Distinct Clinicopathologic Entity Research Articles

CD274 (PD-L1), CDKN2A (p16), TP53, and EGFR immunohistochemical profile in primary, recurrent and metastatic vulvar cancer.

Vulvar squamous cell carcinoma can be divided by human papillomaviruses (HPV) status into two distinct clinicopathological and molecular entities. New agents targeting the tumor surface expression of programmed cell death-1/programmed cell death-ligand-1 are becoming a therapeutic option in an increasing number of carcinomas. We evaluate CD274 (PD-L1), CDKN2A (p16), tumor protein p53 (TP53), and epidermal growth factor receptor (EGFR) immunoexpression in primary tumors, recurrences and lymph node metastases and its correlations with prognosis and HPV status. We report 93 cases of vulvar squamous cell carcinoma diagnosed between 2002 and 2016 with the description of their clinicopathological features and prognosis data. Immunohistochemistry for CD274, CDKN2A, TP53, and EGFR was performed on tissue microarrays collecting from primary tumor, recurrences and lymph node metastasis. Kaplan-Meier estimator and multivariable Cox regression analysis controlling for FIGO stage and age were used. Patients who underwent surgery had a superior overall survival (HR = 0.51, 95% CI = 0.26-0.99 p = 0.04). Lymph node metastasis size ≥5 mm was associated with an inferior overall survival (HR = 1.88, 95% CI = 1.22-2.92 p = 0.004). CDKN2A expression was correlated with an inferior rate of recurrent disease (p = 0.02). In high-risk HPV DNA+ vulvar squamous cell carcinomas patients with CDKN2A- carcinomas showed a significantly worse overall survival than women with CDKN2A+ tumors (56% vs.100%, p = 0.003). TP53 expression was associated with an increased rate of recurrent disease (p = 0.0005). CD274 expression was associated with lymph node metastasis (p = 0.04). In 16 patients the CD274, CDKN2A, TP53, and EGFR expression changed between primary tumors, recurrences and lymph node metastases during tumor progression. In conclusion, a significant percentage of vulvar squamous cell carcinoma has a heterogeneous biomarker expression during tumor progression. We highlight the importance of some of these markers to be used as prognostic biomarkers. This data brings new light to future treatment using targeted therapy to EGFR or CD274 to include retesting such biomarkers in recurrence and lymph nodes metastases.

6mer Seed Toxicity in Viral microRNAs.

SummaryMicroRNAs (miRNAs) are short double-stranded noncoding RNAs (19-23 nucleotides) that regulate gene expression by suppressing mRNAs through RNA interference. Targeting is determined by the seed sequence (position 2-7/8) of the mature miRNA. A minimal G-rich seed of just six nucleotides is highly toxic to cells by targeting genes essential for cell survival. A screen of 215 miRNAs encoded by 17 human pathogenic viruses (v-miRNAs) now suggests that a number of v-miRNAs can kill cells through a G-rich 6mer sequence embedded in their seed. Specifically, we demonstrate that miR-K12-6-5p, an oncoviral mimic of the tumor suppressive miR-15/16 family encoded by human Kaposi sarcoma-associated herpes virus, harbors a noncanonical toxic 6mer seed (position 3-8) and that v-miRNAs are more likely than cellular miRNAs to utilize a noncanonical 6mer seed. Our data suggest that during evolution viruses evolved to use 6mer seed toxicity to kill cells.

Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct

Intraductal papillary neoplasm of the bile duct (IPNB) is a mass-forming neoplasm in the bile duct considered to be the biliary counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN). By its cell lineage, IPNB can be classified into gastric, intestinal, pancreatobiliary, and oncocytic types. Recently, a group of Japanese and Korean pathologists proposed that IPNB be classified into two types, with type 1, being the histological counterpart of IPMN and type 2, having a more complex histological architecture. We used targeted next-generation sequencing to study the molecular change of 37 IPNBs and identified frequent mutations of KRAS (49%), GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and CTNNB1 (11%) in IPNBs. Intestinal-type IPNB was associated with KRAS, GNAS, and RNF43 mutations. Japan–Korea consensus type 1 was associated with KRAS and GNAS mutations. All four IPNBs with CTNNB1 mutations were of pancreatobiliary type and located in the extrahepatic bile duct. A hierarchical analysis identified three distinct groups within IPNB: group 1 was Japan–Korea consensus type 1 tumors with macroscopic mucin, old age, and frequent KRAS, GNAS, and RNF43 mutations. Group 2 was Japan–Korea consensus type 2 with intestinal differentiation and frequent KRAS mutation but rare GNAS mutation, MUC2 expression, and macroscopic mucin. Group 3 was characterized by CTNNB1 mutation, extrahepatic location, lack of expression of intestinal markers, Japan–Korea consensus type 2, and lack of mutations in KRAS, APC, RNF43, and GNAS. Our results indicated that IPNB is a heterogeneous disease and that the activation of Ras-mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and G-protein-coupled receptor (GPCR)–cAMP signaling is the main oncogenic mechanism of IPNB.

EP1.15-03 SMARCA4-Deficient Thoracic Malignancies: A Unifying Genetic Aberration Across Tumors of Divergent Differentiation

Mutations in ATPase-dependant chromatin remodelling units are one of the most common genetic alterations observed in human cancer. Germline mutations in SMARCA4 encoding for Brg-1 protein, a subunit of the SWI/SNF chromatin modifier unit, are well recognised as the causative genetic event in rhabdoid tumor predisposition syndromes that occur in infants and young children. In recent years, somatic mutations in SMARCA4 have been increasingly identified in many adult-onset malignancies ranging from well differentiated carcinomas to poorly differentiated high grade sarcomas in a variety of anatomical sites, including thorax. Documentation of such tumors is essential to our understanding of the pathogenesis and possible mechanisms of therapeutic targetting. Case 1: A 60-year-old male smoker presented with chronic emphyema thoracis of non-tubercular etiology which was treated by intercostal drainage. He had repeated episodes of blockade of chest drain over the next 6 months and eventually a thoracic window was surgically created. Five months following thoracotomy, patient presented with a mass growing at the site of the thoracic window. No other masses in the lung parenchyma or mediastinal lymphadenopathy was seen. Patient underwent an excision of the granulation tissue-like mass. Formalin fixed paraffin embedded sections were subject to microscopy and immunohistochemistry for vimentin, CD34, MIC2, p53, SALL4, pan-cytokeratin (AE1/AE3), EMA, p40, TTF-1, cytokeratin-7, Hepar-1, desmin, myogenin, CD31, S100, Melan-A, HMB-45, GATA-3, calretinin, WT1, INI-1, brg-1 and hematolymphoid markers. Case 2: A 58-year old male smoker presented with hemoptysis and cough. On evaluation, an endobronchial mass was identified and was excised. Formalin fixed paraffin embedded sections from excised tumor mass was subject to microscopy and immunohistochemistry for cytokeratin 7, cytokeratin 19, epithelial membrane antigen, chromogranin, synaptophysin, cytokeratin 20, CD117, TTF-1, NUT1, Her2neu, GATA3, p40, S100, INI-1 and brg-1. Case 1: Microscopy revealed a tumor centred in the soft tissue of the chest wall ulcerating the overlying skin. No lung parenchymal involvement was seen. The tumor was arranged in sheets composed of monomorphic large tumor cells with abundant eosinophilic cytoplasm and prominent nucleoli showing frequent mitoses and foci of necrosis. No squamous or glandular differentiation was seen. Tumor cells were only immunopositive for vimentin, CD34, MIC2, p53, and SALL4, very focally immunopositive for CK (AE1/AE3) and showed retained INI-1 protein expression. Brg-1 expression was lost in tumor cells leading to a diagnosis of SMARCA4-deficient thoracic sarcoma. Case 2: Microscopy revealed a high grade tumor arising from the main bronchi with parenchymal and tracheal extension ulcerating the overlying squamous epithelium. Tumor cells were arranged in lobules with peripheral palisading and central necrosis. The tumor cells were large with frequent cytoplasmic clearing and frequent mitoses. Tumor cells were immunopositive for CK-7, CK-19, EMA, CG while were negative for others. INI-1 was retained while brg-1 was lost leading to a diagnosis of SMARCA4-deficient carcinoma. Two independant studies have delineated SMARCA4-deficient thoracic sarcomas and SMARCA4-deficient lung carcinomas as distinct clinicopathological entities. Despite a unifying genetic alteration, these tumors appear to show varied histomorphology and immunoprofiles. Long term follow-up and molecular analysis of such tumors is necessary.

SMARCA4-deficient Uterine Sarcoma and Undifferentiated Endometrial Carcinoma Are Distinct Clinicopathologic Entities.

Undifferentiated and dedifferentiated endometrial carcinomas (UDEC) are aggressive uterine tumors which may show loss of expression of SMARCA4 (BRG1) or SMARCB1 (INI-1). The recently described SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) has a morphology which overlaps with UDEC. In this study, we compared clinical, morphologic, immunohistochemical, and molecular characteristics to identify features which differentiate SDUS from UDEC. Cases of SDUS (n=12) were compared with cases of UDEC (n=84, 55 of which were previously published). Immunohistochemistry was performed for p53, mismatch repair proteins, claudin-4, SMARCA4, and SMARCB1. Targeted molecular profiling was performed on 15 cases. Patients with SDUS were significantly younger than those with UDEC (mean 35.8 vs. 61.2 y, P=0.0001). UDEC and SDUS showed morphologic overlap; however, phyllodiform architecture favored a diagnosis of SDUS (36% vs. 0%, P=0.005), while prominent nuclear pleomorphism was only seen in some cases of UDEC (0% vs. 24%, P=0.15). Compared with SDUS, UDEC more frequently showed TP53 mutations (0% vs. 34%, P=0.03), microsatellite instability (0% vs. 44%, P=0.006), and intact SMARCA4 and SMARCB1 (0% vs. 80%); a panel combining these immunohistochemical markers had a sensitivity of 100% and specificity of 92% in distinguishing SDUS and UDEC. Cases of UDEC had mutations in genes associated with endometrial adenocarcinomas (eg, TP53, PTEN, PIK3CA) and occasionally SMARCA4, while SDUS was characterized solely by inactivating mutations in SMARCA4. Disease-specific survival was shorter in SDUS than UDEC (median survival 9 and 36 mo, P=0.01). In conclusion, SDUS occurs in younger patients than UDEC, has a worse prognosis, and in most cases has a distinct molecular and immunohistochemical profile.

Neuroblastoma rat sarcoma mutated melanoma: That's what we got so far.

Neuroblastoma rat sarcoma (NRAS) mutation, occurring in about 20%-30% of cutaneous melanomas, leads to activation of RAS-RAF-MAPK cascade and represents a clear distinct clinicopathological entity in melanoma. In contrast with BRAF mutant melanoma, no specific target therapies are available outside the setting of clinical trials. In the field of immunoncology, the predictive role of NRAS mutation with respect to checkpoint inhibitors treatment has not clearly established and deserves further investigation. At present, the standard treatment is the same as for BRAF wild type melanoma. Ongoing trials are exploring novel combination strategies among patients with advanced NRAS mutant melanoma.

Clinical, pathologic, and imaging characteristics of pituitary null cell adenomas as defined according to the 2017 World Health Organization criteria: a case series from two pituitary centers.

The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.

Oncogenic driver mutations in Swiss never smoker patients with lung adenocarcinoma and correlation with clinicopathologic characteristics and outcome.

PurposeLung cancer in never smokers is recognized as a distinct molecular, clinicopathologic and epidemiologic entity. The aim of the study was to investigate the molecular profile in Swiss never smokers with lung adenocarcinoma and to correlate the mutation status with clinicopathologic and demographic patient characteristics and outcome.MethodsOne hundred thirty-eight never smokers diagnosed with lung adenocarcinoma at the University Hospital Zurich between 2011–2018 were included in the study. Data from the electronic medical records were reviewed to characterize clinicopathologic and demographic features, molecular profile, treatment and outcome.ResultsThe majority of patients were female (58.7%) with a median age at diagnosis of 64.5 years (range, 27.1–94.2 years). The most common mutations were EGFR (58.7%) followed by ALK (12.3%), TP53 (5.8%), MET (5.8%), KRAS (4.3%), ERBB2 (4.3%), PIK3CA (2.9%), BRAF (2.2%), ROS1 (1.4%), RET (1.4%), CTNNB1 (0.7%), PARP1 (0.7%), TET1 (0.7%) and PIK3CG (0.7%). Median overall survival (mOS) was 51.0 months (mo). Early clinical stage (p = 0.002) and treatment with targeted therapy (HR 2.53, 95% CI 1.35–4.74, p = 0.004) were independently associated with longer mOS. Patients with oncogenic driver mutations had significantly longer mOS (52.2 mo) compared to patients without mutations (16.9 mo) (HR 3.38, 95% CI 1.52–7.55, p = 0.003). Besides, patients with EGFR mutated (57.8 mo) or ALK rearranged (59.9 mo) tumors had significantly longer mOS compared to the EGFR wildtype (35.0 mo), ALK wildtype (46.5 mo) and pan-negative (16.9 mo) cohorts (HR 2.35, 95% CI 1.37–4.04, p = 0.002; HR 7.80, 95% CI 3.28–18.55, p < 0.001; HR 3.96, 95% CI 1.21–12.95, p = 0.023 and HR 34.78, 95% CI 3.48–34.65, p = 0.003).ConclusionNever smokers with lung adenocarcinoma display distinct clinicopathologic and molecular features and are characterized by a high incidence of targetable mutations. Never smokers with targetable mutations have significantly longer survival compared to patients without mutations.

BENIGN ALVEOLAR RIDGE KERATOSIS: CLINICOPATHOLOGICAL STUDY OF 174 CASES AND P53 EXPRESSION PATTERN

Objectives Benign alveolar ridge keratosis (BARK) is a benign hyperkeratosis that occurs as a poorly demarcated white papule or plaque on the retromolar area or edentulous alveolar ridge mucosa caused by trauma. Histopathologic features are identical to cutaneous lichen simplex chronicus, a condition that results from chronic habitual skin scratching/picking. P53 protein is a tumor suppressor protein that plays a critical role in DNA repair. P53 protein has been shown to be present within 5-25% of the basal cell nuclei in normal oral mucosa and reactive lesions. The objective of this study is to report on the histopathologic features of BARK and to explore P53 expression pattern. Study Design Cases of BARK were identified from the biopsy service of the Harvard School of Dental Medicine from January, 2016 to December, 2017. Randomly selected cases were studied for the presence of P53. Results There were 174 cases comprising 119 males and 55 females (2.2:1; M:F) with a median age of 57 years (range 15-86). The majority were in the sixth (31.0%) and seventh (29.3%) decades. There were 112 (64.4%) cases on the retromolar pad and 62 (35.6%) on the edentulous alveolar mucosa; 27 (15.5%) cases were bilateral. Histopatho-logically, the oral mucosa showed hyperkeratosis often with wedge-shaped hypergranulosis and occasional focal parakeratosis. The epithelium exhibited mild to moderate acanthosis and slight surface undulations or papillomatosis, with tapered rete ridges, often confluent at the tips. The study for P53 performed in 11 cases showed less than 25 % nuclear positivity. Conclusion BARK is a distinct benign clinicopathologic entity caused by friction that is the intraoral counterpart of cutaneous lichen simplex chronicus with which it shares similar histopathologic features. It is not a mere hyperkeratosis which would relegate it to the clinical entity of leukoplakia, and which is a potentially malignant condition.

Tubulocystic renal cell carcinoma: a distinct clinicopathologic entity with a characteristic genomic profile

Tubulocystic renal cell carcinoma, a unique tumor, was recently included as a new entity in the World Health Organization classification of renal tumors. It has variably been reported to be related to other renal cell carcinomas, including papillary renal cell carcinoma, fumarate hydratase-deficient carcinoma, and others, likely because many such carcinomas may show variable amounts of tubulocystic architecture. The published data characterizing the molecular features of these tumors are inconsistent. We studied nine “pure” tubulocystic renal cell carcinomas, as defined by International Society of Urologic Pathologists (ISUP) and World Health Organization (WHO), by targeted next-generation sequencing, and fluorescence in situ hybridization for X and Y chromosomes, to investigate if these show any unique characteristics or any overlap with known mutational/molecular profiles or copy number alterations in other subtypes of renal cell carcinoma. All nine tubulocystic carcinomas demonstrated combined losses at chromosome 9 and gains at chromosome 17, as well as, loss of chromosome Y (in 5/5). None of the tumors showed mutational profiles characteristic of other renal neoplasms, including those seen in fumarate hydratase-deficient renal cell carcinoma. Recurrent mutations in chromatin-modifying genes, KMT2C and KDM5C, were detected in two of nine tumors. Thus, tubulocystic renal cell carcinoma, if defined strictly, at the clinical and pathologic level, demonstrates genomic features distinct from other subtypes of renal cell carcinoma. These findings support the contention that tubulocystic renal cell carcinoma should be diagnosed only using strict morphological criteria and only when presenting in a “pure” form; presence of variable papillary, poorly differentiated, or other architectural patterns most likely do not belong to the category of tubulocystic renal cell carcinoma.

Impact of primary colorectal Cancer location on the KRAS status and its prognostic value

BackgroundColorectal cancer (CRC) originating from the right-sided or left-sided colon is distinct clinicopathological entity. The KRAS status and its prognostic value in CRC remain controversial. This study aimed to investigate the association of KRAS status with clinicopathological features and prognostic value in CRC.Methods178 colon cancer and 145 rectal cancer patients were enrolled. KRAS mutation test was performed on paraffin-embedded tumor samples using PCR methods. The colon cancer was divided into right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Studies that reported the association of KRAS mutation with CRC clinical features and prognosis in databases were searched prior to 2018. The data of the present study was combined with the data of published studies using meta-analysis methods.ResultsNo significant difference between colon cancer and rectal cancer regarding the KRAS status. The KRAS mutation was much frequent in RCC than in LCC (p = 0.010). 17 studies with 11,385 colon cancer patients were selected, the pooled results of our data and previous published data showed that KRAS mutation was more frequent in RCC compared with in LCC (p < 0.01); KRAS mutation was not associated with the prognosis in RCC patient; however, KRAS mutation indicated a poor prognosis in LCC patients compared with KRAS wild type (p < 0.01).ConclusionKRAS status has no difference between colon cancer and rectal cancer. KRAS mutation was more frequent in RCC than in LCC, and associated with a poor prognosis in LCC patients, but not in RCC patients.

Clinicopathological and immunological features of follicular pancreatitis - a distinct disease entity characterised by Th17 activation.

Follicular pancreatitis is a recently recognised, distinct clinicopathological entity characterised by the presence of many intrapancreatic lymphoid follicles with reactive germinal centres. However, the clinicopathological and immunological features and causes have not yet been established. We assessed the clinicopathological and immunological profiles of patients with follicular pancreatitis who underwent surgery. This study included three patients with pancreatic masses (age range = 62-75 years; women:men: 1:2). A histopathological study of the resected pancreatic masses revealed abundant lymphoid follicles with reactive germinal centres in both periductal regions and diffusely within the parenchyma. No storiform fibrosis, obliterative phlebitis or granulocytic epithelial lesions were observed. The immunohistochemical examination revealed an IgG4/IgG-positive plasma cell ratio <30% in all patients. Podoplanin (Th17 marker)-expressing lymphocytes were present in the lymphoid follicles of those with follicular pancreatitis, whereas these were absent in normal lymph nodes and in lymphoid follicles of those with IgG4-related autoimmune pancreatitis (AIP). An RNA digital counting assay clearly demonstrated that the expression counts of 20 genes, including dendritic cells and lymphoid follicles markers, and related cytokines were significantly higher in follicular pancreatitis than in IgG4-related AIP (P < 0.01). The expressions of CCR6 and IL23A, which are genes related to Th17, were high. This study shows that follicular pancreatitis is a histopathologically and immunologically distinct disease entity of pancreatitis and is characterised by upregulated Th17 expression.

Rare Breast Malignancy Subtypes: A Cytological, Histological, and Immunohistochemical Correlation.

Background:Breast malignancies encompass various subtypes which differ in their clinical presentations, outcomes, and response to the treatment regimens. Thus, a proper histological diagnosis and a special mention of the rare histologic subtypes are required to formulate clear recommendations of their treatment protocols.Materials and Methods:This is a 1-year retrospective study highlighting the rarely encountered subtypes on the mastectomy specimens received.Results:We encountered only 11 rare cases out of the total 153 mastectomy specimens received. The rare subtypes were as follows mucinous cystadenocarcinoma (0.6%), mucinous carcinoma (0.6%), dermatofibrosarcoma protuberans (0.6%), Squamous cell carcinoma (0.6%), papillary carcinoma (2.6%), medullary carcinoma (0.6%), and malignant mesenchymal tumor (1.3%).Conclusion:Our data suggest that these variants are distinct clinicopathological entities with a unique hormonal receptor status. Scant information is available on the rare breast tumor subtypes.

Lichenoid pseudovesicular papular eruption on nose: A papular facial dermatosis probably related to actinic lichen nitidus or micropapular polymorphous light eruption.

Facial papules are a feature of several clinical conditions and may present both diagnostic and therapeutic challenges. To describe a grouped papular eruption on the nose and adjoining cheeks that has not been well characterized previously. A series of consecutive patients with a papular eruption predominantly involving nose and cheeks were evaluated, treated and followed up prospectively at tertiary care centers. Demographic details, clinical features, histopathology and response to treatment were recorded. There were five men and six women (mean age 29.9 ± 6.9 years) who had disease for a mean duration of 17.3 ± 11.1 months. All patients presented with a predominantly asymptomatic eruption of monomorphic, pseudovesicular, grouped, skin colored to slightly erythematous papules prominently involving the tip of nose, nasal alae, philtrum and the adjoining cheeks. A total of 15 biopsies from 11 patients were analyzed and the predominant finding was a dense, focal lymphoid infiltrate restricted to the upper dermis with basal cell damage and atrophy of the overlying epidermis. The eruption ran a chronic course from several months to years. Direct immunofluorescence could not be performed except in one case. Immunohistochemical stains for CD4 and CD8 could not be done owing to nonavailability. Phototesting was undertaken in one patient only. Small grouped papules on the nose and adjoining skin with a lichenoid histopathology appear to represent a distinct clinicopathological entity. It may be related to actinic lichen nitidus/micropapular variant of polymorphous light eruption.

Primary Malignant Deciduoid Mesothelioma: A Challenging Diagnosis.

Primary malignant deciduoid mesothelioma is a rare subtype of epithelioid mesothelioma that was first described in the peritoneum in young women without a history of asbestos exposure. It was thought to be a distinct clinicopathologic entity with ominous prognosis; recent studies have better characterized this entity. On morphology, primary malignant deciduoid mesothelioma is characterized by cytomorphologic features resembling decidualized tissue. Pleomorphism is variable. The immunoprofile is similar to other epithelioid mesotheliomas. The prognosis is the same as other epithelioid mesotheliomas and seems to depend on histological grade.

Impact of Allogeneic Hematopoietic Cell Transplantation (allo-HCT) on the Outcomes of Angioimmunoblastic T-Cell Lymphoma (AITL): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS).Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months).The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure.Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. DisclosuresKharfan-Dabaja:Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

Granulomatous Rosacea Versus Lupus Miliaris Disseminatus Faciei-2 Faces of Facial Granulomatous Disorder: A Clinicohistological and Molecular Study.

Granulomatous rosacea (GR) and lupus miliaris disseminatus faciei (LMDF) are 2 forms of facial granulomatous diseases. Although they show some morphological overlap, they have distinct clinical presentation. This study was performed to demonstrate the clinical and histological features of GR and LMDF and to establish their relationship to tuberculous etiology by molecular technique. All the cases of GR (n = 20) and LMDF (n = 10) diagnosed on skin biopsy over the past 6 years were reviewed along with their clinical detail. Polymerase chain reaction (PCR) was performed using primers specific for Mycobacterium tuberculosis. The mean age of patients with GR was 45 years 10 months (range 18-75 years) as compared to 33 years 5 months (range 18-57 years) in patients with LMDF. The GR cases comprised 13 men and 7 women patients, whereas all 10 LMDF cases were seen in men. GR cases had papular lesion over an erythematous base on face, whereas LMDF cases had papular/nodular/nodulocystic lesions on the face and neck. Histologically, GR cases showed small granulomas without necrosis in a background of variable lymphoid infiltrate and dilated capillaries, whereas LMDF showed large granulomas with caseous necrosis and minimal inflammation. Five cases (25%) of GR showed degenerating Demodex folliculorum mites. No case of GR or LMDF showed positivity for mycobacterial polymerase chain reaction. Despite some similarities, GR and LMDF show distinct clinical and histological features. Thus, LMDF is a distinct clinicopathological entity separate from the GR, with different etiopathogenesis. However, none of the conditions are related to a tuberculous etiology.

Hyperplastic polyps arising in autoimmune metaplastic atrophic gastritis patients: is this a distinct clinicopathological entity?

Objectives: Gastric hyperplastic polyp (GHP) commonly arises in the abnormal surrounding mucosa, including autoimmune metaplastic atrophic gastritis (AMAG). We aimed to compare clinicopathological features in patients with GHPs associated with AMAG with those in patients with GHPs associated with non-AMAG.Patients and methods: A total of 1170 patients with GHP(s) were enrolled, and their clinical and pathological data were analyzed, retrospectively.Results: The GHP patients were divided into 181 A-GHP (type A GHP, AMAG-associated GHP) participants, 312 B-GHP (type B GHP, Helicobacter pylori infection-associated GHP) participants, and 677 other GHP participants (non-A-GHP and non-B-GHP) based on pathological status of the surrounding non-polypoid mucosa. The A-GHP patients were older and predominantly female (p < .05). Gastroscopically, A-GHPs showed less distal and more multiple-region distribution in the stomach (p < .001). In addition, the A-GHPs were observed to be usually numerous (55.8%), larger (mean maximum diameter 12.3 mm), and more pedunculated or sub-pedunculated (45.3%) (p < .001). Histopathologically, the intestinal metaplasia, intraepithelial neoplasia, and carcinomatous transformation within GHPs were present in 24.3%, 9.9%, and 2.8% of AMAG patients, respectively, which were significantly higher than those in the B-GHPs and other GHPs (p < .05). However, the differences of intraepithelial neoplasia and adenocarcinoma in surrounding non-polypoid mucosa did not reach statistical significance (p > .05).Conclusions: The GHP(s) arising in AMAG patients is a distinct subgroup of GHP(s) and was an important precancerous lesion. The biopsy from surrounding non-polypoid mucosa was essential to evaluate the underlying etiology of the GHPs, and endoscopists should pay attention to these.

Conserved cell populations in doxorubicin-resistant human nasal natural killer/T cell lymphoma cell line: super multidrug resistant cells?

BackgroundExtranodal NK/T-cell lymphoma, nasal type (ENKL) is a distinct clinicopathological entity and EBV-associated disease that is highly aggressive. Many patients had failed to respond to conventional chemotherapy or relapsed after treatment. Multi-drug resistance is a major cause that leads to these desperate failures. However, the specific mechanism of drug resistance is still unclear.MethodsIn the previous study, we firstly developed a doxorubicin-resistant ENKL cell line known as SNK-6/ADM, and then a small quantity of side population (SP) cells were derived from SNK-6/ADM and named SNK-6/ADM-SP. In order to explore the biological characteristics and mechanism of drug-resistance of these cells, SNK-6, SNK-6/ADM and SNK-6/ADM-SP cells were utilized to evaluate potentially differences of chemotherapy resistance index (RI), morphology, proliferation, cell cycles, expression of ATP-binding cassette (ABC) transporters (ABCG1, ABCG2 and ABCC4) and surface markers, cytokine sensitivity, and situation of EBV infection.ResultsWe identified SNK-6/ADM-SP is a specific multidrug resistant cell population with a higher level of RI than SNK-6/ADM. Relevant evaluations showed that SNK-6/ADM-SP presented a series of conserved biological behaviors including relatively poor proliferation ability, high expression of ABCG2, weak sensitivity to IL-15 which could stimulate normal ENKL cells’ proliferation and differentiation, and EBV inhibition with low level of EBV-DNA replication and EBV-antigen expression.ConclusionsThis discovered cellular heterogeneity of ENKL could provide a new perspective to better understand the mechanisms of drug resistance and overcome elusive response to chemotherapy of ENKL.

PLEUROPARENCHYMAL FIBROELASTOSIS: A RARE CASE OF INTERSTITIAL LUNG DISEASE AND PNEUMOTHORACES

SESSION TITLE: Diffuse Lung Disease 2 SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/07/2018 04:45 pm - 05:45 pm INTRODUCTION: In 1992, an interstitial lung disease with upper lobe predominant fibrosis was first described in Japan; approximately 20 years later, the disease entity was coined as Pleuroparenchymal Fibroelastosis (PPFE). To date, there have been approximately 120 cases reported world-wide in the literature. The most common presenting complaints are shortness of breath, significant weight loss, pneumothorax, or chest pain. The pathogenesis remains unclear and the disease is often rapidly progressive with a poor prognosis. CASE PRESENTATION: We present a 65 year old female with a history of interstitial lung disease complicated by multiple pneumothoraces and GERD was admitted to our hospital with worsening shortness of breath. The patient’s history was significant for three years of profound weight loss (BMI 14), chest pain, and shortness of breath at rest and with exertion that were unresponsive to prednisone. The patient had previously worked in a many different factories, but was a lifetime non-smoker and had no other known exposure history. The physical exam was significant for a seven liter oxygen requirement, cachexia, decreased breath sounds at the apices and diffuse fine dry crackles, without skin or nail changes. CT chest revealed changes of interstitial lung disease with septal thickening and cystic changes, as well as traction bronchiectasis and ground glass opacities with upper lobe predominance and subpleural distribution, as well as bilateral apical pneumothoraces. Pulmonary function testing was consistent with a severe restrictive defect, while autoimmune and infectious work-up were unrevealing. The decision was made to perform an open lung biopsy for definitive diagnosis, which revealed features consistent with idiopathic PPFE. DISCUSSION: Idiopathic PPFE is a rare fibrosing lung disease with an upper lobe predilection that has recently been described as a distinct clinicopathological entity with definite radiological and pathological characteristics. Due in part to the heterogeneous spectrum of clinical presentation, course, and overlap with other interstitial lung disease, it remains difficult to diagnosis and lung transplantation remains the only definitive treatment. As was the case for our patient, open lung biopsy can be crucial for diagnosis and typically reveals fibrous thickening of the visceral pleura and homogeneous, dense intra-alveolar fibrosis with septal elastosis, sharply separated from the adjacent lung parenchyma. CONCLUSIONS: PPFE should be considered in the differential diagnosis of interstitial lung diseases, especially in cases where imaging reveals subpleural fibrosis and upper lobe predominance or in patients with a history of pneumothorax, as was the case with our patient. Raising awareness of this disease entity will be crucial in the future, as the prognosis is poor and early referral for lung transplantation remains the only definitive treatment. Reference #1: English JC, Mayo JR, Levy R, Yee J, Leslie KO. Pleuroparenchymal fibroelastosis: a rare interstitial lung disease. Respirology Case Reports. 2015;3(2):82-84. https://doi.org/10.1002/rcr2.108. Reference #2: Bonifazi M, Montero MA, Renzoni EA. Idiopathic Pleuroparenchymal Fibroelastosis. Current Pulmonology Reports. 2017;6(1):9-15. https://doi.org/10.1007/s13665-017-0160-5. Reference #3: Hong SK, Khoon C, Chuah L. Pleuroparenchymal Fibroelastosis: A Review. Archives of Pathology & Laboratory Medicine. 2016;140(8):849-853 DISCLOSURES: No relevant relationships by Vijayalakshmi Ananthanarayanan, source=Web Response No relevant relationships by Aaron Muhlbauer, source=Web Response No relevant relationships by Katie Young, source=Web Response