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Perivascular epithelioid tumours (PEComas) of the gynaecological tract are rare tumours which were first recognised and diagnosed within the last 20 years. They represent a unique diagnostic challenge with regard to their accurate and reproducible distinction from more common entities such as smooth muscle tumours of the uterine corpus. In this review article, we trace the development of the concept of the PEComa tumour family, highlight what is known about extra-gynaecological tract PEComa at an immunohistochemical, molecular and therapeutic level and then present a summary of all reported cases of gynaecological tract PEComa to date. In the summary, we highlight rare subtypes of gynaecological tract PEComa and compare the performances of extant prognostic classification systems for malignancy in these tumours.

TFE3 translocation-associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion. Recent investigation has found a lack of TSC gene mutation in these tumors compared with their nonrearranged counterparts, which underscores the importance of recognizing the translocated variant because of hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified, and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Patient age ranged from 46 to 66 years (median 50 y), and none had a history of a tuberous sclerosis complex. Three cases arose in the uterine corpus, 1 in the vagina, 1 pelvic tumor, and 1 pulmonary tumor that was likely a recurrence/metastasis from a probable uterine primary. Five cases had clear cell epithelioid morphology that showed a spectrum of atypia, while 1 case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, cathepsinK labeling, either focal or no melanA staining, and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar expression pattern in its epithelioid component but strong muscle marker positivity in its spindle cell component. Follow-up ranged from 1 to 57 months. Three cases demonstrated aggressive behavior, and 3 cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model.

Summary Large cell transformation of mycosis fungoides (MF-LCT) occurs in 20–50% of advanced MF, and is generally associated with poor prognosis, although some patients have indolent disease. We sought to identify clinicopathological prognostic factors in a large number of patients with MF-LCT. We identified patients with MF-LCT treated between 1991 and 2012 at a referral centre for cutaneous lymphoma. Clinical and pathological records, and histopathological slides were reviewed. Associations of clinicopathological variables with disease-specific survival were analysed. In 51 patients with MF-LCT, factors significantly associated with shorter survival were: age >60 years (25 versus 61 months, p = 0.01), stage lll/IV (25 versus 44 months, p = 0.049), high serum lactate dehydrogenase (LDH; 24 versus 53 months, p = 0.007), absent papillary dermal involvement (8 versus 30 months, p = 0.008); follicular mucin at transformation (24 versus 42 months, p = 0.007); and the absence of fibrosis at transformation (21 versus 42 months, p = 0.03). Patients presenting with transformation at diagnosis had better survival than those who started with a small cell phenotype ( p = 0.02). Age >60 years was independently associated with poorer survival (HR 5.61, 95%CI 1.17-26.8, p = 0.03), and the presence of fibrosis at transformation was independently associated with improved survival (HR 0.30, 95%CI 0.09–0.97, p = 0.045). In patients with MF-LCT, clinical features (age, stage, serum LDH) are important in assessing prognosis. Additional clinical and pathological features identified in this study may also assist in prognostic stratification. Studies of larger cohorts should be performed to validate the prognostic significance of these features.

Background: Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy. Methods: We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study. Results: Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival (n = 160; HR, 0.56; P = 0.03) and 5-year overall survival (HR, 0.53; P = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology. Conclusions: The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer. Impact: TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. Cancer Epidemiol Biomarkers Prev; 27(6); 680–8. ©2018 AACR.

A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes., Although the locus at 3p13-14 is commonly deleted in prostate cancer, the identity of the potential driver genes is still unclear. Here, the authors, using a PTEN loss-driven prostate cancer mouse model, show that a multigenic FOXP1-SHQ1 deletion is a driver event with prognostic value.

MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss.

Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.

Context.—Patients with pneumothorax occasionally require limited lung resections to control persistent air leaks. In some patients, especially smokers, histopathologic findings suggest that a ruptured bulla or bleb caused the pneumothorax. Other patients only exhibit histopathologic changes related to the physical trauma of acute, and likely occult recurrent, peripheral lung injury in the setting of “spontaneous,” or idiopathic, lung rupture. Sometimes, pneumothorax occurs secondary to an underlying localized or diffuse parenchymal lung disease. A comprehensive description of the morphologic findings that may be seen in these specimens will help the surgical pathologist distinguish patients with more common and indolent occurrences of pneumothorax from those requiring additional workup or treatment.Objective.—To develop a diagnostic approach for surgical pathologists encountering lung specimens obtained in the context of pneumothorax repair.Data Sources.—Literature review and consultation experience of the authors.Conclusions.—Two general categories of histopathologic changes can be identified: (1) nonspecific changes, reflecting the lung's acute and chronic response to localized injury, and (2) changes suggesting an underlying lung disease that may have played an etiologic role in the development of pneumothorax. The latter changes are important to recognize because they may require additional workup or treatment of clinically occult lung disease. Difficulty arises when nonspecific histopathologic changes overlap with those of an underlying lung disease. Awareness of these diagnostic challenges and pitfalls, together with clinicoradiographic correlation, is essential in these situations and will help guide the surgical pathologist toward an accurate diagnosis and the appropriate management of clinically occult disease.

Melanoma brain metastasis (MBM) represents a frequent complication of cutaneous melanoma. Despite aggressive multi-modality therapy, patients with MBM often have a survival rate of

Background:Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations.Methods:The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas.Results:Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma.Conclusion:Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas. © 2013 Cancer Research UK. All rights reserved.

Background: When completion lymph node dissection (CLND) is performed in sentinel node (SN)-positive melanoma patients, a positive non-sentinel node (NSN) is found in approximately 20% of them. Recently, Murali et al. proposed a new scoring system (non-sentinel node risk score, N-SNORE) to predict the risk of NSN positivity in SN-positive patients. The objectives of the current study were to identify factors predicting NSN positivity and to assess the validity of the N-SNORE in an independent patient cohort.Methods: All SN-positive patients who underwent CLND at a single institution between 1995 and 2010 were analyzed. Characteristics of the patient, primary melanoma, and SN(s) were tested for association with NSN positivity. Missing values were reconstructed using multiple imputation to enable multivariable analysis.Results: CLND revealed positive NSNs in 30 (23%) of 130 SN-positive patients Primary melanoma regression (p = 0.03) was independently associated with NSN positivity. After adjustment because of missing data on perinodal lymphatic invasion, N-SNORE proved to be a significant stratification model in our patient cohort (p = 0.003): 5.9% NSN positivity in the very low risk category and 75.0% NSN positivity in the very high risk category.Conclusions: Presence of regression in the primary melanoma was independently associated with a higher risk of NSN positivity. The slightly modified N-SNORE scoring system provided useful stratification of the risk for NSN positivity. However, lack of perinodal lymphatic invasion data may have reduced its predictive value. (C) 2012 Elsevier Ltd. All rights reserved.

Summary Uveal melanoma is the most common malignant tumour of the adult eye. Around half of all uveal melanoma patients will eventually die of their disease. There are a number of effective options to treat the primary tumour locally, but once the tumour has metastasised, there are no curative therapies. Traditionally, the diagnosis of uveal melanoma and prognostic prediction was based solely on the clinical presentation and detailed histopathological evaluation. Recent genetic findings have shed light on the biology of these tumours, and led to the development of genetic tests that can help assess their malignant potential and prognosis. The genes, proteins and pathways that have been (and continue to be) discovered will likely result in novel targeted therapeutic approaches with high efficacy and low toxicity. In this review, we summarise the clinical, pathological and genetic features of uveal melanoma, with emphasis on recent discoveries.

Background Endometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers. Methods Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas (TCGA) were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry. Results We observed that the clinical behaviour of endometrial cancers as a group was associated with hormone receptor signalling, PI3K pathway signalling and DNA mismatch repair processes. When analysed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behaviour of serous cancers was likely governed by apoptosis and Wnt signalling. Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level. Conclusion Endometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group.

Growing evidence has established two major types of vulvar intraepithelial neoplasia (VIN), which correspond to two distinct oncogenic pathways to vulvar squamous cell carcinoma (VSCC). While the incidence of VSCC has remained relatively stable over the last three decades, the incidence of VIN has increased. VIN of usual type (uVIN) is human papillomavirus (HPV)-driven, affects younger women and is a multicentric disease. In contrast, VIN of differentiated type (dVIN) occurs in post-menopausal women and develops independent of HPV infection. dVIN often arises in a background of lichen sclerosus and chronic inflammatory dermatoses. Although isolated dVIN is significantly less common than uVIN, dVIN bears a greater risk for malignant transformation to VSCC and progresses over a shorter time interval. On histological examination, uVIN displays conspicuous architectural and cytological abnormalities, while the morphological features that characterise dVIN are much more subtle and raise a wide differential diagnosis. On the molecular level, dVIN is characterised by a higher number of somatic mutations, particularly in TP53. Here we review the classification, epidemiology, clinical features, histomorphology, ancillary markers and molecular genetics of both types of VIN, and discuss the morphological challenges faced by pathologists in interpreting these lesions.

Melanocytic tumors originating in the central nervous system (MT-CNS) are rare tumors that generally have a favorable prognosis, however malignant tumors do occur. Pathogenetically MT-CNS are not well characterized. Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations. Rare NRAS mutations have also been reported. Other mutations have not yet been described. We analyzed 19 MT-CNS, 7 uveal melanomas and 19 cutaneous melanomas using a targeted next generation sequencing approach analyzing 29 genes known to be frequently mutated in other melanocytic tumors (in particular uveal and cutaneous melanomas). In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g. NF1, RAC1, PIK3CA, ARID1A). Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1. In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %). Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred. One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3. Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas. Considering chromosome 3 and BAP1 loss are robust markers of poor prognosis in uveal melanoma, it will prove interesting to determine whether these genomic alterations are also of prognostic significance in MT-CNS.

Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.

Purpose To determine whether density and distribution of tumor-infiltrating lymphocytes (TILs; TIL grade) is an independent predictor of sentinel lymph node (SLN) status and survival in patients with clinically localized primary cutaneous melanoma. Methods From the Melanoma Institute Australia database, 1,865 patients with a single primary melanoma ≥ 0.75 mm in thickness were identified. The associations of clinical and pathologic factors with SLN status, recurrence-free survival (RFS), and melanoma-specific survival (MSS) were analyzed. Results The majority of patients had either no (TIL grade 0; 35.4%) or few (TIL grade 1; 45.1%) TILs, with a minority showing moderate (TIL grade 2; 16.3%) or marked (TIL grade 3; 3.2%) TILs. Tumor thickness, mitotic rate, and Clark level were inversely correlated with TIL grade (each P < .001). SLN biopsy was performed in 1,138 patients (61.0%) and was positive in 252 (22.1%). There was a significant inverse association between SLN status and TIL grade (SLN positivity rates for each TIL grade: 0, 27.8%; 1, 20.1%; 2, 18.3%; 3, 5.6%; P < .001). Predictors of SLN positivity were decreasing age (P < .001), decreasing TIL grade (P < .001), ulceration (P = .003), increasing tumor thickness (P = .01), satellitosis (P = .03), and increasing mitoses (P = .03). The 5-year MSS and RFS rates were 83% and 76%, respectively (median follow-up, 43 months). Tumor thickness (P < .001), ulceration (P < .001), satellitosis (P < .001), mitotic rate (P = .003), TIL grade (P < .001), and sex (P = .01) were independent predictors of MSS. Patients with TIL grade 3 tumors had 100% survival. Conclusion TIL grade is an independent predictor of survival and SLN status in patients with melanoma. Patients with a pronounced TIL infiltrate have an excellent prognosis.

Shayan R, Karnezis T, Murali R, Wilmott J S, Ashton M W, Taylor G I, Thompson J F, Hersey P, Achen M G, Scolyer R A & Stacker S A (2012) Histopathology 61, 702–710 Lymphatic vessel density in primary melanomas predicts sentinel lymph node status and risk of metastasis Aims: Important prognostic factors in patients with cutaneous melanoma include primary tumour thickness/depth of invasion, ulceration and mitotic rate, and the presence of tumour cells in regional lymph nodes. More recently, features of stromal components, such as blood and lymphatic vessel density, have been suggested as additional indicators of metastatic potential. Our aim was to investigate the relationship between tumour lymphatic vessels and lymph node metastasis. Methods and results: Metastasizing (n = 11) and non-metastasizing (n = 11) primary melanoma samples matched for depth/thickness, mitotic rate and ulceration were examined for lymphatic vessel density (LVD) in the primary tumour, using an antibody to podoplanin. Significant differences were found between LVD (vessels/unit area) in the peripheral (5.73 ± 0.67) versus central (1.72 ± 0.42) regions of the metastasizing tumour group (P

We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinct clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called "atypical Spitz tumors" (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biological behavior cannot be reliably predicted. In view of the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations and for BAP1 expression. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which 8 (89%) had concomitant BRAF mutations. Only 1 of the BAP1-positive ASTs (4%) had a BRAF mutation (P

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

Background Debate on how to manage pediatric cutaneous melanoma patients continues; particularly in those with sentinel lymph node(SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between pediatric and adult patients suggests that melanoma in pediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences.

Some authors have suggested that patients with very small (0.1 mm) deposits of metastatic melanoma in sentinel lymph nodes (SLNs) should be considered SLN-negative, whereas others have reported that such patients can have adverse long-term outcomes. The aims of the present study were to determine whether extensive sectioning of SLNs resulted in more accurate categorization of histologic features of tumor deposits and to assess prognostic associations of histologic parameters obtained using more intensive sectioning protocols.From patients with a single primary cutaneous melanoma who underwent SLN biopsy between 1991 and 2008, those in which the maximum size of the largest tumor deposit (MaxSize) in SLNs was0.1 mm in the original sections were identified. Five batches of additional sections were cut from the SLN tissue blocks at intervals of 250 μm. The 1st batch was cut from the blocks without any trimming; these sections were therefore immediately adjacent to the original sections. Each batch included 5 sequential sections, the 1st and 5th stained with hematoxylin-eosin, and the 2nd, 3rd, and 4th stained immunohistochemically with S-100, HMB-45, and Melan-A, respectively. In each batch of sections, the following histologic features of tumor deposit(s) in the SLNs were evaluated: MaxSize; tumor penetrative depth (TPD) (defined as the maximum depth of tumor deposit(s) from the inner margin of the lymph node capsule), and intranodal location (classified as subcapsular if the tumor deposit(s) were confined to the subcapsular zone or parenchymal if there was any involvement of the nodal parenchyma beyond the subcapsular zone). The measured histologic parameters were compared in each batch of sections. The association of histologic parameters with overall survival was assessed for the parameters measured in each batch of sections.There were 20 eligible patients (15 females, 5 males, median age 60 years). After a median follow-up duration of 40 months, 4 patients had died from melanoma and 2 patients of unknown causes. Completion lymph node dissection (CLND) was performed in 13 cases (65%) and was negative in all cases. Relative to the measured values on the original sections, all 3 parameters were upstaged in subsequent batches of sections, but no further upstaging of MaxSize, TPD, or location was seen beyond batch 3, batch 4, and batch 2, respectively. Increasing MaxSize was associated with significantly poorer overall survival in batches 1, 2, and 3. Parenchymal involvement was significantly associated with poorer survival in batches 2-5. TPD was not significantly associated with overall survival.The results of this study indicate that very small (0.1 mm) deposits of melanoma in SLNs may be associated with adverse clinical outcomes and that this is due, at least in part, to the underestimation of SLN tumor burden in the initial sections. Our evidence does not support clinical decision-making on the assumption that patients with very small melanoma deposits in SLNs have the same outcome as those who are SLN-negative.

Background Extranodal spread (ENS) is an established adverse prognostic factor in metastatic cutaneous squamous cell carcinoma (cSCC); however, the clinical significance of soft tissue metastases (STM) is unknown. The aim of this study was to evaluate the prognosis of patients with STM from head and neck cSCC, and to compare this with that of node metastases with and without ENS. Methods Patients with cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007 were included. Metastatic nodes >3 cm in size were an exclusion criterion. A Cox proportional hazard model was used to determine the effect of STM adjusting for other relevant prognostic factors. Results The population included 164 patients with a median follow-up of 26 months. There were 8 distant and 37 regional recurrences. There were 22 were cancer-specific deaths, and 29 patients died. STM was a significant predictor of reduced overall (hazard ratio 3.3; 95% confidence interval 1.6–6.4; P = 0.001) and disease-free survival (hazard ratio 2.4; 95% confidence interval 1.4–4.1; P = 0.001) when compared to patients with node disease with or without ENS. After adjusting for covariates, STM and number of involved nodes were significant independent predictors of overall and disease-free survival. Conclusions In metastatic cSCC of the head and neck, the presence of STM is an independent predictor of reduced survival and is associated with a greater adverse effect than ENS alone.

To determine cytologic features of epithelioid hemangioendothelioma (EHE) that would enable accurate diagnosis, we evaluated fine-needle aspiration biopsy (FNAB) smears from 11 histologically confirmed EHEs. The variably cellular smears comprised dispersed single cells and occasional cell aggregates. Dense stromal fragments were present in association with some tissue fragments. The cells were epithelioid, containing moderate or large amounts of dense cytoplasm. Nuclei exhibited mild pleomorphism, and nuclear grooves were identified in all cases. At least occasional intranuclear pseudoinclusions (INPIs) and intracytoplasmic lumina (ICLs) were present in all cases and in 9 cases (82%), respectively, and rare erythrocytes were seen within ICLs in 5 cases (45%). Mitotic figures were identified in 4 cases (36%). The background was bloody in 6 cases (55%) and contained hemosiderin and/or hemosiderin-laden macrophages in 5 cases (45%). The combination of the following features in FNAB samples should raise strong suspicion for EHE: predominantly dispersed single cells with occasional cohesive cell clusters; epithelioid cytomorphology; dense cytoplasm with well-defined cytoplasmic borders; ICLs (with or without erythrocytes), INPIs, and nuclear grooves. The presence of these features should prompt correlation with clinical, radiologic, and histologic features and immunohistochemical evaluation using vascular markers.

0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large, international, multicenter, case–control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas. Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared. A total of 473 pairs comprising a subsequent and a first melanoma and 1,989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared with first melanomas, subsequent melanomas were more commonly contiguous with a dysplastic nevus, more prevalent on the head/neck and legs than other sites, and thinner. Compared with single primary melanomas, subsequent melanomas were more likely to be associated with a contiguous dysplastic nevus, more prevalent on the head/neck and legs, and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses. Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.

Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Studies which have found that histologic features of metastatic melanoma in sentinel lymph nodes (SNs) were predictive of survival have differed considerably in their design and results. We investigated in detail the influence of SN tumor characteristics and clinical and primary tumor parameters on clinical outcomes in a large cohort of patients treated in a single center.In SN-positive melanoma patients, the association of clinical, primary tumor, and SN tumor features [maximum size (MaxSize), % cross-sectional area of SN occupied by tumor (%CS), tumor-penetrative depth (TPD), intranodal location of tumor, extranodal spread (ENS), and perinodal lymphatic invasion (PLI)] with disease-free (DFS), distant metastasis-free (DMFS), and melanoma-specific (MSS) survival was analyzed.In 409 SN-positive patients, independent predictors of poorer DFS were primary tumor features [anatomic site: head/neck (HR = 3.65, 95% CI 1.65-8.08) and limbs (HR = 2.46, 95% CI 1.21-4.98) compared with trunk; ulceration (HR = 1.70, 95% CI 1.15-2.51); satellites (HR = 2.85, 95% CI 1.49-5.44)], SN tumor features [MaxSize (HR = 1.53, 95% CI 1.04-2.26); ENS in SN (HR = 2.05, 95% CI 1.06-4.00); PLI (HR = 1.85, 95% CI 1.11-3.07)], and positive CLND (HR = 1.92, 95% CI 1.26-2.91). Factors independently predictive of poorer MSS were age ≥50 years (HR 1.64, 95% CI 1.01-2.67), primary tumor features [ulceration (HR = 2.55, 95% CI 1.44-4.52); satellites (HR = 3.95, 95% CI 1.83-8.49)], and ENS in SN (HR = 2.34, 95% CI 1.06-5.13).The use of clinical, primary tumor, and SN tumor characteristics shown to be independent predictors of clinical outcomes in melanoma patients will assist in accurate prediction of prognosis and optimize clinical management.

Melanoma arising in the uveal tract (choroid, ciliary body and iris) is the most common intraocular malignant tumor [1]. The incidence of uveal melanoma (UM) in the US population is approximately f...

Murali R, Zannino D, Synnott M, McCarthy S W, Thompson J F & Scolyer R A (2011) Histopathology 58, 886–895 Clinical and pathological features of metastases of primary cutaneous desmoplastic melanoma Aims: Primary cutaneous desmoplastic melanoma (DM) may be entirely desmoplastic [‘pure’ DM (pDM)] or exhibit a desmoplastic component admixed with a non-desmoplastic component [‘combined’ DM (cDM)]. Our aim was to describe the histological features of metastases of primary DM and to determine whether they were predictive of outcome. Methods: The effect of clinicopathological parameters on overall survival (OS) was analysed, and the correlation between histological features of the primary melanoma and metastases was studied in patients with metastatic DM. Results: Twenty-six patients (18 males; eight females) developed 50 metastases in sentinel nodes (13; 26.0%), regional nodes (10; 20.0%), skin (14; 28.0%), and distant sites (13; 26.0%). The cellular composition of metastases correlated with that of the corresponding primary tumours. Time to development of first non-sentinel lymph node metastasis was shorter in cDM than in pDM (median 11.2 versus 24.9 months, P = 0.075). The only independent predictors of poorer OS were cDM type [hazard ratio 6.17, 95% confidence interval (CI) 1.61–23.81, P = 0.008] and male sex (hazard ratio 5.98, 95% CI 1.34–26.66, P = 0.019). Conclusions: The cellular composition of primary DM correlates with that of metastatic DM and with outcome. It is important to consider the possibility of primary or metastatic DM when examining tumours composed of spindle cells.

BACKGROUND: A study was undertaken to determine whether bone invasion is an independent prognostic factor in oral squamous cell carcinoma (SCC) after taking into account the extent of bone invasion. METHODS: The study was a retrospective review of 498 patients with oral SCC undergoing surgery with curative intent, 102 of whom had pathologically proven bone invasion. Bone invasion was categorized as absent, cortical, or medullary and tested for association with disease control and survival. RESULTS: After adjusting for potential confounding factors in multivariate analysis, there was no association between cortical invasion and overall (P = .48) or disease-specific survival (P = .63). In contrast, medullary invasion was an independent predictor of reduced overall (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1; P = .006) and disease-specific survival (HR, 2.1; 95% CI, 1.2-3.6; P = .01), and this appeared to result from an increased risk of distant metastatic failure (P = .037) rather than local (P = .51) or regional recurrence (P = .14). Within the subset of patients with medullary invasion, survival differed significantly according to tumor size (P = .029). CONCLUSIONS: Patients with oral SCC and bone invasion have widely variable outcomes depending on the depth of bone invasion and tumor size. The results suggest that the current American Joint Committee on Cancer staging system, which classifies all tumors invading through cortical bone as T4, has limited prognostic utility. The authors recommend a revision of the T staging system such that tumors are classified as T1 to T3 based on size and then upstaged by 1 T stage in the presence of medullary bone invasion. Cancer 2011. © 2011 American Cancer Society.

Aim: To study the outcome of biopsy-diagnosed cervical intraepithelial neoplasia (CIN) 2 in patients treated by loop electrosurgical excision procedure (LEEP) or cold knife cone biopsy (CKC). Material and Methods: Patients (n = 131) were analyzed for histological results on LEEP/CKC specimen. Demographic and risk factors, referral cytology, high risk human papilloma virus (HR HPV) test and follow-up colposcopic clinic visits were studied. Results: Excisional specimens from LEEP/CKC demonstrated no CIN in 20 (15%), CIN 1 in 17 (13%), CIN 2 in 57 (44%) and CIN 3 in 37 (28%). No invasive cancers were identified. The referral Pap smear was high grade or possible high grade in 52 (40%), low grade in 59 (45%) and inconclusive in 20 (15%). Fourteen patients (11%) had positive excisional margins, eight of the 14 were tested for HR HPV infection before LEEP, and all were positive. Post-treatment HPV testing was performed at the 12-month visit in 6 of the 14 patients who had positive excision margins, and all 6 tested were negative. Two women (1.5%) with clear margins had recurrence of CIN 2, both tested positive for HR HPV after treatment. Conclusion: Our data showed that a significant number of women (28%) with biopsy-diagnosed CIN 2 had CIN 1 or no dysplasia on subsequent excisional biopsy. The recurrence risk of high grade dysplasia in CIN 2 is low (1.5%). However, due to the high number of patients (72%) with high grade dysplasia at treatment biopsy, caution needs to be exercised when a conservative approach is adopted in the management of CIN 2.

A wide variety of local, regional, and systemic diseases may have pleural manifestations. The scope of this pathology encompasses a wide spectrum ranging from minimal inflammatory changes to highly malignant neoplasms. An overview of the normal structure of the pleura is provided, along with the diseases that may be encountered. Pleural specimens from patients with pneumothorax are rarely encountered by pathologists. In contrast, pathologists frequently receive pleural specimens showing evidence of inflammation, repair, or neoplasm. In these circumstances, an awareness of less common (and often clinically highly important) conditions such as epithelioid hemangioendothelioma and primary pleural malignant mesothelioma is essential. Knowledge of the clinical setting (e.g., disease tempo) and radiological picture (e.g., laterality) is often of great value to the pathologist in arriving at a correct diagnosis. Similarly, knowledge of the normal anatomical considerations and familiarity with the expected pleural histopathology for the most clinically relevant pleural diseases are critical assets for pulmonary physicians in providing optimal care for their patients.

Purpose Sentinel node (SN) biopsy allows identification of patients with melanoma at risk of further metastatic disease in regional non-sentinel nodes (NSN). We investigated clinicopathologic factors that predict NSN positivity in an attempt to identify patients who may be safely spared completion lymph node dissection (CLND). Patients and Methods Clinicopathologic factors previously shown to be predictive of NSN positivity were analyzed in 409 patients with SN-positive disease (309 of whom underwent CLND) managed at a single melanoma center. A weighted score Non-Sentinel Node Risk Score [N-SNORE] incorporating predictive factors was derived, and the efficacy of N-SNORE at stratifying risk of NSN involvement was studied. Results Factors independently predictive of NSN positivity included primary tumor regression, proportion of harvested SNs involved by melanoma (%PosSN), sex (trend), and SN tumor burden indices (maximum size of largest deposit [MaxSize], % cross-sectional area of SN occupied by tumor, tumor penetrative depth, intranodal location of tumor) and perinodal lymphatic invasion (PLI). Of SN tumor burden criteria, MaxSize was the strongest predictor. N-SNORE was the sum of scores for five parameters: sex (female = 0, male = 1), regression (absent = 0, present = 2), %PosSN (absent = 0, present = 2), MaxSize (≤ 0.5 mm = 0, 0.51 to 2.00 mm = 1, 2.01 to 10.00 mm = 2, > 10.00 mm = 3), and PLI (absent = 0, present = 3). N-SNOREs of 0, 1 to 3, 4 to 5, 6 to 7, and ≥ 8 were associated with very low (0%), low (5% to 10%), intermediate (15% to 20%), high (40% to 50%), and very high (70% to 80%) risks of NSN involvement. Conclusion A weighted score (N-SNORE) based on clinicopathologic characteristics accurately stratifies risk of NSN involvement in patients with melanoma. If validated in future studies, N-SNORE will better predict prognosis, aid in management decisions, and stratify patient groups for entry into clinical trials.

Atypical fibroxanthoma (AFX) is an uncommon cutaneous neoplasm that usually presents as a rapidly-growing nodule in sun-exposed sites in elderly patients. Despite its highly atypical histological appearance it is almost always associated with innocuous clinical behaviour. AFX is now generally regarded as the superficial counterpart of undifferentiated pleomorphic sarcoma (so-called malignant fibrous histiocytoma [MFH]). The former lesion is associated with an excellent prognosis in view of its small size, superficial location, and amenability to complete excision. Because a distinction between AFX and MFH requires assessment of the depth of invasion, a definitive diagnosis of AFX cannot be made on the basis of shallow biopsies. Other cutaneous tumours, including sarcomatoid squamous cell carcinoma (SCC) and spindle-cell melanoma, may have a histologic appearance that is indistinguishable from AFX on haematoxylin–eosin stained slides; immunochemical stains are therefore mandatory in the pathologic evaluation of such cases. There are no currently-known specific immunohistochemical markers (including CD10) which are diagnostic of AFX, and it remains a diagnosis of exclusion. Recent studies have highlighted the importance of other markers, such as high molecular-weight keratins (e.g., CK5/6, 34BE12, and MNF116) and p63 in the diagnosis of sarcomatoid squamous cell carcinoma; that tumour may fail to label for other keratin proteins. Recently, uncommon variants of AFX have been described that broaden its histological differential diagnosis.

Sir,Papillary tumours of the central nervous system are very uncommon. Even rarer are reports of tumours with papillary features occurring in the pineal region, which include choroid plexus tumours...

BACKGROUND: Desmoplastic melanoma (DM) is a rare subtype of melanoma that is characterized by malignant spindle cells separated by prominent, fibrocollagenous stroma. Primary melanomas either may be entirely desmoplastic or almost entirely desmoplastic (pure DM [pDM]) or may exhibit a desmoplastic component admixed with a nondesmoplastic component (combined DM [cDM]). METHODS: Patients who were diagnosed between 1993 and 2007 at a single institution with clinically localized, primary cutaneous melanoma (PCM) that contained a desmoplastic component and who underwent sentinel lymph node (SLN) biopsy were identified. Clinical and pathologic features of the primary tumors were correlated with DM type, SLN status, and patient outcome. RESULTS: Two hundred fifty-two patients (167 men, 85 women) were identified (median age, 61 years). The median tumor thickness was 2.0 mm. One hundred twenty-three patients (48.8%) had pDM, and 129 patients (51.2%) had cDM. Overall, 17 patients (6.7%) had positive SLN status, including 12 patients with cDM and 5 patients with pDM. Because of the low SLN-positive rate, a statistically significant difference in SLN status between patients with cDM (8.5%) and patients with pDM (4.9%; P = .25) could not be demonstrated. Older patient age, being a man, positive SLN status, and increasing tumor thickness were associated significantly with poorer disease-free survival (P < .05), although only the latter 2 variables were independently predictive. In addition, cDM type (P = .017) was associated significantly and independently with a shorter time to recurrence. CONCLUSIONS: In this largest study to date of patients with DM who underwent SLN biopsy, the SLN-positive rate in patients with DM was lower than that in patients with conventional melanoma. The results indicated that DM type is associated significantly and independently with the time to recurrence and should be evaluated routinely in all patients with PCM. Cancer 2010. © 2010 American Cancer Society.

Summary Aims Transitional cell metaplasia (TCM) of the cervix and vaginal vault is rarely reported. We sought to describe the clinical and cytological features and cytological differential diagnosis of TCM. Methods Cervical and vaginal vault smears reported as TCM or smears from patients with histologically confirmed TCM were examined for the following features: cellularity, architecture, background cell population, cell group thickness, cell shape, nuclear features (shape, chromatin, nucleoli, outline), perinuclear haloes, the presence in cell groups of a surface layer of cuboidal cells, and associated pathology. The cases of TCM were compared with smears of conventional atrophy and high grade squamous intraepithelial lesion (HSIL). Results Six cases (five cervical, one vaginal vault) of TCM were identified from six patients (age range 34–80 years, median 60 years). The smears showed three-dimensional cell groups (2–5 cells in thickness) composed of oval-shaped cells with small amounts of cytoplasm and spindle/ovalshaped nuclei, with the impression of ‘streaming’ in some groups. The nuclei showed mild membrane irregularities, evenly distributed chromatin, and small nucleoli. Nuclear grooves were identified in at least occasional cells in four cases. A surface layer of cuboidal cells was identified in two cases. The background contained dysplastic squamous cells in three cases. Atrophic changes were present and in one case some cell groups exhibited transition from TCM at one end to more conventional atrophic parabasal cells at the other. Conclusions Awareness of the cytological features of TCM is critical to avoid a false-positive diagnosis of HSIL, and the consequent ramifications for patients. TCM should always be considered in the differential diagnosis of multilayered cell groups in cervicovaginal smears, particularly in peri- and post-menopausal women and in atrophic conditions.

The serum level of lactate dehydrogenase (LDH) is an important predictor of prognosis and treatment response in melanoma patients. It is unknown whether the expression of LDH-5 in tissue sections also has prognostic significance and whether it is related to the expression of the anti-apoptotic proteins, Bcl-2, Bcl-XL and Mcl-1, and endoplasmic reticulum stress protein glucose-regulated protein 78 (GRP78). Identification of an association between LDH-5 expression and anti-apoptotic proteins may have important therapeutic implications for melanoma patients. Sections from 159 pigmented lesions, including nevi and melanoma at different stages of progression were studied by immunohistochemistry. Correlation of LDH-5 expression with clinicopathological factors and with the expression of Bcl-2, Bcl-XL, Mcl-1 and GRP78 was examined. LDH-5 was detected at low levels in 6 of 10 compound nevi (60%) and 6 of 10 dysplastic nevi (60%). The percentage of positive cases was greater in thin (or=1.0 mm) (74%) and thick primary melanoma (1.0 mm) (95%) and in metastatic melanoma in the skin (100%) and lymph node (81%). The immunoreactive score was highly related to progression of melanoma (P0.0001). LDH-5 expression was positively associated with increasing tumor thickness (P=0.02) and dermal tumor mitotic rate (P=0.02). LDH-5 above the median immunoreactive score was associated with reduced disease-free survival and overall survival (P0.02). LDH-5 expression was negatively associated with Bcl-2 expression. In contrast, LDH-5 expression was strongly associated with Bcl-XL and Mcl-1 expression and also positively associated with GRP78 expression (P0.0001). The low Bcl-2 expression in melanomas with high LDH-5 expression provides an explanation for the poor response of patients with high serum LDH levels to treatment with the Bcl-2 antisense drug 'Genasense'. The strong correlation of LDH-5 expression with Mcl-1 expression suggests that treatment strategies inhibiting the activity of Mcl-1 in melanoma patients should be investigated.

BACKGROUND: Histologic parameters of melanoma deposits in sentinel lymph nodes (SLNs) have been shown to be predictive of clinical outcome and the presence or absence of tumor in non-SLNs, but assessment of these parameters is prone to interobserver variation. METHODS: Histologic sections of 44 SLNs containing metastatic melanoma were examined by 7 pathologists. Parameters assessed included cross-sectional area of tumor deposits, cross-sectional area of SLNs, percentage of SLN area involved by tumor calculated from the 2 previous parameters, estimated percentage of SLN area involved by tumor, tumor penetrative depth, location of tumor within the SLN, and presence of extracapsular spread. Levels of interobserver agreement were measured by using intraclass correlation coefficients (ICC). RESULTS: There was good to excellent interobserver agreement on measurement of quantitative parameters: maximal size of largest tumor deposits, calculated area of 3 largest tumor deposits, percentage of the area of SLN involved by tumor, and tumor penetrative depth (ICC, 0.88, 0.73, 0.68, and 0.83, respectively). There was moderate agreement on the evaluation of subcapsular versus nonsubcapsular location of tumor deposits (ICC = 0.50). Agreement on assessment of extracapsular spread was fair (ICC = 0.39). CONCLUSIONS: Assessment of some of the quantitative parameters was highly reproducible between pathologists. However, evaluation of the location of tumor deposits within SLNs and assessment of extracapsular spread was less reproducible. Clearer definitions and training can be expected to improve the reproducibility of assessment. These results have important implications for reliability and reproducibility of these parameters in staging, prediction of outcome, and clinical management of melanoma patients. Cancer 2009. © 2009 American Cancer Society.