Peripheral nerve mucoid degeneration involving the sciatic nerve.

Peripheral nerve mucoid degeneration (PNMD) is a rare non-neoplastic degenerative condition characterized by endoneural deposit of mucoid matrix. Herein, we report a case of PNMD involving the sciatic nerve with preoperative features, surgical treatment and pathological findings.

New evidence of cutaneous leishmaniasis in north-eastern Italy.

BACKGROUND: Human leishmaniasis is on increase in the Mediterranean Europe. However, the exact prevalence of cutaneous leishmaniasis (CL) is largely unknown as underdiagnosis and under reporting are common. OBJECTIVE: To evaluate epidemiological, clinicopathological and microbiological aspects of CL cases occurring in the Bologna Province, north-eastern Italy. METHODS: We performed a retrospective, observational study on CL cases diagnosed in the Bologna Province between January 2013 and December 2015. RESULTS: During 2013-2015, 30 cases of CL were identified in the Bologna Province with an average incidence of 1.00/100 000, with an increase of fourfold to 12-fold as compared to previous years. 16 of 30 (53%) CL cases presented as single, typical lesions. CL diagnosis was carried out by histological and molecular techniques, although in 7 of 29 (24%) PCR-positive cases, amastigotes were not visible on histology. CONCLUSIONS: We report new evidence of CL cases in a focal area of north-eastern Italy in 2013-2015. Our study highlights the importance of CL surveillance in the Mediterranean basin and emphasizes the need for the molecular laboratory surveillance of CL in endemic areas.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

Standardized approach for evaluating tumor infiltrating lymphocytes in canine mammary carcinoma: Spatial distribution and score as relevant features of tumor malignancy.

Neoplastic cells, through immunoediting mechanisms, can establish a state of immunosuppression to evade host immune defenses. The aims of this study were: (1) to validate a standard method for assessing tumor infiltrating lymphocytes (TILs) in canine mammary carcinoma by applying international human breast cancer guidelines; (2) to investigate if the TILs population was composed of a subset of regulatory T lymphocytes (Tregs); and (3) to evaluate the relationship between the number of TILs and Tregs and the biological behavior of the tumors. One hundred and twenty-nine canine mammary tumors were retrospectively selected for this study. Histological diagnosis, grading and histological evaluation of TILs was performed on hematoxylin and eosin-stained sections. TILs were evaluated using a three-tier semiquantitative method, previously validated in human medicine, based on the percentage of TILs (0-10%, 11-40% and 41-90%). Lymphocyte immunophenotype was confirmed by CD3 and CD79, while an anti-FoxP3 antibody was used to determine the presence of Tregs. The number of stromal TILs and invasive front TILs significantly correlated with each other (P < 0.0001) and increased with increasing histological grade (P = 0.002 and P = 0.004, respectively). A subset of TILs was composed of FOXP3+ Tregs. Stromal Tregs and invasive front Tregs were associated with stromal TILs and invasive front TILs (P = 0.03; P = 0.01 and P = 0.003; P = 0.007, respectively). In conclusion, in canine mammary carcinomas, an increased number of stromal and invasive front TILs is associated with increased malignancy and significant increase of Tregs that could lead to immunosuppression and evasion of the host immune system.

Triple-negative breast carcinomas of low malignant potential: review on diagnostic criteria and differential diagnoses.

Triple-negative breast carcinomas constitute a wide spectrum of lesions, mostly being highly aggressive. Nevertheless, some special histologic subtypes can have low malignant potential. The purpose of the present paper is to review diagnostic criteria and prognostic parameters of breast neoplasms of special histotypes. Specifically, adenoid cystic carcinoma, adenomyoepithelioma, acinic cell carcinoma, mucoepidermoid carcinoma, tall cell carcinoma with reverse polarity, and secretory carcinoma will be discussed. For each tumour, definition and morphological and molecular features, together with prognostic parameters, will be presented. Paradigmatic cases will be illustrated.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre.

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas' score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

Neuroglial choristoma of the middle ear.

Neuroglial choristoma is a rare cerebral heterotopia which can involve various locations. Even if its occurrence is more frequent in midline structures, it can also be found in the non-midline structure such as, for example, even if only rarely, the middle ear. The described case is that of a 74-year-old male who had been operated on for a neuroglial choristoma located in the tympanic cavity and in the mastoid bone. High resolution computed tomography and intra-operative findings did not reveal any connection with the upper cerebral structures, thus excluding the hypothesis of an encephalocele. After careful histopathological examination, the aetiopathogenetic hypothesis are analysed. Only 8 similar cases have been reported in the literature.

Oral field cancerization: history and future perspectives.

Notwithstanding extended surgical approaches or adjuvant chemoradiotherapy, the development of multiple neoplastic lesions arising in the oral cavity after treatment still represents a critical clinical challenge in the management of patients with oral squamous cell carcinoma. Such clinical behavior of oral squamous cell carcinoma is nowadays better known as "field" cancerization effect as suggested by Slaughter, the author that for the first time tried to describe it in a scientific paper. Field cancerization is now widely accepted not only in head and neck oncology but also in other anatomical districts as well as in different types of epithelial neoplasia. A brief history of the theory of field cancerization is here proposed and future perspectives deriving from new molecular techniques are discussed.

Salivary epithelial-myoepithelial carcinoma: clinical, morphological and molecular features.

Epithelial-myoepithelial carcinoma (EMC) is a rare biphasic tumor accounting for less than 2% of all salivary gland malignancies. It presents as a slowly growing, asymptomatic small size mass, with ulceration of overlying mucosa in some cases. Microscopically, it is characterized by glands lined by the simultaneous presence of two different cell components, inner epithelial cells and outer myoepithelial cells. Immunohistochemical staining of myoepithelial cells is variably positive for vimentin, Smooth Muscle Actin (SMA), Muscle Specific Actin (MSA), S100, Smooth Muscle Myosin Heavy Chain I(SM-MHC), calponin and p63. Several molecular alterations, mainly point mutations, have been described. Mutations of HRAS, AKT1, CTNNB1 and PIK3CA were highlighted in variable percentage of EMC samples. EMC is considered a low-grade malignant tumor with a 5-year survival rate of 94% that may commonly recur locally after resection in 30-50% of cases. At the moment, adequate resection with negative margins is the minimum recommended and necessary treatment.

Clonal analysis as a prognostic factor in multiple oral squamous cell carcinoma.

OBJECTIVES: A novel classification based on molecular methods to assess clonality defines three types of secondary oral squamous cell carcinoma (OSCC): second primary tumour (SPT) independent from the index tumour, local recurrence (LR), clonally related to the primary tumour, and second field tumour (SFT), derived from the same genetically altered mucosal field as the primary tumour. The present study applied mtDNA analysis in a group of patients experiencing a second loco-regional neoplastic manifestation. The purpose was to differentiate secondary tumours into LRs, SPTs and SFTs and evaluate the prognostic impact in terms of survival rate. MATERIAL AND METHODS: The study population comprised 23 patients who experienced a second neoplastic lesion after a surgical resection of primary OSCC. mtDNA D-loop analysis was applied in paired neoplastic lesions and in clinically and histologically normal mucosa. On the basis of mtDNA results, the second OSCC was classified as LR or SPT or SFT. Disease-free survival was defined as the duration between the appearance of the second neoplastic lesion and death of disease, or last follow-up visit. RESULTS: Seven secondary tumours were classified as LR, 12 as SFT, 4 as SPT. An altered mucosal field proved a variable significantly related to a better survival rate (p<0.05); 2/12 (16.6%) SFT events failed as compared to 5/7 LRs (71.4%) and 3/4 SPTs (75%). CONCLUSION: mtDNA analysis may be considered a useful tool to differentiate secondary tumours and might influence the choice of the most appropriate treatment in patients with multiple OSCCs.

Prognostic impact of macrometastasis linear size in sentinel node biopsy for breast carcinoma.

AIM: The aim of the present study was to evaluate the risk of axillary non-sentinel lymph-node metastases (ALN) in breast cancer patients presenting macrometastasis (Mac-m) in the sentinel lymph node (SN). MATERIALS AND METHODS: A retrospective series of 1464 breast cancers from patients who underwent ALN dissection following the diagnosis of Mac-m in the sentinel node (SN) was studied. In all the cases the MAC-m linear size was evaluated and correlated with presence or absence of non-SN ALN metastases. RESULTS: Non-SN metastases were detected in 644∖1464 cases (43.98%). The risk of further axillary metastases ranged from 20.2% (37/183) in cases with Mac-m between 2 and 2.9 mm, to 65.3% (262/401) in cases with Mac-m measuring > 10 mm. The risk of non-SN ALN metastases showed a 3% increase, parallel to each mm increment in SN metastasis size. The data evaluated with the receiver operating characteristic (ROC) curve showed that the Mac-m could be subdivided according to a new cut-off of 7 mm. pT1 tumours, with Mac-m < 7 mm had a risk of non-SN ALN metastases of <30%. Furthermore 109/127 of these (85.8%) had 3 or less non-SN ALN -metastases. CONCLUSIONS: The present data give a detailed description on the risk of non-SN ALN involvement, that may be useful in the evaluation of breast cancer patients. It is suggested that a Mac-m size of <7 mm is related to a low residual axillary disease burden in breast cancer patients with small (pT1) tumours.

High proliferative activity and chromosomal instability in oral lichen planus.

The study aimed to assess the proliferative activity and karyotype in Oral Lichen Planus (OLP) lesions. G-banding chromosomal analysis of short-term primary cultures, and immunohistochemical expression of Ki67 and p53 were applied in 30 consecutive OLP patients divided into two groups according to clinical presentation of the lesions, and in nine subjects as negative controls. Mean values of Ki67 and p53 expression differed significantly (P<.01) between controls and patients groups with reticular or atrophic-erosive forms of OLP, whereas there was no significant difference between the two groups of patients with reticular or atrophic-erosive lesions. Six OLP patients showed clonal chromosome alterations, four of them associated with p53 overexpression. In conclusion, OLP is characterized by a high cellular turnover in most patients irrespective of clinical disease presentation. The genetic instability found in some patients should be interpreted as a consequence of the enhanced epithelial turnover, although we cannot rule out the possibility that some of the cytogenetic non-random anomalies observed represent early steps in cancer development.

The impact of field cancerization on the extent of duct carcinoma in situ (DCIS) in breast tissue after conservative excision.

AIM: Aim of the present study is to evaluate the risk of residual neoplastic foci, in patients treated with breast conservative surgery, based on duct carcinoma in situ (DCIS) grading. MATERIALS AND METHODS: The study is based on a retrospective analysis of 419 resection specimens relative to 161 patients. All these patients underwent surgical re-excision when the first specimen had shown one or more margins involved by DCIS. Margins were oriented and the side of margin involved was recorded. Clonal analysis, using the mitochondrial DNA (mtDNA) technique, was obtained in selected cases. RESULTS: Residual neoplastic foci were found in 145 out of 419 (34.6%) re-excised specimens. Specifically, residual foci of DCIS grade 2 and 3 were found more frequently in the margin facing the nipple (33.3% and 51.6%, respectively). On the contrary foci of DCIS grade 1 did not show any specific distribution. Clonal mt DNA analysis evidenced that DCIS grade 3 foci present in the re-excision specimens were genetically similar to the tumor removed in the first specimen, while DCIS grade 1 foci were not clonally related each other. CONCLUSIONS: The present data further confirm that DCIS grade 3 is characterized by a circumscribed neoplastic process extending along the large ducts probably of a single mammary lobe. On the contrary DCIS grade 1 is characterized by multiple independent neoplastic foci, dispersed through several lobes indicating a field where multiple independent foci of cancer harbor.

Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100% agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Pathological spectrum in recurrences of glioblastoma multiforme.

INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant brain tumour. Despite advances in treatment its prognosis remains poor. Histological features of GBM are well known. On the contrary histological description of recurrences is still not available. The aim of this study was to describe the morphological, immunohistochemical and molecular features of recurrent GBMs. METHODS: 25 recurrent GBMs, diagnosed after 2005, were collected. All patients had undergone an adjuvant treatment regimen (temozolomide and/or radiotherapy). All cases were immunostained using anti-GFAP, Olig2 and Nogo-A antisera. MGMT and IDH1 status was reassessed. Features of the recurrences were compared with those of primary GBMs, time of recurrence and survival. RESULTS: Recurrences were divided morphologically into three groups: 1) recurrences displaying the same features of primary GBM, were highly cellular, had the fastest progression and the worst prognosis; 2) recurrences changing dramatically morphological appearance, had a slightly longer survival, 3) poorly cellular recurrences, with sparse neoplastic cells intermingled with reactive and necrotic tissue, displayed the slowest progression and longer survival. MGMT and IDH1 status remained unchanged between primary tumours and recurrences. DISCUSSION: GBM histological subtypes display different reactions to adjuvant treatments, offering a possible role in predicting different recurrence and survival time.

Myoblastomatoid (histiocytoid) carcinoma of the breast. A type of apocrine carcinoma.

Thirteen carcinomas of the breast having in common neoplastic cells with granular to foamy cytoplasm are described. These cells exhibit apocrine differentiation as demonstrated by immunocytochemical and in situ hybridization studies. These tumors can be easily misinterpreted as either fibrohistiocytic or myoblastomatoid (granular cell) tumors. Therefore, the designation of myoblastomatoid (histiocytoid) invasive carcinomas seems the most appropriate for this specific group of apocrine carcinomas.

Microglandular adenosis, apocrine adenosis, and tubular carcinoma of the breast. An immunohistochemical comparison.

Four cases of microglandular adenosis (MA), together with four cases of apocrine adenosis (AA) and 10 cases of tubular carcinoma (TC) of the breast were studied at the light and immunohistochemical level. One case of MA was studied with electron microscopy. MA is characterized by an absence of myoepithelial cells (ME), epithelial membrane antigen (EMA), and gross cystic disease fluid protein (GCDFP-15). The absence of EMA in MA makes it unique among benign glandular hyperplasias of the breast. AA contains myoepithelial cells and a distinct basal lamina. It is characterized by the presence of GCDFP-15, the specific apocrine marker, which is not present in MA. TC lacks both myoepithelial cells and a basal lamina. It is negative for GCDFP-15. Periductal and vascular elastosis are common and usually prominent, whereas they are not found in either MA and AA. Other stromal changes further distinguish the three lesions. These three distinct entities can be separated objectively and unequivocally and it is essential that this be done so as to prevent confusion.

Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin's disease, paragranuloma subtype.

This study reports six non-Hodgkin's lymphoma cases that we called histiocyte-rich B-cell lymphoma (BCL) because of the prominent reactive histiocytic infiltrate obscuring the malignant B-cell population. The involved lymph nodes are characterized by a mixed nodular and diffuse infiltrate and occasionally feature prominent sinuses. The infiltrate is composed of reactive lymphocytes and numerous histiocytes obscuring a tumor population composed of variably sized scattered cells with irregular or multilobar vesicular nuclei. Immunostaining of paraffin sections for the B-cell marker recognized by L26 helps in the identification of these neoplastic cells. The clonal nature and further evidence of the B-cell lineage of this condition is shown by immunoglobulin gene rearrangements detected in three cases. The six cases of histiocyte-rich BCL are remarkably similar clinically: all presented with stage IVB disease with splenomegaly and follow an aggressive clinical course. Except for these features, our series show striking similarities to paragranuloma lymphocyte-predominant Hodgkin's disease, including male preponderance (all patients are male), age distribution (mean age, 41 years), propensity to progress to a diffuse, large B-cell lymphoma (two cases), as well as morphology of the neoplastic B-cell population and expression of Hodgkin's cell markers (Leu-M1 positivity after neuraminidase digestion in three cases, Leu-M1 positivity without neuraminidase digestion in one case, and additional epithelial membrane antigen [EMA] positivity in two cases). Both morphologically and clinically, the present series can be differentiated from other types of infiltrate-rich BCL, such as T-cell-rich BCL. Although additional cases will have to be recognized, histiocyte-rich B-cell lymphoma most likely represents a distinct clinicopathological entity. We speculate that it develops from a subset of B cells that also gives rise to the lymphocytic-histiocytic (L/H) cell, the Hodgkin's cell variant of lymphocyte-predominant Hodgkin's disease, paragranuloma subtype.

Microcalcifications in ductal carcinoma in situ of the breast: histochemical and immunohistochemical study.

Thirty cases of ductal carcinoma in situ (DCIS) of the breast, showing histological microcalcifications, were studied to clarify their mechanism of formation. Undecalcified sections revealed three types of calcium precipitates: type I and II granular calcifications (GCs) and laminar calcifications (LCs). In type I GCs the core on which the calcium had deposited was constituted mainly by nuclear debris. Type II GCs were predominantly composed by mucosubstances. LCs were the result of calcium deposits on mucoid or proteinaceous material, arranged in concentric lamellae. LCs and type II GCs were mainly present in well and intermediately differentiated DCIS. Type I GCs were observed in only DCIS with necrosis, frequently being present in intermediately and poorly differentiated DCIS.

Squamous cell carcinoma with prominent myxoid stroma.

Three cases of a squamous cell carcinoma with a prominent myxoid stroma are reported. One case in a 70-year-old woman had presented as a lump in the breast, the other two presented as polypoid lesions of the larynx and cervix uteri in a 65-year-old man and 61-year-old woman, respectively. The carcinomatous component was immersed in abundant extracellular mucosubstances. In addition to occasional squamous pearls, it displayed immunocytochemical evidence of high-weight keratin present in the neoplastic cells and, in one case, desmosomal attachment under electron microscopy. The extracellular mucosubstances proved to be similar to those seen in connective tissue. The differential diagnosis with histologically similar lesions has been taken into consideration, and it has been suggested that this newly described entity showing abundant myxoid stroma has to be distinguished from numerous benign and malignant myxoid soft tissue tumors.