast carcinomas until recently. Indeed, the actual incidence of NEBC in BC populations has remained largely unknown due to the lack of unambiguous diagnostic criteria. In 2003, the World Health Organization (WHO) classification of breast tumors definitely established that the immunohistochemical expression of NE markers in more than 50% of the tumor cell population is the unique requisite for NEBC diagnosis. Herein, we sought to determine the incidence, the clinico-pathological features and the immunohistochemical profile of NEBC in a large series of 1368 infiltrating breast tumors collected from 1989 to 2008 in our institution (Dr Josep Trueta University Hospital, Girona, Catalonia). Twelve cases were initially selected to fulfil histopathological patterns compatible with NEBC. Clinical data along with histological and immunohistochemical profiles were collected in all cases. The criterion inclusion was the presence of more than 50% tumor immunoreactivity for one of NE markers including chromogranin, synaptophysin and CD56. Only 7 tumors fully satisfied the NEBC criteria established by the WHO (0.5% prevalence). All the NECB were grade 2 ductal carcinoma infiltrating (DCI) with tumor sizes ranging from 7 to 55 mm. Lymphovascular tumoral emboli was present in 4 cases (57.1% of NEBC) and mucinous features occurred in 2 cases (28.5% of NEBC). Axillary lymph nodes were metastatic in 3 cases (42.8% of NEBC). A positive status for estrogen receptor (ER), progesterone receptor (PR) and synaptophysin was observed in 7 cases (100% of NEBC). None of the NEBC displayed HER2 overexpression. All the patients bearing NECB received hormone therapy and 4 of them underwent radiotherapy and/or chemotherapy. Of note, none of the NEBC patients died from BC-related causes after a median follow-up of 51 months. These findings revealed that: a) Pure solid NEBC do not significantly differ from other breast carcinomas in terms of general clinical features; b) NEBC do not exhibit an aggressive behavior despite the presence of adverse prognostic factors; and c) NEBC immunohistochemical profile mainly corresponds to that of the Luminal A BC subtype. Although it remains to be elucidated whether the good prognosis of NEBC relates to the intrinsic nature of the tumor and/or to a high rate of treatment responses, their immunohistochemical profile strongly suggest that NEBC belong to the Luminal A BC subtype. Forthcoming studies should definitely determine if the clinico-pathological features of NEBC indeed represent an independent good-prognosis subgroup of BC gene signature.

We report here a case of systemic lupus erythematosus with severe, active pauci-immune necrotizing and crescentic glomerulonephritis. This patient had been diagnosed of a lupus nephritis type III previously and treated with steroids and azathioprine. After a renal symptomless period of nine years, she developed heavy proteinuria and hypertension. A second kidney biopsy was then performed. The pathological study disclosed a pauci-immune necrotizing crescentic and segmental glomerulonephritis. The absence of subendothelial and mesangial deposits was confirmed by both immunofluorescent microscopy and electron microscopy. The simultaneous immunological study showed normal ANCA levels while complement, anti-dsDNA and ANA were altered. The patient was treated with steroids and cyclophosphamide eith good response. This case points out the possibility previously recognized by others of an association between lupus and an pauci-immune necrotizing glomerulonephritis.

We describe a 76-year-old woman who had persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course. Skin biopsy specimens obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement. This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.

We report the case of a 19-year-old woman who presented with a hepatic mass without cirrhosis. Light microscopy revealed a cholangiocarcinoma having both well-differentiated adenocarcinoma and lymphoepithelioma-like undifferentiated carcinoma components. By immunohistochemistry, the tumor showed strong and diffuse expression for cytokeratin AE1, 5D3, and CK22. The tumor cells were positive for p53 protein (more than 75% of the cells) but negative for bcl-2 and LMP1. Abundant Epstein-Barr virus EBER (1/2) oligonucleotides were detected in both tumor components, but not in the lymphoid stroma or the nontumor liver. To the best of our knowledge, this is the third report of an Epstein-Barr virus-associated primary hepatobiliary adenocarcinoma with lymphoepithelioma-like component. Int J Surg Pathol 8(4):347-351, 2000

We describe a 76-year-old woman who presented persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course. Skin biopsies obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement. This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.

The columnar-cell variant of papillary carcinoma is a rare tumor of the thyroid, associated with aggressive behavior, early visceral metastasis, and a rapidly fatal course. In this report we present the fine-needle aspiration cytologic findings of two examples of this variant of papillary carcinoma with cytohistologic correlation. In the smears, clusters, monolayered sheets, and scattered papillary fronds of tumor cells were present. The tumor cells were columnar and exhibited overlapping and stratification of the nuclei. In the first case the tumoral cells showed round nuclei with finely granular chromatin pattern, small nucleoli and vacuolated-appearing cytoplasm. The malignant cells in the second case presented oval to elongated nuclei with stippled chromatin, inconspicuous nucleoli and indistinct cytoplasmic borders. It is important to distinguish this tumor from the common thyroid papillary carcinoma because of its much more aggressive behavior.

Massive crystal deposition is unusual in lymphoproliferative disorders. In this report, a mucosa-associated lymphoid tissue (MALT) low-grade B-cell lymphoma of the parotid gland containing large numbers of crystal-storing histiocytes is described. The patient, an 81-yr-old female, presented with a history of long-standing left parotid gland enlargement. FNA cytology of the tumor showed a lymphoplasmacytic infiltrate and sheets of large benign histiocytes with abundant eosinophilic intracytoplasmic inclusions. Paraffinsection immunohistochemistry performed on the cell block demonstrated that the histiocytic cells were immunoreactive for the KP-1 (CD-68) antibody and monotypic for cytoplasmic IGM and L-light chain. The cytological diagnosis was consistent with a low-grade B-cell lymphoma with plasmacytic differentiation associated with crystal-storing histiosis. A periparotid lymph node was biopsied and showed involvement by a monocytoid B-cell lymphoma with plasmacytic differentiation and crystal-storing histiocytosis in the pericapsular region.

Purkinje cells were examined in three familial cases of olivopontocerebellar atrophy (OPCA) by means of the Golgi method, and neurofilament and calcium-binding protein immunocytochemistry. Reduced dendritic arborizations, as seen with different techniques, early formation of axonal spheroids, and abnormal accumulation of phosphorylated neurofilament epitopes in dendrites, somata and axonal spheroids, together with limited formation of proximal spine-like protrusions were the main changes in Purkinje cells. These lesions are unlikely to be the consequence of anterograde degeneration secondary to olivary atrophy, as postulated by some investigators, but probably represent primary damage to Purkinje cells in patients with OPCA. Reduced dendritic arborizations result in a decrease of receptor sites for parallel fibres and deprive granule cells of their main targets. Abnormal accumulation of neurofilaments in somata, dendrites and axonal spheroids may contribute to an abnormal transport and may impair protein turnover in the distal regions of Purkinje cells.

A 24 year old male diagnosed of type II diabetes mellitus of 2 years of known clinical evolution discovered by an episode of hyperglycemic decompensation without ketoacidosis is presented. In the study of possible visceral involvement of the disease agenesis of the left kidney with compensating hypertrophy of the right kidney, increase of glomerular filtrate and proteinuria of 1.8 g/24 hours were observed. Renal histologic study demonstrated the existence of diffuse intercapillar glomerulosclerosis compatible with diabetic glomerulopathy. From these data and review of the literature the possibility of the greater risk of individuals with a single kidney to present nephropathy in the case of coexistence of associated diabetes mellitus.

Eight cases of chronic eosinophilic pneumonia (CEP) diagnosed between January 1977 and December 1979 are described. Clinical manifestations included toxic syndrome, cough and fever, lasting from 1 to 15 months. Chest x-ray revealed peripheric bilateral infiltrates, with the exception of one case. In two patients there was no peripheral eosinophilia and five received antituberculous drugs at some point during the illness. In all cases tests for fungi and parasites were negative. In only two patients was an increase in IgE found. Hystological study confirmed CEP in 7 patients through either trans-bronchial biopsy or minimal thoracotomy. Treatment with corticosteroids was dramatically effective in all patients; both clinically and radiologically. In two cases which were asymptomatic, decreased carbon monoxide diffusing capacity persisted six months later. One hundred fifteen cases of CEP published since Carrington et al. first described CEP as a separate entity of the pulmonary infiltrates with eosinophilia syndrome are reviewed.

We describe the clinical presentation and pathological features of an infantile fibrosarcoma of the femur that occurred in a 3 1/2-month-old male infant. The tumor grew rapidly, reaching large size within a few months, finally requiring amputation. The tumor was poorly circumscribed, infiltrating the adjacent soft tissue extensively. Microscopically, it was a highly cellular tumor composed of immature-appearing spindle-shaped cells. Ultrastructural study revealed mesenchymal cells with fibroblastic and histiocytic differentiation.

The clinical and histopathological findings of 8 patients with a diagnosis of Churg-Strauss syndrome seen in our institution in a 10 year period have been reviewed. All patients had asthma and hypereosinophilia (mean eosinophil count 7.64 x 10(9); range: 0.748 x 10(9)-31.46 x 10(9) eosinophils/l). The organs and systems involved in the late phase of the syndrome (vasculitic phase) were: nervous system (16 cases), respiratory system (5 cases), skin and subcutaneous tissue (5 cases), heart (3 cases), digestive system (3 cases) and kidney (1 case). The diagnosis was made on the basis of the clinical and histopathological findings. In 7 cases necrotizing angiitis was shown, tissue eosinophilia in 4, and extravascular granulomas in 2. In most cases, corticosteroid therapy resulted in a favorable course, but cyclophosphamide was required in two patients. In the discussion, the evolution of the criteria for the diagnosis of this condition is analyzed.

Of 25 cases of idiopathic pulmonary fibrosis, confirmed by open chest lung biopsy between January 1979 and July 1981, 5 patients had been taking amiodarone in doses less than 600 mg daily for 1 to 6 years. No lung disease had been observed in any patient before the administration of amiodarone, and other drugs, factors and diseases thought to play a role in the causation of pulmonary fibrosis were ruled out. Two patients died of respiratory insufficiency, and only 1 does not now suffer from serious sequelae. Review of a further 5 cases reported in the literature and the present data suggest a causal link between administration of amiodarone and pulmonary fibrosis, and tend to indicate a hypersensitivity mechanism.

A case of nephrogenic metaplasia of the left ureter occurring in a 7-year-old male child, associated with recurrent urinary infection and previous surgical intervention, is described. This is to our knowledge the third reported case of this entity. Nephrogenic metaplasia involves the transitional epithelium of the urinary tract and results in the formation of structures histologically similar to renal tubules.