Histological Grading Criteria Research Articles

Proposing Clinicopathological Staging and Mitotic Count as Prognostic Factors for Canine Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are a heterogeneous group of malignant mesenchymal tumors with similar histological features and biological behaviors. They are characterized by a low to moderate local recurrence rate and low metastasis, affecting approximately 20% of patients. Although this tumor set is vital in veterinary medicine, no previous unified staging system or mitotic count has been associated with patient prognosis. Therefore, this study proposed a new clinicopathological staging method and evaluated a cut-off value for mitosis related to the survival of dogs affected by STS. This study included 105 dogs affected by STS, treated only with surgery, and a complete follow-up evaluation. The new clinicopathological staging system evaluated tumor size (T), nodal involvement (N), distant metastasis (M), and histological grading criteria (G) to categorize the tumor stage into four groups (stages I, II, III, and IV). The proposed tumor staging system was able to differentiate patients' prognoses, with dogs with stage IV disease experiencing the lowest survival time and dogs with stage I disease having the highest survival time (p < 0.001). Moreover, we assessed the median mitosis (based on mitotic count) and its association with overall survival. Our study's median mitosis was 5, and patients with ≤5 mitoses had a higher survival time (p = 0.006). Overall, the proposed staging system and mitotic count seemed promising in the prediction of patient prognosis.

PATH-07. INFRATENTORIAL HIGH-GRADE GLIOMAS: NEUROSURGICAL CASE SERIES WITH MOLECULAR ANALYSIS

Abstract INTRODUCTION Most high grade gliomas (HGG) are located supratentorially, while less than 1% arise infratentorially. Growing evidence suggests that infratentorial HGGs (iHGG) represent a collection of distinct molecular entities and that further elucidation of their molecular features can help guide management. We perform here a clinical and molecular analysis of our institutional iHGG case series. METHODS We retrospectively reviewed iHGG patients treated surgically at Brigham and Women’s Hospital (1992-2020), and evaluated their history of prior malignancies, tumor location, treatment, molecular profile, tumor recurrence, and survival. iHGG were identified by review of pathology records, using WHO Histologic Grading Criteria as grade III-IV gliomas located infratentorially. Molecular analysis data was obtained from pathology records. RESULTS Among 37 iHGGs, 16 (43%) were glioblastomas, 11 (30%) were anaplastic astrocytomas, 2 (5%) were diffuse midline gliomas, 2 (5%) were infiltrating gliomas, 2 (5%) were anaplastic ependymomas, 1 (3%) was an anaplastic oligodendroglioma, and 3 (8%) were HGG not otherwise specific. Sixteen (43%) patients were female, median age was 49 years. Fifteen patients had history prior malignancy, 11 of which received radiation and 8 chemotherapy. Surgical resection of iHGG included gross total resection in 4 (11%) and subtotal in 33 (89%). Twenty-one patients (57%) received adjuvant radiation and 19 (51%) chemotherapy. At follow-up, 13 (35%) patients demonstrated symptomatic deterioration, 15 (41%) were stable, and 7 (19%) were improved. Seven patients (19%) experienced recurrence at a mean time of 19 months, and one-year survival was 35%. Molecular analysis revealed 7/15 (47%) tumors were MGMT promoter methylated, IDH was mutated in 3/24 (13%), EGFR was amplified in 3/10 (30%), CDKN2A/B homozygous deletion in 4/7 (57%), TP53 was mutated in 14/15 (93%), and H3K27M was present in 4/10 (40%). CONCLUSIONS iHGGs demonstrate substantial distinction from their supratentorial counterparts. Herein we examined their clinical course, molecular features, management, and outcomes.

Automatic segmentation algorithm for magnetic resonance imaging in prediction of breast tumour histological grading

AbstractTo analyse the application value of dynamic contrast enhanced magnetic resonance imaging (DCE‐MRI) based on computer semi‐automatic segmentation (CSS) algorithm in tumour histological grading of breast cancer patients, the CSS algorithm of DCE‐MRI breast image was established based on Canny edge detection operator and dynamic binarization (DB) algorithm to compare with the fuzzy‐c‐means (FCM) algorithm based on FCM clustering and wavelet transform (WT) algorithm. Besides, CSS was applied to DCE‐MRI image diagnosis in 121 breast cancer patients, who were then classified as grade I, II, and III according to the 2019 edition of the World Health Organization Histological Grading Criteria for Breast Tumors. The results showed that the false positive rate (FPR) of CSS was sharply lower than that of FCM and WT, while the true positive rate (TPR) of CSS increased greatly in contrast to FCM and WT, indicating that there were statistically significant (p &lt; 0.05). The area under the curve (AUC) predicted by FCM, WT, and CSS for histological classification were 0.818, 0.801, and 0.924, respectively. The fractional anisotropy (FA) value of patients with grade III was less than that of patients with grade I and II, while the apparent diffusion coefficient (ADC) value of patients with grade III was greater than that of patients with grade I and II (p &lt; 0.05). The tumour diameter, number of lesions, and number of lymph node metastasis of patients with grade III increased markedly compared to patients with grade I and II (p &lt; 0.05). To sum up, DCE‐MRI image segmentation results based on CSS were superior to FCM and WT in the evaluation of breast tumour histological grading. What's more, there were substantial differences in the obtained tumour diameter, FA value, ADC value, and number of lymph node metastasis based on DCE‐MRI of patients with grade I, II, and III, which could be applied to predict the histological grading of patients with breast cancer.

Clinical Significance of Low Grade Follicular Lymphoma with High Proliferative Index

Introduction: Follicular lymphoma (FL) accounts for about 20% of lymphomas. The time to treatment, time to progression and overall survival are widely variable and additional prognostic factors are needed to identify patients who might benefit from upfront therapy. The association of high Ki67 proliferative index in FL with recurrence, progression, and decreased survival in unclear. Furthermore, the contribution of Ki67 proliferative index score in follicular versus interfollicular area for prognosis has not been reported.Methods: We performed a retrospective observational analysis of newly diagnosed patients with FL evaluated at University of Minnesota, from 2003 to April 2016. All cases were graded using WHO Classification histologic grading criteria. We excluded patients with no follow-up and grade 3B. We examined medical records and performed Ki67 immunohistochemical nuclear stains. Two pathologists reviewed Ki67 staining in follicular and interfollicular area and selected areas with maximum staining. Ten consecutive follicular and interfollicular areas were scored separately for Ki67 nuclear staining. Association of Ki67 with overall survival (OS) and progression-free survival (PFS) from date of diagnosis was analyzed using Cox regression. We defined PFS as time from diagnosis to initiation of first treatment or death, whichever occurred first.Results: We examined 69 cases, 63 were grade 1 and 2 follicular lymphoma and 6 were grade 3A. Median age at diagnosis was 59 years. Gender was distributed equally. At time of diagnosis FLIPI score was 0 in 9 patients (13%), 1 in 15 patients (21.7%), 2 in 19 patients (27.5%), 3 in 15 patients (21.7%), 4 in 3 patients (4.3%), and unknown in 8 patients (11.6%). 27.5% patients (27 cases) showed bone marrow involvement at the time of diagnosis. Median (interquartile range) Ki67 was 25% (15%, 40%) in follicular area and 5% (5%, 15%) in interfollicular area.Median follow-up time was 4.0 years (range 0.1 to 11.7 years). 37.7% underwent upfront observation, 14.5% were treated with RCHOP as first line of therapy, 23.2% received rituximab as maintenance therapy, few (13%) cases transformed into diffuse large B-cell lymphoma, and 20% of the patients died. OS at 5-years was 86% (95% CI: 76%, 97%), and PFS at 5-years was 25% (95% CI: 16%, 40%). Median PFS was 1.6 months. In univariate analysis, follicular Ki67 was not associated with PFS (p > 0.40) or OS. Interfollicular Ki67 was highly associated with shorter PFS with hazard ratio 1.32 per 10 units of Ki67 (95% CI: 1.08, 1.63). Results were similar adjusting for FLIPI score.Conclusions: Our data suggests that interfollicular area Ki67 score at diagnosis is prognostic to predict PFS in patients with FL. The relationship appears to be linear and doesn't change when adjusting for FLIPI score. Follicular area Ki67 has no impact on clinical outcomes. We propose that the Ki67 proliferative index should be scored in the interfollicular areas to assess the prognosis in FL. DisclosuresBachanova:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

CD24 and PRAME Are Novel Grading and Prognostic Indicators for Pineal Parenchymal Tumors of Intermediate Differentiation.

The pineal parenchymal tumors of intermediate differentiation (PPTIDs) are extremely rare tumor entities. They exhibit low-risk (grade II) and high-risk (grade III) malignancies, which may lead to different therapies and prognosis. However, the histological grading criteria remains elusive, and novel biomarkers may be helpful to differentiate the grade of PPTIDs. Immunohistochemical staining for CD24, PRAME, POU4F2, and HOXD13, and their clinicopathologic analyses were performed in pineal parenchymal tumors and other tumors in the pineal region. CD24 and PRAME were expressed in 9/11 (81.8%) and 8/11(72.7%) cases of PPTIDs grade III, compared with 6/18 (33.3%) and 5/18(27.8%) cases of PPTIDs grade II. The levels of CD24 and PRAME were significantly higher in PPTIDs grade III than grade II. However, there were no differences of HOXD13 and POU4F2 expression levels in PPTIDs grade II and grade III. Interestingly, high expression of CD24 and PRAME were prevalently found in high-grade tumors of the central nervous system. In addition, PPTIDs patients with high expression levels of CD24 and PRAME exhibited a significant shorter survival time. The results of PPTIDs grading by CD24 and PRAME were mostly consistent with WHO criteria, except for two cases. According to the prognostic information of patients, we found that the combination of CD24 and PRAME expression for grading PPTIDs might be more valuable than WHO criteria only. CD24 and PRAME are novel markers for grading and prognostic evaluation of PPTIDs that may be helpful to determine the therapeutic decision for PPTIDs patients.

Clinical, radiological, and histopathological predictors for long-term prognosis after surgery for atypical meningiomas.

Despite considerable rates of recurrence and mortality in atypical meningiomas, reliable predictors for estimating postoperative long-term prognosis remain elusive. Clinical, histopathological, and radiological variables from 138 patients, including 64 females and 74 males (46% and 54%, median age 62years), who underwent surgery for intracranial atypical meningioma were retrospectively analyzed. Associations between variables and recurrence and mortality were investigated using uni- and multivariate analyses. Gross total (GTR) and subtotal resection (STR) was achieved in 81% and 19% of cases, respectively. Within a median follow-up of 62months, recurrence occurred in 52 (38%) and mortality in 22 (16%) cases. In patients who did not receive adjuvant irradiation, recurrence rates were higher after STR than after GTR (32% vs 63%, p = 0.025). In univariate analyses, only intratumoral calcifications on preoperative MRI (p = 0.012) and the presence of brain invasion in the absence of other histological grading criteria (p = 0.010) were correlated with longer progression-free intervals (PFI). In multivariate analyses, patient age was positively (HR 1.03, 95%CI 1.04-1.05; p = 0.018) and the presence of brain invasion as the only grading criterion (HR 0.37, 95%CI 0.19-0.74; p = 0.005) was negatively related with progression, while rising age at the time of surgery (HR 1.07, 95%CI 1.03-1.12; p = 0.001) was prognostic for mortality. PFI was longer in brain invasive but otherwise histological benign meningiomas and in tumors displaying calcifications on preoperative MRI. Advancing patient age and lower Karnofsky Performance Score were associated with higher overall mortality.

Changes in the pathomorphological diagnosis of gastrointestinal neuroendocrine neoplasms in 2017

The following changes were introduced in 2017 WHO and TnM classifications: 1. a new group of well-differentiated neuroendocrine tumors with the proliferation index of more than 20% and mitotic count of 20 per 10 hpf (NET G3), formerly classified under neuroendocrine carcinomas (NEC G3) 2. the division of poorly differentiated neuroendocrine tumors (PD NET) with the Ki-67 index of more than 20% into two groups in terms of the degree of differentiation and prognosis: NET G3 and NEC. 3. the replacement of MANEC with MINEN within the mixed group 4. the verification of histological grading (G) criteria 5. new TNM staging criteria, based on ENETS guidelines.

Histological features of malignancy correlate with growth patterns and patient outcome in lung adenocarcinoma.

Until the launch of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society adenocarcinoma classification in 2011, there were no uniform histological grading criteria for pulmonary adenocarcinomas. The current classification highlights the prognostic importance of the various histological growth patterns observed in these morphologically heterogeneous neoplasias. In this study, we aimed to evaluate the classic histological parameters of malignancy in correlation with the growth patterns and patient outcomes in a series of 112 surgically operated stage I-IV lung adenocarcinomas. Architectural growth pattern analysis was performed according to the current adenocarcinoma classification. Histological features including, for example, nuclear atypia, mitotic activity, tumour necrosis, and different patterns of invasion were assessed and correlated statistically with the architecture and the clinical data. A solid predominant histology was associated with increased levels of atypia (P=0.027), mitotic activity (P<0.001), necrosis (P<0.001), and lymphovascular invasion (P=0.001), and a non-predominant solid pattern was associated with intra-alveolar tumour spread (P=0.004). The presence of a non-predominant lepidic tumour component showed inverse correlations with atypia (P=0.002), mitotic rate (P=0.009), and tumour necrosis (P<0.001). Tumour size (P<0.001), mitotic activity (P=0.019), tumour necrosis (P=0.002), lymphovascular invasion (P=0.001) and visceral pleural involvement (P=0.001) were all associated with reduced disease-specific survival. The classic histological features of malignancy correlate with tumour architecture and patient outcome, confirming the prognostic value of the growth pattern analysis and questioning the needfor a parallel grading system in pulmonary adenocarcinoma.

Immunoexpression of programmed cell death 4 protein in normal oral mucosa, oral epithelial dysplasia and oral squamous cell carcinoma

Background:Oral squamous cell carcinoma (OSCC) is the frequently reported cancer of the head and neck. Recent studies are being conducted to evaluate the role of potential markers for diagnosing the stages of development of OSCC from normal cells.Aim:The aim of this study is to evaluate and compare the immunoexpression of programmed cell death 4 (PDCD4) protein in normal oral mucosa, oral epithelial dysplasia (OED) and OSCC.Materials and Methods:Histologically diagnosed, formalin-fixed paraffin-embedded archived cases (n = 100) of normal mucosa (n = 10), OED (n = 60) and OSCC (n = 30) were analyzed immunohistochemically in the present retrospective study using monoclonal rabbit antihuman PDCD4. OED and squamous cell carcinoma were graded according to the World Health Organization and Broder's histological grading criteria, respectively. Clinical parameters and immunohistochemical results were analyzed by Fisher exact test using SPSS software. P <0.05 was indicative of significant differences.Results:PDCD4 expression was observed in the normal oral mucosa, OED and OSCC. The maximum expression was observed in the normal oral mucosa, which reduced significantly in OED and OSCC (P = 0.017). With the increase in the transformation from normal cells to cancer cells, a shift from nuclear to cytoplasmic staining was observed indicating predominant cytoplasmic localization of stain as a feature of altered cells.Conclusion:The present study delineates the molecular difference between the normal, dysplastic and carcinomatous cells; and points toward the role of PDCD4 localization in the proliferation of cells. This study thus highlights the need for further research with inclusion of long follow-up period and other pathological criteria such as inflammation and microenvironment, immune status of patient and tumor stage, which could aid in the development of prospective diagnostic options.

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.

Papillary tumor of the pineal region: Histopathological characterization and review of the literature

Background and purposeThe papillary tumor of the pineal region (PTPR) was described as a distinct new entity for the first time in 2003 by our team and has been included in the last 2007 WHO classification of tumors of the Central Nervous System. We describe the histopathological characterization of PTPR and present a review of the literature. MethodsThe description of the histological and immunological features of PTPR is based on the 2007 WHO classification. ResultsPTPR affects both children and adults, and mostly young adults in the third decade. PTPR is a neuroepithelial tumor occurring in the vicinity of the pineal gland, and characterized by its papillary architecture. The papillae are lined by multi-layered cuboidal to columnar epithelioid tumoral cells arranged in perivascular pseudorosettes. Immunohistochemistry shows strong reactivity for cytokeratins, particularly for cytokeratin 18. On electron microscopy, PTPR reveals ultrastructural features indicative of ependymal differentiation, including abundant microvilli at the apical cell pole. The differential diagnosis includes a variety of other papillary tumors, most notably papillary ependymoma, choroid plexus papilloma, papillary meningioma, and metastatic papillary carcinoma in adults. On the basis of ultrastructural and immunohistochemical features, it has been suggested that a PTPR arises from specialized cytokeratin-positive and nestin-positive ependymal cells that are derived from the subcommissural organ. Although the precise histological grading criteria of PTPR remain to be defined, its biological behavior may correspond to WHO grade II or III.

Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma

Extracapsular extension in squamous cell carcinoma nodal metastases usually predicts worse outcome. However, there are no standard histologic grading criteria for extracapsular extension, and there have been few studies on oropharyngeal squamous cell carcinoma alone. We studied the extent of extracapsular extension utilizing a novel grading system and correlated grades with outcomes while controlling for p16 status. A cohort of surgically treated oropharyngeal squamous cell carcinoma cases were reviewed and metastases graded as 0 (within substance of node), 1 (filling subcapsular sinus with thickened capsule/pseudocapsule, but no irregular peripheral extension), 2 (≤1 mm beyond capsule), 3 (>1 mm beyond capsule), or 4 (no residual nodal tissue or architecture; ‘soft tissue metastasis‘). There were 101 cases, for which p16 was positive in 90 (89%). Extracapsular extension grades did not correlate with nodal size (P=0.28) or p16 status (P=0.8). In follow up, 10 patients (10%) had disease recurrence with only 3 of 64 (5%) grade 0–3 cases and 7 of 37 (19%) with grade 4 recurring (P=0.04). Grade 4 extracapsular extension was associated with poorer survival (P<0.01). However, grade 4 extracapsular extension correlated with higher T-stage (P=0.02), and in multivariate analysis, was not significantly associated with poorer overall (P=0.14) disease-free (P=0.2), or disease-specific survival (P=0.09). The impact of extracapsular extension in nodal metastases is limited in oropharyngeal squamous cell carcinoma. Only extracapsular extension grade 4 associates with poorer outcomes, but not independently of T-stage and other variables.

Solitary plasmacytoma of bone: a clinicopathologic, immunohistochemical and immunoglobulin gene rearrangement study

To investigate clinicopathologic features of solitary plasmacytoma of bone (SPB) and the role of immuno-phenotype and immunoglobulin gene rearrangement detection in the diagnosis and differential diagnosis of SPB. A total of 21 cases of SPB were selected during a period from 1990 to 2008. A retrospective clinicopathologic study and immunohistochemistry (EnVision or EliVision methods) of 17 antigens were performed. In addition, universal IgH (FR3A/LJH/VLJH) primers and BIOMED-2 PCR multiplex tubes were used for IgK and IgL rearrangement analysis. The age of patients ranged from 36 to 72 years with a media of 50 years. Axial skeleton was the most common site of involvement, accounting for 66.7% of the cases (14 of 21), followed by the extremities of 33.3% (7 cases). Low serum level of M-components was found in 5 cases, including two of IgG type (21.4 g/L) and three of IgA type. Clinical manifestations were closely related to the anatomic sites involved, such as pain due to bone destruction, symptoms and signs caused by compression of spinal cord or nerve root, and pathological fracture. All cases presented as a solitary osteolytic lesion. According to the histological grading criteria, grade I tumor was seen in 12 of 21 cases (57.1%). The remaining were grade II (5 cases, 23.8%) and grade III (4 cases, 19.0%). Immunohistochemically, the neoplastic cells expressed two or more plasma cell antigens, including CD138, CD38 and PC, but no CD19 and CD20. CD79a expression detected in 23.8%(5/21) of the cases. Expression of CD56, CD27 and CD44v6 were 57.1% (12/21), 15.0% (3/20) and 23.8% (5/21), respectively. Follow-up data were available in 12 of the 21 patients (57.1%). Five patients were alive and 7 died. Three patients developed multiple myeloma (MM) and died of the tumor. SPB is a rare tumor with bone pain as the most common presenting symptom due to bone destruction. The diagnosis of EMP can only be established after exclusion of an extramedullay invasion by MM. Immunophenotype and IgH gene rearrangement analysis play important roles in the diagnosis of SPB.

Cytokeratin and Vimentin Co-Expression in 21 Canine Primary Pulmonary Epithelial Neoplasms

Co-expression of cytokeratin and vimentin has been traditionally associated with a few select tumors. However, this phenomenon is being recognized in a wider range of tumors. Twenty-one canine primary pulmonary epithelial neoplasms were evaluated for the co-expression of cytokeratin and vimentin. The histologic pattern and grade, and an immunohistochemical grade for cytokeratin and vimentin staining, were determined for each neoplasm. Adenocarcinomas predominated, and histologically, most tumors were grade II. All of the neoplasms stained positive for cytokeratin, while only 8 (38%) stained positive for both vimentin and cytokeratin. Papillary adenocarcinomas were consistently vimentin negative. The anaplastic histologic pattern had significantly more vimentin staining than the other histologic patterns. There was no significant difference in histologic grade or grading criteria between those tumors that stained with vimentin and those that did not. The present study established that cytokeratin and vimentin co-expression occurs in canine primary pulmonary epithelial tumors at a similar frequency to human pulmonary neoplasms. Further investigation will be needed to characterize the significance of this finding, particularly with respect to prognosis.

Salivary Mucoepidermoid Carcinoma: Revisited

Mucoepidermoid carcinoma (MEC) is a malignant epithelial neoplasm composed of varying proportions of mucous, epidermoid, intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. MEC is usually subclassified as low, intermediate, or high grade on the basis of its histologic features, including the presence of cystic spaces, cellular differentiation, proportion of mucous cells, growth pattern, type of invasion, and cytologic atypia. Because even low-grade neoplasms may metastasize, the term mucoepidermoid tumor is inappropriate. The 3-level grading approach to tumor classification has found general acceptance among pathologists; differences in biologic behavior can be demonstrated even though clinical stage has become a better prognosticator. However, in the case of MEC, no universal agreement exists regarding which histologic grading criteria are most the useful, and grading has varied. These issues have led to the investigation of more subjective systems. We describe these new schemes, the histologic variants of MEC, and the ancillary methods that allow for further stratification of patients with MEC, especially for patients with grade 2 tumors, which have a variable and unpredictable clinical course.

Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment

AbstractFollicular lymphoma (FL) is a disease characterized by a long clinical course marked by frequent relapses that vary in clinical aggressiveness over time. Therefore, the main dilemma at each relapse is the choice for the most effective treatment for optimal disease control and failure-free survival while at the same time avoiding overtreatment and harmful side effects. The selection for more aggressive treatment is currently based on histologic grading and clinical criteria; however, in up to 30% of all cases these methods prove to be insufficient. Using supervised classification on a training set of paired samples from patients who experienced either an indolent or aggressive disease course, a gene expression profile of 81 genes was established that could, with an accuracy of 100%, distinguish low-grade from high-grade disease. This profile accurately classified 93% of the FL samples in an independent validation set. Most important, in a third series of FL cases where histologic grading was ambiguous, precluding meaningful morphologic guidance, the 81-gene profile shows a classification accuracy of 94%. The FL stratification profile is a more reliable marker of clinical behavior than the currently used histologic grading and clinical criteria and may provide an important alternative to guide the choice of therapy in patients with FL both at presentation and at relapse. (Blood. 2005;105:301-307)

Gene Expression Profiles Are Best Suited To Assess Present Though Not Future Clinical Aggressiveness in Follicular Lymphoma.

Follicular lymphoma (FL) is characterized by an indolent clinical course and frequent relapses. Transformation to more aggressive disease is common and one of the main causes of death. The time to transformation may vary widely and some patients show early transformation and a poor prognosis. Main questions in FL center on markers to predict transformation (and prognosis) at the time of diagnosis and to accurately assess the transformed phase to tailor the choice of therapy. Currently, prognostic stratification for actual aggressiveness and overall survival is based on histological grading and clinical criteria; however, in up to 30% of all cases these methods prove to be insufficient. Using 18k cDNA arrays, we analyzed gene-expression patterns of 135 cases of FL addressing both issues.1) Using supervised classification on a training set of paired samples from the indolent and aggressive disease episodes and on an independent validation set, a 81-gene-expression profile was established that could, with an accuracy of 100% and 93% respectively distinguish indolent from aggressive disease. Importantly, in a third series of FL with ambiguous histological grade, precluding meaningful morphological guidance, the profile showed a 94% classification accuracy supporting the value of this method for practical clinical use. The profile consists of genes involved in cell cycle control, DNA synthesis and metabolism (upregulated in high-grade disease), T-cell related genes (upregulated in low-grade disease) and T-cell and macrophage activation markers, that are significantly upregulated upon transformation. This profile, however, did not predict future transformation in FL samples at diagnosis.2) A separate analysis was performed in a selection of the biopsy samples of not previously treated patients with grade 1 and 2 FL with transformation to DLBCL within 7–22 months after diagnosis and no transformation with a minimum follow-up of 108 months. Supervised and unsupervised cluster analysis showed no differences between both groups exceeding the threshold of significance to construct a predictor profile with a validated significance, underlining the biological homogeneity of the study cohort. Direct comparison analysis on the basis of signal-to-noise ratio's suggested a discriminative role of the immune response with enhanced cytokine- and chemokine-mediated T-cell activation and antigen-processing in the extremes of the spectrum. However, differences were slight and the immune-response seemed to play a less distinctive role in patients with transformed disease after more than 3 years.In conclusion, actual indolent and aggressive clinical behavior can be more reliably distinguished using a FL-stratification profile than the currently used histological grading and clinical criteria, and may provide an important alternative to guide the choice of therapy in FL patients both at presentation and at relapse. Although there may be subtle differences between rapidly transforming disease and long-term stable indolent disease, possible inherent variations are insufficient to reliably predict future transformation.

Extramedullary plasmacytoma: clinical and histopathologic study

Purpose : To review the histories of extramedullary plasmacytoma patients diagnosed in Slovenia between 1969 and 1999, to determine the relationship between radiotherapy (XRT) dose and local tumor control, and to clarify the role of elective nodal XRT and the prognostic value of Bartl’s histologic grading criteria (originally devised for multiple myeloma [MM]). Methods and Materials : The database of the Cancer Registry of Slovenia was used for the identification of patients. The inclusion criteria were as follows: bone marrow biopsy showing less than 10% plasma cells, normal skeletal survey, and immunohistochemically determined tumor monoclonality. Simulation/portal films were reviewed to assess the extent of elective nodal XRT. Results : Twenty-six patients with 31 tumors fulfilled the inclusion criteria. In 4 patients, nine metachronously appearing solitary tumors were diagnosed. The head-and-neck region and other body sites were the sites of origin of primary tumors in 84% and 16% of patients, respectively, whereas in the two regions, regional disease was seen in 15% and 60% of patients, respectively. Therapy was as follows: XRT, 12 patients; surgery and postoperative XRT, 15 patients; and surgery, 4 patients. Ultimate local and regional control rates were 90% and 97%, respectively, and MM developed in 2 (8%) patients. The 10-year disease-specific and overall survival rates were 87% and 61%, respectively. The analysis of the dose-effect relationship showed that more conservative treatment is justified: for macroscopic disease, 40–50 Gy (2 Gy/day), adjusted to the bulk of disease; for microscopic disease, 36–40 Gy; after R0 surgery, no XRT is required, but close observation is needed. No attempts should be made to treat uninvolved nodal regions. Using Bartl’s histologic grading criteria, trends were detected in patients with higher tumor grades: regional lymph node involvement ( p = 0.04) and shorter disease-specific survival ( p = 0.08). Conclusions : Extramedullary plasmacytoma is a highly curable disease when XRT is used with or without previous surgery. The rate of conversion to MM is low. Moderate-dose XRT using limited fields is recommended. The prognostic value of Bartl’s grading system needs further evaluation.

Clinical features of small hepatocellular carcinomas as assessed by histologic grades

Ninety-seven patients with small hepatocellular carcinomas (HCCs) measuring 3 cm or less in size and three patients with adenomatous hyperplasia who underwent radical hepatic resection were examined in this study. The lesions were classified into four groups according to the following histologic grading criteria: group A, adenomatous hyperplasia (n = 3); group B, early HCC (n = 6); group C, well-differentiated HCC (wHCC) (n = 32); and group D, moderately or poorly differentiated HCC (n = 59). The involvement factors that seemed to be important or to characterize the progression of HCC and the survival rates were compared among the four histologic groups. The frequency of patients with tumors larger than 2.0 cm in size and that of patients with 200 or more ng/ml serum alpha-fetoprotein increased with the progression of histologic malignancy. Tumor staining on the angiogram, capsular formation, and extranodular invasion were never seen in groups A and B, but they began to appear in group C and increased remarkably in group D. The 5-year survival rates of the patients in groups B, C, and D were 100%, 60%, and 27%, respectively, and statistically significant differences were seen among them. In comparative evaluation of the group C patients the lesions that showed no tumor staining had no capsule, and those that had no capsule had no extranodular invasion. The 5-year survival rate of patients with wHCC without extranodular invasion (81%) was significantly higher than that of patients with extranodular invasion (35%) (p < 0.05). It may be recommended to provide the category of wHCC without extranodular invasion for pathologic classification of clinically early HCC (i.e., HCC of high curability).

Correlation between argyrophilic nucleolar organizer region (AgNOR) counts and histologic grades with respect to biologic behavior of salivary adenoid cystic carcinoma

The quantification of argyrophilic nucleolar organizer regions (AgNOR) was performed in 34 cases of adenoid cystic carcinoma (ACC) to determine (1) whether AgNOR count correlates with its different histologic grades pertinent to prognosis, and (2) whether AgNOR counts can offer any additional prognostic advantage over histologic grading. According to Szanto et al.'s histologic grading criteria (4), 12 cases were Grade 1, 7 cases Grade 2, and 15 were Grade 3. Patients were divided into 20 favorable cases (without metastases) and 14 unfavorable cases (with metastases). Although most Grade 3 tumors had high AgNOR counts (> or = 4) and Grade 1 tumors with low (< 4) AgNOR counts outnumbered those with high AgNOR counts, considerable overlap of AgNOR values in different grades was observed. However, all unfavorable cases had high AgNOR counts regardless of their histologic grades, suggesting that the metabolic alterations associated with the malignancy level of ACC may partly be portrayed by the AgNOR count, irrespective of the histologic appearance. Cumulative survival rates of Grade 1 tumors and of tumors with low AgNOR counts were better than those of Grade 3 tumors and those with high AgNOR counts. Within the limited number of cases in this series the AgNOR count exhibits a potential for identifying some aggressive ACCs that cannot be detected by histology alone.