SMARCB1/INI1-deficient peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a rare entity with limited reported cases. We present two additional cases in young women presenting with aggressive, treatment-refractory PTCL-NOS, and further characterizing their clinicopathologic and molecular features. Both cases demonstrated a monotonous proliferation of medium-sized atypical αβ T cells with clear cytoplasm, dual CD4/CD8 negativity, aberrant CD117 expression, cytotoxic and PTCL-TBX21 phenotype, and loss of SMARCB1/INI1 expression. Molecular analyses revealed copy-neutral loss of heterozygosity and two-copy/homozygous deletion involving the SMARCB1 gene, supporting a heterogeneous genetic basis for SMARCB1 inactivation. Clinically, both patients exhibited rapidly progressive disease with poor response to multi-modality treatment, highlighting the aggressive nature of this tumor. Our findings are consistent with prior reports, suggesting that SMARCB1/INI1-deficient PTCL-NOS preferentially affects children and young adults and demonstrates distinctive morphologic and molecular features that may facilitate recognition. Emerging evidence also indicates that SMARCB1/INI1 loss may confer sensitivity to histone deacetylase inhibitors (HDACi), supporting their potential therapeutic role in this tumor. Given the dismal outcomes associated with this entity, assessment of SMARCB1/INI1 expression should be considered in younger patients with PTCL-NOS displaying these characteristic features. Continued accumulation of cases with integrated molecular profiling, along with prospective evaluation of HDACi-based therapies, will be essential to better define disease biology and establish evidence-based treatment strategies for this aggressive lymphoma.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths globally. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor heterogeneities. However, these studies only enable gene-level quantification but neglect alterations in transcript structures arising from alternative end processing or splicing. In this study, we integrated short- and long-read scRNA-seq of CRC samples to build an isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of splicing events. Second, we characterized genes and isoforms associated with epithelial lineages and subpopulations exhibiting distinct prognoses. Among 31,935 isoforms with novel junctions, 330 were supported by The Cancer Genome Atlas RNA-seq and mass spectrometry data. Finally, we built an algorithm that integrated novel peptides derived from open reading frames of recurrent tumor-specific transcripts with mass spectrometry data and identified recurring neoepitopes that may aid the development of cancer vaccines.

Wang, Samuel Sherng Young Bmed MD1,*; Wu, Ian Qianhuang MRCP (UK), MMed2,*; Yin, Cecilia BSc3; Wang, Shi MBBS (Singapore), FRCPA (Australia)4; de Mel, Sanjay MRCP (UK), FRCPath5 Author Information

Multiple myeloma generally occurs in older adults, with the clonal proliferation of plasma cells and accumulation of monoclonal protein resulting in a broad range of clinical manifestations and complications, including hypercalcemia, renal dysfunction, anaemia, and bone destruction (termed CRAB features). A 64-year-old man with no history of malignancy presented with an enlarging precordial lump occurring three years post-sternotomy for uneventful coronary artery bypass grafting surgery. Initial investigations showed anaemia and impaired renal function. Multimodal imaging performed for further evaluation showcases the radio-pathological features which can be encountered in haematological malignancy. Subsequent percutaneous biopsy confirmed an underlying plasma cell neoplasm, and a diagnosis of multiple myeloma was achieved. The prompt resolution of the lesions upon the initiation of treatment highlights the importance of early diagnosis and treatment.

In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC) and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3 ' UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3 ' UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3 ' UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR (http://www.cbrc.kaust.edu.sa/spur/home/). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.

The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.

3'UTR shortening in cancer has been shown to activate oncogenes, partly through the loss of microRNA-mediated repression. This suggests that many reported microRNA-oncogene target interactions may not be present in cancer cells. One of the most well-studied oncogenes is the transcription factor MYC, which is overexpressed in more than half of all cancers. MYC overexpression is not always accompanied by underlying genetic aberrations. In this study, we demonstrate that the MYC 3'UTR is shortened in colorectal cancer (CRC). Using unbiased computational and experimental approaches, we identify and validate microRNAs that target the MYC coding region. In particular, we show that miR-138 inhibits MYC expression and suppresses tumor growth of CRC and hepatocellular carcinoma (HCC) cell lines. Critically, the intravenous administration of miR-138 significantly impedes MYC-driven tumor growth in vivo. Taken together, our results highlight the previously uncharacterized shortening of the MYC 3'UTR in cancer, and identify miR-138 as a potent regulator of the heterogenous MYC transcript population.

Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.

Objectives: Characterisation of tumor-infiltrating lymphocytes (TILS) population for cancer prognostication has enabled deeper understanding of tumor immune interactions in cancer immunology. We aim to examine the significance of both the density and functional status of NK cells in a cohort of Epstein Barr Virus (EBV) associated Nasopharyngeal Cancer (NPC) patients. Methods: NK TILS of 50 NPC samples were quantified on immunohistochemistry and the density of NK TILS was correlated with clinical outcomes. Next, NK cells and a panel of cytokines of 10 newly diagnosed NPC patients were characterized in both NPC tissue and peripheral circulation. Exhausted NK cells were identified using co-expression of PD-1 and/or Tim-3. Comparison of percentage of NK cells in NPC and healthy controls was performed using student t-test for two groups; and a p value of less than 0.05 values was considered significant. Results: NK TILS exhibited a bimodal distribution; with the NKhigh cohort demonstrating a poorer 2-year overall survival rate (p < 0.035). In-vitro studies revealed a higher proportion of infiltrated NK cells in the NKhigh cohort co-expressed PD-1. Additionally, IL-18 levels in NPC tissue were significantly higher than in healthy nasopharynx; and IL-18 alone induced PD-1 expression on NK cells. Expectedly, plasma IL-18 concentration and percentage of circulating PD-1-expressing NK cells were similar among NPC patients and healthy controls. Conclusion: The cytotoxic function of NK TILS is mitigated by an elevated IL-18 levels within the NPC micro-environment. Hence, the functional status, and the density of NK cells in TILS should be considered when prognosticating NPC.

A 40-year-old man, ex-smoker with a history of type 2 diabetes mellitus and previous Helicobacter pylori associated gastritis, presented with heartburn, globus sensation, and early satiety. An esophagogastroduodenoscopy was performed and noted multiple flat hyperpigmented areas in the mid-esophagus (Figures A, arrows and B). Targeted biopsies of the esophageal lesion showed scattered squamous cells and melanocytes containing brownish melanin pigments in the basal portion of the esophageal squamous mucosa (Figure C, arrows). The presence of melanocytes in the squamous mucosa was confirmed on SOX10 stain (Figure D, arrows). Esophageal melanocytosis is a rare endoscopic finding that is found in up to 0.2% of esophagogastroduodenoscopies. It is characterized by proliferation of melanocytes and accumulation of melanin pigments in the esophageal squamous mucosa.1Chang F. Deere H. Esophageal melanocytosis morphologic features and review of the literature.Arch Pathol Lab Med. 2006; 130: 552-557Crossref PubMed Google Scholar The presence of melanocytes can be confirmed by a variety of immunohistochemical melanocytic markers such as S100, Melan-A, SOX10, and HMB-45. It is a benign finding that is more commonly found in men and is associated with gastroesophageal reflux disease.2Ohashi K. Kato Y. Kanno J. et al.Melanocytes and melanosis of the oesophagus in Japanese subjects: analysis of factors effecting their increase.Virchows Arch A Pathol Anat Histopathol. 1990; 417: 137-143Crossref PubMed Scopus (70) Google Scholar Some case reports have suggested that melanocytosis may be a precursor lesion toward primary malignant melanoma of the esophagus, although there are currently no formal recommendations for endoscopic surveillance. Our patient’s symptoms improved following lifestyle and dietary advice for gastroesophageal reflux disease as well as the initiation of high-dose proton pump inhibitor therapy.

Epstein-Barr virus (EBV)-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases (EBV-TNKLPD) are a group of uncommon disorders characterised by EBV infection of T- and NK-cells. As a group, EBV-TNKLPD are more commonly encountered in Asians and Native Americans from Central and South America compared to Western populations. They encompass a spectrum of entities that range from non-neoplastic lesions such as EBV-associated haemophagocytic lymphohistiocytosis (EBV-HLH) to more chronic conditions with variable outcomes such as chronic active EBV infections (CAEBV) of T- and NK-cell type (cutaneous and systemic forms) and malignant diseases such as systemic EBV-positive T-cell lymphoma of childhood, aggressive NK-cell leukaemia, extranodal NK/T-cell lymphoma, nasal-type, and primary EBV-positive nodal T/NK-cell lymphoma. Due to their rarity, broad clinicopathological spectrum and significant morphological and immunophenotypic overlap, the diagnosis and precise classification of EBV-TNKLPD often pose a challenge to clinicians and pathologists. Correct classification of this group of rare diseases relies heavily on the age of onset, disease presentation, duration of symptoms and cell of origin (T- vs NK-cell lineage). In this review, we provide an update on the clinicopathological and molecular features of the various EBV-TNKLPD entities occurring in non-immunocompromised patients and present a practical algorithmic approach for the general pathologist who is confronted with these disorders in routine clinical practice.

Post-transplant lymphoproliferative disorders (PTLDs) are uncommon lymphoid and/or plasmacytic proliferations that can occur in patients after undergoing solid organ or haematopoietic stem cell transplantation, secondary to extrinsic immunosuppression inherent in these procedures. In the context of haematopoietic stem cell transplantation, the large majority of reported PTLDs occur in patients who received allogenic haematopoietic stem cell transplantation (AlloHSCT). Only a few cases of PTLD following autologous haematopoietic stem cell transplantation (AHSCT) have been reported.1Awaya N. Adachi A. Mori T. et al.Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem cell transplantation for relapsed angioimmunoblastic T-cell lymphoma.Leuk Res. 2006; 30: 1059-1062Crossref PubMed Scopus (27) Google Scholar, 2Jenkins D. DiFrancesco L. Chaudhry A. et al.Successful treatment of post-transplant lymphoproliferative disorder in autologous blood stem cell transplant recipients.Bone Marrow Transpl. 2002; 30: 321-326Google Scholar, 3Zambelli A. Lilleri D. Baldanti F. et al.Hodgkin's disease as unusual presentation of post-transplant lymphoproliferative disorder after autologous hematopoietic cell transplantation for malignant glioma.BMC Cancer. 2005; 5: 109Google Scholar, 4Lohrisch C.A. Nevill T.J. Barnett M.J. et al.Development of a biologically distinct EBV-related lymphoproliferative disorder following autologous bone marrow transplantation for an EBV-negative post-renal allograft Burkitt's lymphoma.Leuk Lymphoma. 2000; 39: 195-201Google Scholar, 5Lones M.A. Kirov I. Said J.W. et al.Post-transplant lymphoproliferative disorder after autologous peripheral stem cell transplantation in a pediatric patient.Bone Marrow Transplant. 2000; 26: 1021-1024Crossref PubMed Scopus (29) Google Scholar, 6Peniket A.J. Perry A.R. Williams C.D. et al.A case of EBV-associated lymphoproliferative disease following high-dose therapy and CD34-purified autologous peripheral blood progenitor cell transplantation.Bone Marrow Transplant. 1998; 22: 307-309Crossref PubMed Scopus (35) Google Scholar We herein report the rare interesting case of an Epstein–Barr virus (EBV) negative monomorphic B-cell plasmacytoma post-transplant lymphoproliferative disorder (PTLD), developing in a patient who received AHSCT for treatment of advanced stage classic Hodgkin lymphoma (CHL). A 23-year-old male presented to our institution 4 years previously with fever, weight loss and shortness of breath of 2–4 months duration. Positron emission tomography (PET) scan performed showed a fluorodeoxyglucose (FDG) avid, large, bulky, 10.6 cm anterior mediastinal mass, multiple FDG avid lymph nodes above and below the diaphragm, as well as multiple FDG lesions in the axial skeleton. A biopsy of the anterior mediastinal mass was performed, and the patient was diagnosed with nodular sclerosis CHL (Fig. 1A). The patient was treated with six cycles of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) and radiotherapy to the mediastinum. The patient achieved complete remission based on positron emission tomography (PET) scan findings after the treatment. However, 2 years later he developed new FDG avid lymphadenopathy above and below the diaphragm, as well as new FDG avid iliac bone lesions. Biopsy of the iliac bone showed disease relapse of CHL. The patient received platinum-based salvage chemotherapy for the disease relapse. After harvesting of peripheral blood stem cells, he underwent AHSCT. The conditioning regimen consisted of carmustine, etoposide, cytarabine and melphalan. Unmanipulated haematopoietic stem cells were administered at a cell dose of 2.78 × 106 CD34+ cells/kg. The patient had an episode of culture negative neutropenic fever post-AHSCT, from which he subsequently recovered. He was not put on any immunosuppressive drug regimen post-AHSCT. Three and a half months following AHSCT, the follow-up PET scan showed new FDG avid left submental and level II cervical lymph nodes. An excision biopsy of a left level II cervical lymph node was performed. On histology, the cervical lymph node architecture was preserved with presence of reactive lymphoid follicles. There were increased numbers of small mature plasma cells noted in the paracortical areas and sinuses (Fig. 1B). No neoplastic Reed–Sternberg cells were seen. The histological diagnosis at that time was a lymph node with reactive changes. However, the patient had a persistently enlarged submental lymph node on follow-up, which was excised 2 months later. On histology, the submental lymph node showed notable architectural effacement by confluent sheets of small mature plasma cells and medium to large lymphoid cells with eccentric nuclei and conspicuous nucleoli, consistent with plasmablasts (Fig. 1C,D). Immunohistochemical (IHC) studies were performed (Fig. 2A–G). The plasma cells and plasmablasts were positive for CD79A and CD138. Only a small proportion of plasmablasts expressed CD20 and CD30. The plasma cells and plasmablasts were negative for CD3, PAX5 and CD56. Kappa and lambda light chains encoded RNA in situ hybridisation was performed. The plasma cells and plasmablasts showed evidence of lambda light chain restriction, indicating a monoclonal mature B-cell population. EBV encoded RNA (EBER) in situ hybridisation was also performed. The plasma cells and plasmablasts showed no evidence of EBV infection. The Ki-67 proliferative index of the plasmacytic/plasmablastic infiltrate was up to ∼50%. Immunoglobulin heavy chain (IgH) gene rearrangement study performed using BIOMED2 primers showed a monoclonal gene rearrangement (Fig. 2H). A final diagnosis of an EBV-negative monomorphic B-cell plasmacytoma PTLD was made. Bone marrow studies, bone skeletal survey and other blood investigations performed excluded the diagnosis of myeloma. A subsequent PET scan showed localised disease, comprising mild uptake FDG-avid small volume lymph nodes, confined to the cervical region. The patient was otherwise clinically well with no B symptoms of fever, night sweats and weight loss. After a multi-disciplinary tumour board discussion, the decision was made for watchful waiting with no chemotherapy given for his PTLD. Three months later, follow-up PET scan surprisingly showed resolution of FDG-avid lymph nodes with minimal uptake seen. The resolution was attributed to the patient's immune reconstitution.Fig. 2(A) The plasma cells and plasmablasts are positive for CD79A and (B) CD138. (C) The Ki-67 proliferative index is up to ∼50%. (D) Kappa-ISH and (E) lambda-ISH: the plasma cells and plasmablasts show evidence of lambda light chain restriction. (F) The plasma cells and plasmablasts are negative for EBER-ISH and (G) CD56. (H) A monoclonal gene rearrangement is detected on immunoglobulin heavy chain (IgH) gene clonality assay by polymerase chain reaction.View Large Image Figure ViewerDownload Hi-res image Download (PPT) PTLDs are lymphoid or plasmacytic proliferations that can occur as a result of immunosuppression after solid organ and haematopoietic stem cell transplant (HSCT). The four main categories of PTLDs are non-destructive (early), polymorphic, monomorphic and classic Hodgkin lymphoma.7Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.Revised 4th ed. IARC Press, Lyon2017: 453-462Google Scholar PTLDs are more often EBV positive, but can also be EBV negative. In contrast to EBV positive PTLDs, EBV negative cases are more common in adults, of later onset after transplant, and are more likely to be of monomorphic subtype.8Nelson B.P. Nalesnik M.A. Bahler D.W. et al.Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?.Am J Surg Pathol. 2000; 24: 375-385Crossref PubMed Scopus (262) Google Scholar Most cases of PTLD developing after HSCT occurred in the first 6 months post-transplant.9Heslop H.E. How I treat EBV lymphoproliferation.Blood. 2009; 114: 4002-4008Crossref PubMed Scopus (212) Google Scholar There have only been a few reported cases, mostly in the form of case reports, of PTLDs developing after AHSCT as compared to AlloHSCT. This is unsurprising as AHSCT involves a lesser degree of immune suppression than AlloHSCT. The large majority of reported cases of PTLDs developing after AHSCT are EBV positive. Only one case of an EBV negative PTLD with features of Hodgkin lymphoma has been reported.3Zambelli A. Lilleri D. Baldanti F. et al.Hodgkin's disease as unusual presentation of post-transplant lymphoproliferative disorder after autologous hematopoietic cell transplantation for malignant glioma.BMC Cancer. 2005; 5: 109Google Scholar To the best of our knowledge, ours is the first reported case of an EBV negative monomorphic B-cell plasmacytoma PTLD following AHSCT. The main differential diagnosis considered for our case was a de novo primary nodal plasma cell neoplasm/plasmacytoma. The diagnosis of PTLD, rather than a de novo plasmacytoma, was supported by disease presentation within 6 months following AHSCT and the apparent improvement of disease without chemotherapy. The disease improvement was attributed to the gradual full restoration of the patient's immune system after the immunosuppressive effects of the AHSCT had dissipated. The histological findings of plasmacytic hyperplasia with preserved nodal architecture in the initial cervical lymph node biopsy specimen were most likely on hindsight a form of non-destructive PTLD. This was followed by progression into a monomorphic PTLD with architectural effacement, as evident in the subsequent submental lymph node biopsy specimen. Non-destructive PTLDs, in contrast with the other subtypes, are defined as lymphoid or plasmacytic proliferations that do not show architectural effacement and do not meet any diagnostic criteria of any known lymphoid neoplasms. The old term of ‘early PTLD’ was dropped in the revised 4th Edition World Health Organization (WHO) classification to avoid confusion with various PTLDs that occur with an early onset after transplantation.7Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.Revised 4th ed. IARC Press, Lyon2017: 453-462Google Scholar Non-destructive PTLDs occur more commonly in younger patients with no prior EBV infection. Polymorphic PTLDs show features of architectural effacement, but do not meet diagnostic criteria of any known lymphoid neoplasms. The histological features of monomorphic PTLDs on the other hand will meet the diagnostic criteria of known lymphoid neoplasms as seen in immunocompetent patients. The survival outcomes and treatment modalities of PTLDs are highly variable. The non-destructive PTLDs generally have good clinical response to just reduction in immune suppression. On the other hand, polymorphic and monomorphic PTLDs, besides reduction in immune suppression, may need additional treatment like radiotherapy, surgery, anti-CD20 rituximab drug therapy, immunotherapy and other forms of systemic chemotherapy for disease control. The type of treatment is dependent on the exact PTLD histological subtype, age, disease stage and other blood investigations like lactate dehydrogenase levels. Plasmacytoma PTLD is a rare form of monomorphic B-cell PTLD that is more commonly reported in adult patients. The histological features are similar to those of plasmacytoma in immunocompetent patients, and are usually composed of sheets of plasma cells with light chain restriction. Some cases also have smaller foci of large lymphoid cells with nucleoli resembling plasmablasts. Many cases of plasmacytoma PTLD have had good clinical outcomes even with limited therapy.10Trappe R. Zimmermann H. Fink S. et al.Plasmacytoma-like post-transplant lymphoproliferative disorder, a rare subtype of monomorphic B-cell post-transplant lymphoprolifertion, is associated with a favourable outcome in localized as well as in advanced disease: a prospective analysis of 8 cases.Haematologica. 2011; 96: 1067-1071Crossref PubMed Scopus (46) Google Scholar, 11Perry A.M. Aoun P. Culter D.W. et al.Early onset, EBV(-)PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis.Blood. 2013; 121: 1377-1383Crossref Scopus (23) Google Scholar The resolution of plasmacytoma PTLD in our case, attributed to the patient's immune reconstitution, supported those findings. Various treatment options of plasamcytoma PTLD include reduction of immune suppression, localised radiation, surgery and systemic chemotherapy based on myeloma protocols.10Trappe R. Zimmermann H. Fink S. et al.Plasmacytoma-like post-transplant lymphoproliferative disorder, a rare subtype of monomorphic B-cell post-transplant lymphoprolifertion, is associated with a favourable outcome in localized as well as in advanced disease: a prospective analysis of 8 cases.Haematologica. 2011; 96: 1067-1071Crossref PubMed Scopus (46) Google Scholar, 11Perry A.M. Aoun P. Culter D.W. et al.Early onset, EBV(-)PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis.Blood. 2013; 121: 1377-1383Crossref Scopus (23) Google Scholar In summary, we present a case of EBV negative monomorphic B-cell plasmacytoma PTLD in a patient who received AHSCT for advanced stage CHL. It is important for pathologists and treating haematologists to diagnose and recognise PTLDs, as their first line of treatment is usually reduction in immune suppression. Some forms of PTLD also have good prognosis even with minimal to limited therapy. The authors state that there are no conflicts of interest to disclose.

Polo-like kinase-1 (PLK1) regulates the MYC-dependent kinome in aggressive B-cell lymphoma. However, the role of PLK1 and MYC toward proliferation in diffuse large B-cell lymphoma (DLBCL) is unknown. We use multiplexed fluorescent immunohistochemistry (fIHC) to evaluate the co-localization of MYC, PLK1 and Ki67 to study their association with proliferation in DLBCL. The majority (98%, 95% CI 95-100%) of MYC/PLK1-double positive tumor cells expressed Ki67, underscoring the key role of the MYC/PLK1 circuit in proliferation. However, only 38% (95% CI 23-40%) and 51% (95% CI 46-51%) of Ki67-positive cells expressed MYC and PLK1, respectively. Notably, 40% (95% CI 26-43%) of Ki67-positive cells are MYC- and PLK-negative. A stronger correlation exists between PLK1 and Ki67 expression (R = 0.74, p < .001) than with MYC and Ki67 expression (R = 0.52, p < .001). Overall, the results indicate that PLK1 has a higher association than MYC in DLBCL proliferation and there are mechanisms besides MYC and PLK1 influencing DLBCL proliferation.

A 64-year-old man presented with gastrointestinal bleeding and inguinal lymphadenopathy. His lymph node biopsy is presented in slide A. An IgM paraprotein was detected in his serum while a full blood count and film suggested iron deficiency with no lymphocytosis. A small bowel mass was detected on CT scan but the patient declined further investigations including bone marrow studies. He was treated based on the lymph node histology with transient resolution of the bleeding. He subsequently underwent resection of the small bowel mass due to recurrent bleeding. The histology of the small bowel mass is presented in slide B. Review the high-quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2017-204415\_A/ and http://virtualacp.com/JCPCases/jclinpath-2017-204415\_B/ …

BackgroundA significant proportion of patients with colorectal cancer (CRC) presents with metastatic disease. In younger patients, a more aggressive approach is often adopted in an attempt to achieve cure and improve survival. The aim of this paper is to review the management and outcomes of young patients with metastatic CRC.MethodsAll patients under 50 years diagnosed with CRC in a single institution from January 2007 to December 2015 were reviewed. Patient demographics, details of their treatments, progress and outcomes of treatment were collected for our review.ResultsThere were 154 newly diagnosed CRC patients who were <50 years old during the study period. Thirty-three patients (21.4%) had stage IV disease on presentation. Seventeen (51.5%) of these 33 patients were treated with curative intent; 9 (52.9%) of whom underwent upfront surgical resection alone while the remaining 8 (47.1%) patients had neoadjuvant therapy followed by surgical resection. Among the 16 patients who were treated with palliative intent, 9 (56.3%) had surgery while 7 (43.7%) had definitive chemo- or radio-therapy. There was no significant difference in the median survival of patients treated with curative and palliative intent (29 vs. 24 months, P=0.140).ConclusionsYoung CRC patients with stage IV disease typically survive for 2 years upon diagnosis. Those who were treated and underwent surgery with curative intent have a slightly longer but not statistically significant median survival than those treated with palliative intent. The role of aggressive treatment in these young patients with metastatic patients merits further evaluation.

The biliary duct is an extremely rare site for colon cancer metastasis. It often leads to a diagnostic dilemma, since primary cholangiocarcinoma (potentially treatable with surgery) has a similar presentation. This paper highlights our experience with 5 consecutive patients who had colon malignancy with biliary metastasis, and prognosis of their disease. Five patients, with a history of primary colon cancer since 2010, were identified to have biliary metastasis. Of these, 4 (80.0%) patients were male. The median time to diagnosis of biliary metastasis from diagnosis of colon cancer was 59.2 months (0-70.1 months), and all exhibited symptoms of biliary obstruction or its associated complications. Evaluation of the tumour samples revealed all specimens to be negative for CK7 but positive for CK20, suggestive of a colorectal primary. The median survival of the 5 patients was 23.5 months (1.8-44.5 months) from the diagnosis of biliary metastasis. However, none of their death was related to the direct complication of biliary obstruction. Biliary metastasis is a rare entity for metastatic colon malignancy. Diagnosis may be difficult radiologically, and immunohistochemical staining may help in identification. The overall survival for these patients is dismal.