Clinicopathological Perspective Research Articles

Closing the gap between biology and classification in splenic B-cell lymphomas.

The mature splenic B-cell lymphomas are an enigmatic group of lymphoid neoplasms that have long caused significant difficulty for the practicing pathologist due to overlapping diagnostic features among entities and the decreasing availability of splenic tissue for assessment. While some entities have highly characteristic and specific clinicopathological features (e.g. hairy cell leukaemia), others are substantially more difficult to recognise (e.g. splenic diffuse red pulp lymphoma). At the same time, classification systems have been evolving, resulting in multiple changes to the boundaries among these entities and even the existence of some entities in their own right. Moreover, unbiased multi-omic interrogation (whole genome/transcriptome sequencing, methylome) of the splenic B-cell lymphomas over the past decade has given us significant insights into the underling biology of these neoplasms. We present a clinicopathological perspective on the historical, current and future state of the diagnosis and classification of splenic B-cell lymphomas integrating multi-omic data and highlighting areas of focus for the field in order to continue to strive to improve patient outcomes through accurate diagnosis.

Study of Benign Breast Diseases from a Clinicopathological Perspective and Considering Management

Study of Benign Breast Diseases from a Clinicopathological Perspective and Considering Management

DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases

Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5′) and centromeric (3′) amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5′-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5′-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5′-predominant amplification, can be reclassified out of the UPS category.

History of the Caldwell-Luc surgery

The evolution of Caldwell-Luc surgery is intricately tied to the close anatomical relationship between the maxillary sinus (Highmore cavity) and the nasal cavity (hiatus semilunaris). From a clinicopathological perspective, the discussion and treatment of this border area have become integrated. This confluence stems from recognizing that sinus inflammatory diseases may not only originate from the roots of upper teeth but can easily be infected by inflammations in the surrounding areas. Consequently, a longstanding effort has been made to address chronic and recurrent sinus inflammations caused by various inflammatory diseases through effective and radical surgical means.

T-cell-derived Hodgkin lymphoma has motility characteristics intermediate between Hodgkin and anaplastic large cell lymphoma.

Classic Hodgkin lymphoma (cHL) is usually characterized by a low tumour cell content, derived from crippled germinal centre B cells. Rare cases have been described in which the tumour cells show clonal T‐cell receptor rearrangements. From a clinicopathological perspective, it is unclear if these cases should be classified as cHL or anaplastic large T‐cell lymphoma (ALCL). Since we recently observed differences in the motility of ALCL and cHL tumour cells, here, we aimed to obtain a better understanding of T‐cell‐derived cHL by investigating their global proteomic profiles and their motility. In a proteomics analysis, when only motility‐associated proteins were regarded, T‐cell‐derived cHL cell lines showed the highest similarity to ALK− ALCL cell lines. In contrast, T‐cell‐derived cHL cell lines presented a very low overall motility, similar to that observed in conventional cHL. Whereas all ALCL cell lines, as well as T‐cell‐derived cHL, predominantly presented an amoeboid migration pattern with uropod at the rear, conventional cHL never presented with uropods. The migration of ALCL cell lines was strongly impaired upon application of different inhibitors. This effect was less pronounced in cHL cell lines and almost invisible in T‐cell‐derived cHL. In summary, our cell line‐derived data suggest that based on proteomics and migration behaviour, T‐cell‐derived cHL is a neoplasm that shares features with both cHL and ALCL and is not an ALCL with low tumour cell content. Complementary clinical studies on this lymphoma are warranted.

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

Visualization of neurofibrillary tangle maturity in Alzheimer's disease: A clinicopathologic perspective for biomarker research.

Neurofibrillary tangles, one of the neuropathologic hallmarks of Alzheimer's disease, have a dynamic lifespan of maturity that associates with progressive neuronal dysfunction and cognitive deficits. As neurofibrillary tangles mature, the biology of the neuron undergoes extensive changes that may impact biomarker recognition and therapeutic targeting. Neurofibrillary tangle maturity encompasses three levels: pretangles, mature tangles, and ghost tangles. In this review, we detail distinct and overlapping characteristics observed in the human brain regarding morphologic changes the neuron undergoes, conversion from intracellular to extracellular space, tau immunostaining patterns, and tau isoform expression changes across the lifespan of the neurofibrillary tangle. Post‐translational modifications of tau such as phosphorylation, ubiquitination, conformational events, and truncations are discussed to contextualize tau immunostaining patterns. We summarize accumulated and emerging knowledge of neurofibrillary tangle maturity, discuss the current tools used to interpret the dynamic nature in the postmortem brain, and consider implications for cognitive dysfunction and tau biomarkers.

Extracalvarial Porocarcinoma- A Rare Case Report

Eccrine Porocarcinoma (EPC) is a very rare malignant neoplasm of skin. It usually emerges from the ductal parts of sweat glands. It is seen mostly between the age group of 60 to 80 years with a female preponderance. Several cases of EPC have been reported in medical literature till date. Though, it rarely presents with distant metastasis, still evidences of metastasis to organs like lung, retroperitoneum, breast, urinary bladder and ovaries have been reported. Conventionally, it arises de novo, and may develop on sites of long standing eccrine poroma. Several unusual sites like trunk, head, face, eyelids, upper limbs, and scrotum have been reported; though lower extremities are the most common site of origin. Locoregional recurrence and metastasis have also been reported. Histopathological documentation of mitoses, lymphovascular invasion and measurement of tumour depth predicts adverse prognosis in EPC. Earlier, eccrine adenocarcinoma or malignant eccrine poroma terminology were used. As far as clinical presentation is concerned, the EPC is usually symptomless to begin with, which further ulcerates and may become aching and irritable. From a clinicopathological perspective the importance of the tumour lies in its early correct diagnosis, awareness of the close differentials, adequate surgery and most importantly clearance of surgical margins and adjuvant radiotherapy are mandatory decisions to prevent the high local recurrence. The basis of management involves wide local excision with clear margin. The following case, a 42-year-old male presented with an ulcerated mass on the scalp, which on further evaluation was diagnosed as an EPC of the scalp after histopathologic confirmation. The patient was treated with local wide excision with clear margin and was referred for radiotherapy.

Hypofractionated Radiotherapy With Volumetric Modulated Arc Therapy Decreases Postoperative Complications in Prosthetic Breast Reconstructions: A Clinicopathologic Study.

BackgroundEmerging radiation technologies are expected to provide a positive impact on the reduction in postoperative complications in patients receiving prosthetic breast reconstruction. This study aimed to determine whether hypofractionated radiation therapy(RT) with volumetric modulated arc therapy(VMAT) is superior to conventional RT in the setting of prosthetic reconstruction.MethodsFrom retrospective data collections, postoperative complications were compared for all patients with mastectomy and staged prosthetic reconstruction without RT, with hypofractionation using 40 Gy in 15 fractions with VMAT (Hypo-VMAT) or conventional RT (50 Gy over 5 weeks). After harvesting subpectoral capsules from patients with informed consents, histologic analysis including immunohistochemistry and immunofluorescence for collagen type I, α-smooth muscle actin, CD34 and CD31 expression was performed.ResultsA total of 288 reconstructions without RT, 55 reconstructions with Hypo-VMAT, and 29 reconstructions with conventional RT were examined. During average follow-up period of 34.8 months, rates of overall complications were 6.3% in the no-radiation group, 18.2% in Hypo-VMAT group and 44.8% in conventional-RT group with significant differences (no-RT vs Hypo-VMAT: p=0.006; Hypo-VMAT vs conventional-RT: p=0.012). Levels of myofibroblasts and tissue fibrosis were lower in the Hypo-VMAT group than in conventional-RT group (p=0.016 and p=0.040, respectively), while those of progenitor cells and microvessel density were higher in the Hypo-VMAT group than in conventional-RT group (p<0.001 and p<0.001, respectively).ConclusionWe demonstrated that hypofractionated RT with VMAT served to reduce radiation-related morbidities in prosthetic reconstruction from a clinicopathologic perspective, compared to conventional RT. It may offer a practical strategy to mitigate radiation-related complications in clinical settings.

Etiological classification and treatment strategies for secondary bile duct dilatation.

Secondary intra- and extrahepatic bile duct dilatation is a very common condition that can be caused by several diseases. However, it has been rarely discussed in the specialized literature. Moreover, no distinct etiology can be determined in some cases, which hampers the diagnosis and treatment. Here, we discuss the etiological classification and treatment strategies of secondary intra- and extrahepatic bile duct dilatation based on an extensive literature review, as well as our experimental research and clinical experience. The etiology of secondary intra- and extrahepatic bile duct dilatation can be classified in different ways. From a clinicopathological perspective, it can be classified into obstruction-, lesion-, and compression-induced dilatation. Treatment varies depending on the cause. For example, endoscopic dilation or stenting is used for biliary strictures, laparoscopic choledochectomy for stone removal, and resection for cholangiocarcinoma.

ROCK1 and ROCK2 Are Down-regulated in Aggressive and Advanced Skin Melanomas - A Clinicopathological Perspective.

RhoA and its downstream effectors Rho-associated coiled-coil kinases (ROCK) 1 and 2 are central controllers of cytoskeleton dynamics, and therefore influence cell shape, adhesion and migration. Since modulation of these processes holds promise for an effective anticancer strategy, effects of ROCK inhibition have been evaluated in a number of malignancies. Using immunohistochemistry, ROCK1 and ROCK2 expression was semi-quantitatively assessed in 129 patient-derived primary melanomas. There was a striking predilection for low melanocytic expression of both kinases in thick, ulcerated and mitogenic tumors, as well as in nodular histological type. ROCK1 and -2 expression in tumor-infiltrating lymphocytes (TILs) was preferentially down-regulated in advanced and aggressive tumors. Moreover, diminished ROCK2 reactivity in melanoma cells and TILs was associated with shorter melanoma-specific and recurrence-free survival. This is the first analysis of ROCK1 and -2 protein expression in clinical melanoma samples and the results indicated the suppression of ROCK signaling in melanocytes of aggressive and late-stage tumors. Functional models that more accurately represent the clinical setting are necessary to dissect the role of ROCK1 and -2 in melanoma. Additionally, our study indicates that ROCK activity in TILs may be involved in the pathogenesis of cancer, and thus merits further investigations.

Benign and malignant lesions of the breast: clinico-pathological perspective from a government teaching hospital in West Bengal, India

Background: While breast cancer is one of the most commonly diagnosed cancer more than half of the women develop some benign disease of breast in their lifetime. The current study was conducted to describe the clinico-pathological findings associated with breast diseases and study their relationship.Methods: A record-based cross-sectional study was conducted on the samples of breast tissue obtained by fine needle aspiration cytology (FNAC) examination. The clinical variables like age, sex, presenting complaint, involved side (right/left/both) etc. were taken from the clinical notes sent, and nature of the aspirate, histopathological diagnosis, nature of the diagnosed disease (benign/malignant), and axillary metastasis were taken as variables from pathological examination.Results: The mean age of the patients was 33.49 years (±13.24 years) with majority belonging to 20-40 years. Among the 184 specimens examined, 94.57% belonged to female patients. The most frequent presentation was with lump (95.11%). Complaint arising out of right breast (47.83%) were higher compared to left breast (40.76%). Involvement of the supero-lateral quadrant was seen in 75.54%. In 30.44% of the cases the material was bloody or blood-mixed. Majority of the patients (86.41%) were diagnosed with benign disease commonest being fibroadenoma. Ductal carcinoma was the commonest malignant lesion. Younger age group, absence of bloody discharge and absence of peau d’orange were associated with benign lesion in a statistically significant way (p-value &lt;0.001).Conclusions: In consonance with published literature the findings suggest association of older age group with malignant lesions. Blood-mixed aspirate, peau d’orange appear to be danger signs.

The utility of bronchoalveolar lavage in the evaluation of interstitial lung diseases: A clinicopathological perspective.

Bronchoalveolar lavage (BAL) is a noninvasive and well-tolerated procedure that is performed with a fiberoptic bronchoscope in the wedged position within a selected bronchopulmonary segment. After it was introduced to clinical practice, BAL rapidly gained acceptance in a large number of centers as a procedure that could be applied to the clinical evaluation of patients with various pulmonary disorders, especially the group of interstitial lung diseases (ILD). Cytological and flow cytometric analysis of BAL fluid in ILD is done with knowledge of the clinical presentation and radiological findings. BAL typically reveals variations in the types and numbers of nucleated immune cells and acellular components in patients with ILD, which differ from those seen in normal control subjects. Many clinicians currently use this technique as a guide in the differential diagnoses of ILD; it can also be used to monitor the course of disease and possible response to therapeutic interventions. This article summarizes current clinicopathological information concerning the use of BAL by pulmonologists and pathologists.

The Glasgow prognostic score at diagnosis is an independent predictor of survival in advanced stage classical Hodgkin lymphoma

The Glasgow prognostic score at diagnosis is an independent predictor of survival in advanced stage classical Hodgkin lymphoma

The use of acellular dermal matrix in immediate two-stage prosthetic breast reconstruction provides protection from postmastectomy radiation therapy: a clinicopathologic perspective.

Although there is ample evidence showing that radiation therapy increases the risk of complications of breast reconstruction, the efficacy of human acellular dermal matrix (CGCryoDerm®) in immediate tissue expander breast reconstruction in the setting of postmastectomy radiation therapy has not been fully elucidated. In this study, we report our institutional experience with pertinent refined surgical technique, and determine whether acellular dermal matrices have a protective effect in this increasingly prevalent clinical setting. Twenty-six patients who underwent immediate two-stage breast reconstruction in the setting of postmastectomy radiation therapy with at least 2 years of follow-up were retrieved. Fifteen patents were reconstructed with ADM, whereas 11 patients were reconstructed without ADM. The occurrence of complications was assessed according to the reconstruction type (with ADM vs without ADM). Furthermore, in patients reconstructed with ADM (n = 15), immunohistochemistry was performed to analyze the breast capsule with ADM compared with that without ADM in the same patient, according to the expression of alpha-smooth muscle actin (α-SMA). The occurrence of complications was significantly associated with the reconstruction type (with ADM vs. without ADM, p = 0.015). On the basis of the results of α-SMA staining, α-SMA+ myofibroblasts were relatively highly expressed throughout the breast capsule without ADM. On the contrary, α-SMA+ myofibroblasts present at the breast capsule adjacent to the ADM were scarce and irregularly scattered. Use of an acellular dermal matrix may be recommended to patients who are concerned about complications after immediate two-stage breast reconstruction in the setting of postmastectomy radiation therapy.

Folate receptor α is associated with poor clinicopathological perspectives in breast carcinoma

BackgroundBreast carcinoma is the commonest malignancy in females. Folate is required for the biosynthesis of nucleotide bases, amino acids, and other cellular methylation reactions in proteins and phospholipids. The high affinity folate receptor alpha (FRα) has been shown to be expressed in several kinds of human cancers. MethodsIn this descriptive-analytic study, sections from formalin-fixed paraffin-embedded tissue blocks of 50 cases of invasive ductal breast carcinoma (IDC) as well as 15 cases of non-neoplastic breast specimens were immunohistochemically stained with FRα antibody. Histopathological evaluation for various clinicopathological parameters was done and was correlated with FRα expression. ResultsPositive FRα expression was more frequently detected in IDC (64%) compared to non-neoplastic breast specimens (20%). In IDC, Positive FRα expression was significantly associated with high tumor grade (p = 0.007), large tumor size (p < 0.001), high lymph node stage (p = 0.004), presence of angiolymphatic emboli (p = 0.001), presence of perineural invasion (p = 0.001). Significant association between FRα positivity and negative hormone receptors (estrogen and progesterone) (p < 0.001) and triple negative cases (p = 0.0021). ConclusionOur work demonstrates that FRα is over expressed in IDC compared to non-neoplastic breast tissue. Folate receptor α expression was associated with poor clinicopathological perspective. This work suggests that FRα may be an independent prognostic factor and supports the possibility of using FRα-targeted therapies of breast carcinoma. However, our work requires validation on larger cohort with correlation with survival data of patients.

Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma

ObjectiveOvarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. MethodsA retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. ResultsThe estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. ConclusionsBoth substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival.

Advances in the Pathology and Molecular Biology of Sarcomas and the Impact on Treatment

Sarcomas are a complex group of childhood and adult neoplasms with differentiation towards mesenchymal tissues that can occur at almost every anatomic site. Although pathologically diverse, they frequently show similar clinical presentations and radiological findings, such that correct histopathologic diagnosis, utilising the appropriate ancillary immunohistochemical and molecular techniques, underpins their management. This article gives an overview of the pathology, coupled with recent advances in molecular biology, of a selection of soft tissue sarcomas from a clinicopathological perspective, discussing histopathological diagnosis with developments in molecular diagnosis and the incorporation of these findings into diagnostic practice and current and potential targeted treatments.

Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. © 2017 International Parkinson and Movement Disorder Society.

PIK3CA mutations in HER2-positive Breast Cancer Patients; Frequency and Clinicopathological Perspective in Egyptian Patients

Missense mutations in PIK3CA are common in breast cancers. They mostly involve exons 9 and 20 which encode kinase and helical domains of the protein and may result in its activation. PIK3CA activating mutations were previously shown to predict lower pathologic complete response (pCR) in HER2-positive breast cancer cases undergoing neoadjuvant human epidermal growth factor receptor 2-targeting therapy. Hence, the present work was conducted to estimate the mutation frequency in PIK3CA in 51 HER2-positive patients by direct sequencing. Our results showed 8 out of 51 (15.7%) to harbor PIK3CA mutations in either exon 9 or 20, or both. Three patients had mutations in both exons 9 and 20. Seven (13.7%) possess missense mutations in exon 20 which changed the amino acid sequence of the protein (H1047R, M1040I, and G1049G). Only four cases harbored mutations in exon 9, changing the codon sequences (E545K E545A, and R524K). Taking the clinicopathological data to account, the mutation frequency was greater in ductal than lobular carcinomas, in grade II rather than III and in lymph node positive lesions, with a higher HER2 score and which are ER/PR negative. However, none of the correlations proved statistically significant. In conclusion, to the best of our knowledge, the PIK3CA mutation frequency in this study is the first report regarding HER2-positive breast cancer patients in Egypt. Hereby, we highlight a moderate frequency which could be useful in the future as a predictive marker for anti-HER2 therapy.