Kei Kohno

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL)

Epstein–Barr virus‐positive (EBV+) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patients background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL.

Clinicopathologic Spectrum of Gastrointestinal T-cell Lymphoma: Reappraisal Based on T-cell Receptor Immunophenotypes.

The differential diagnosis of primary gastrointestinal EBV− T-cell lymphoma (GITCL) includes enteropathy-associated T-cell lymphoma (EATL), peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma, and anaplastic large cell lymphoma. Type II EATL is considered to be a tumor of intraepithelial lymphocytes. However, the evaluation of intraepithelial lymphocytosis by biopsy specimens is challenging, which poses a diagnostic problem between the EATL and peripheral T-cell lymphoma, not otherwise specified. This situation requested us to establish a pragmatic diagnostic approach for the classification of GITCL. We identified 42 cases of GITCL and analyzed clinicopathologic features, especially addressing their T-cell receptor (TCR) phenotype. Nine (21%) of 42 GITCL cases were positive for TCR&ggr; protein expression. Among these TCR&ggr;+ cases, TCR&bgr; expression or not was detected in 5 and 4, respectively, but resulted in no further clinicopathologic differences. TCR&bgr; positivity without TCR&ggr; expression (&bgr;+&ggr;−) was seen in 9 GITCL patients (21%). Twenty-four patients (57%) were negative for TCR&bgr; and &ggr; expression (&bgr;−&ggr;−). Compared with TCR&bgr;+&ggr;− or &bgr;−&ggr;− type, TCR&ggr;+ cases were characterized by exclusive involvement of intestinal sites (100% vs. 11%, P<0.001; 100% vs. 58%, P=0.032, respectively), but not of stomach (0% vs. 78%, P=0.002; 0% vs. 38%, P=0.039, respectively). Notably, TCR&ggr; positivity was an independent unfavorable prognostic factor among our GITCL patients (P<0.001). Considering our results, TCR&ggr;+ GITCL, that is, intestinal &ggr;&dgr; T-cell lymphoma, appears to constitute a distinct disease entity.

Clinicopathological analysis of 46 cases with CD4+ and/or CD56+ immature haematolymphoid malignancy: reappraisal of blastic plasmacytoid dendritic cell and related neoplasms

In this study, we aimed to investigate the clinicopathological features of CD4+ and/or CD56+ immature haematolymphoid malignancy (iHLM), including blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression

Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly. Random skin biopsy for IVLBCL diagnosis yielded negative results. The patient experienced a rapidly deteriorating clinical course with no treatment, and died from the disease after 3 months of hospitalization. Post-mortem examination revealed systemic intravascular plugging of lymphoma cells, without mass lesions in the central nervous system or in visceral organs such as the lungs, liver, pituitary gland, ovaries, and uterus. The tumor cells were positive for CD10, CD20, BCL2, BCL6, and MUM1, but not other lineage-specific markers. Notably, the tumor cells showed strong PD-L1 expression. Our case was diagnosed as IVLBCL with neoplastic PD-L1 expression. These findings suggest that PD-L1 is associated with immune evasion of IVLBCL and may play a role in the pathogenesis and peculiar biological behavior of this unique disease. Additionally, PD-L1 may represent a possible therapeutic target for immune check-point inhibitors.

Comparison of Epstein-Barr virus-positive mucocutaneous ulcer associated with treated lymphoma or methotrexate in Japan

The aim of the present study was to compare treated lymphoma‐associated Epstein–Barr virus (EBV)‐positive mucocutaneous ulcer (EBVMCU) and methotrexate (MTX)‐associated EBVMCU.

Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?

Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous (PCNKTL) cases were characterized by an older onset age (median, 76 versus 53 years, P=.012) and a more favorable clinical course (P=.041) compared with 17 patients with stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the PCNKTL group were distributed in the face or neck (n=4) and limbs (n=3) but not the trunk, which was most frequently affected (60%, P=.017) in the latter group. Furthermore, the stage I cutaneous disease showed a female predominance (male-female, 2:5 versus 7:0; P=.021) and a significantly more favorable survival compared with the noncutaneous stage I ENKTL (P=.037). These results suggest that PCNKTL constitute a distinct subgroup in the nasal-type lymphoma spectrum.

Neoplastic PD-L1 expression on interdigitating dendritic cell sarcoma: A supplementary study of a case report: Letter to the Editor

To the Editor: Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm, accounting for slightly more than 100 cases reported in the English literature, with the largest series to date consisting of four cases. The introduction of programmed death 1 (PD1)/PD1 ligand (PD-L1) pathway inhibitors have revolutionized cancer treatment with impressive responses in a broad variety of tumor types. Much interest now focuses on tumor cell (neoplastic) PD-L1 expression in lymphoid malignancies, exemplified by classic Hodgkin lymphoma (CHL). One of the authors (SN) reported this rare disease as a single case report in 1988, the details of which were documented in a series of sequential studies. Here, we show immunohistochemical expression of PD-L1 on the tumor cells of our IDCS patient using anti-PD-L1 antibodies (SP142, 1:50, Spring Bioscience, Pleasanton, CA, USA; E1J2J, 1:50, Cell Signaling Technology, Danvers, MA, USA; and 28-8, 1:50, Abcam, Cambridge, MA, USA) (Fig. 1). Briefly, this 58-year-old male patient presented with a left neck mass in 1982. Our preferred diagnosis was malignant lymphoma, unclassifiable, but the patient posed a challenge of a differential diagnosis of CHL. The tumor recurred twice in the jejunum with involvement of the mesenteric lymph nodes despite CHOP treatment. These recurrent lesions were excised twice in 1986. The patient died of pneumonia in 1990, 101 months after the original biopsy. Autopsy revealed no residual tumor. The tumor cells were positive for CD4, CD68, CD163 (Fig. 1b), and S100 protein, but not for CD1a, CD34, CD207/ langerin, or markers of follicular dendritic cells, or B-cell or other T-cell associated antigens. Notably, our case exhibited strong immunohistochemical expression of PD-L1 on the membrane and/or in the cytoplasm of >80% of the tumor cells with all three anti-PD-L1 clone antibodies (Fig. 1c–f). To the best of our knowledge, this is the first report examining this issue in the English literature. The background T-lymphocytes were largely occupied by Fox-P3þ type, but rarely PD-1þ type, the pattern of which topologically resembled the pattern documented as governing antitumor immunity in CHL. Currently, there is no established standard for the treatment of IDCS patients. This disease also has the uncommon clinical behavior of extranodal localization or involvement of the liver (27%), spleen (18%), skin (15%), lung (12%), or small intestine (11%). We supplementarily described our case for its biological interest in neoplastic PD-L1 expression, which not only represents an attractive therapeutic target in this era of immuno-oncology, but may be associated with peculiar clinical behavior, preferably affecting the unusual extranodal sites uncommon in CHL. On the other hand, our study indicated that a diagnosis of IDCS is still challenging to pathologists because of its superficial resemblance to CHL with neoplastic PD-L1 expression. These issues should be clarified in the future.

Anaplastic variant of diffuse large B‐cell lymphoma with hallmark cell appearance: Two cases highlighting a broad diversity in the diagnostics

The anaplastic variant of diffuse large B‐cell lymphoma (A‐DLBCL) is morphologically defined but remains an enigmatic disease in its clinicopathologic distinctiveness. Here, we report two cases involving Japanese women aged 59 years, both with A‐DLBCL with the hallmark cell appearance and both indistinguishable from common and giant cell‐rich patterns, respectively, of anaplastic lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma. Case 1 was immunohistochemically positive for CD20, CD79a and OCT‐2 but not for the other pan–B‐cell markers, CD30 and ALK. Case 2 showed CD20 and CD30 positivity for 50% and 20% of tumor cells in addition to strong expression of p53 and MYC. Both were positive for fascin without Epstein–Barr virus association. Our cases provide additional support for the earlier reports that A‐DLBCL exhibits clinicopathologic features distinct from ordinal diffuse large B‐cell lymphoma (DLBCL), and documented its broader morphologic diversity than previously recognized. They also shed light on the unique feature of absent expression of pan–B‐cell markers except for CD20 and CD79a, suggesting that A‐DLBCL may biologically mimic a gray zone or intermediate lymphoma between DLBCL and classic Hodgkin lymphoma.

Hyaline vascular-type unicentric Castleman disease presenting as a subcutaneous nodule in a child

nal pain, spontaneous ecchymosis, headaches and ear rubefaction (exceptionally described). Darier’s sign was negative in most patients (5/8 presented dermatographism). We concluded that these forms of “telangiectatic mastocytosis” are not rare and probably unrecognized. It must be suspected in patients with inexplicable telangiectases associated with polymorphous symptomatology. Classical TMEP may be considered as a more infrequent subset among telangiectatic mastocytosis. Perhaps many cases are not diagnosed due to hesitation in performing biopsies of trivial lesions and the wide spectrum of additional symptomatology, which may be confused with other diverse unrelated conditions (i.e. hereditary hemorrhagic telangiectasia, unilateral nevoid telangiectasia, inflammatory ear conditions and many others in which telangiectases are not considered when making a diagnosis). In my experience, these symptoms are usually accepted by most patients and recognized as something inherent to themselves; they are often derived to other specialists, including neurologists, gastroenterologists, cardiologists and even psychiatrists, with no final diagnosis due to the improbable knowledge to link their predominant symptoms with their telangiectases. These symptoms must be obtained by focused interrogation. Repeated epistaxis and spontaneous tachycardia are some of the more frequent I have observed subsequently. Memorable ones were a female diagnosed with rosacea: while being treated with an antihistaminic for acute urticaria she told me that doing so had ceased a 1-year persistent diarrhea; and another woman with telangiectases, under psychiatric control for repeated fainting when nervous (sign exceptionally described). As Moon et al. have stated, there is no cut-off value for the increased number of mast cells; it would be useful to know their average count of mast cells (9400) because it has been the initial methodology used in many previous reports. I believe that telangiectatic mastocytosis does exist, requiring a high index of suspicious for its diagnosis. It apparently runs a benign course, and its symptomatology greatly improves with an antihistaminic, oral sodium cromoglycate or both.

Is immunohistochemical staining for β-catenin the definitive pathological diagnostic tool for desmoid-type fibromatosis?: a multi-institutional study

Immunohistochemical staining with anti-β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatoses (DFs). In recent years, specific gene mutation (CTNNB1) analysis has also been reported to be useful for diagnosis of DF; however, the association between CTNNB1 mutation status and immunohistochemical staining pattern of β-catenin is rarely reported. The purposes of this study are to clarify the relationship of the staining pattern of β-catenin with the CTNNB1 mutation status and various clinical variables, and to investigate the significance of immunohistochemical staining of β-catenin in cases diagnosed as DF. Between 1997 and 2017, 104 cases diagnosed as DF from 6 institutions in Japan were enrolled in this study: Nagoya University, National Cancer Center Hospital, Niigata University, Okayama University, Kyushu University, and Cancer Institute Hospital. For all cases, immunohistochemical staining of β-catenin and gene mutation analysis of CTNNB1 were performed. Of 104 cases, 87 (84%) showed nuclear staining of β-catenin, and 95 (91%) showed positive staining in the cytoplasm. The proportion of cases showing strong nuclear staining of β-catenin was significantly higher in the cases with S45F than in those with T41A or wild type. The proportion of cases stained strongly in the cytoplasm rather than in the nucleus was significantly higher in the group of T41A than that of S45F or wild type. Among 17 cases in which nuclear immunostaining was absent, CTNNB1 mutation was observed in 5 cases (29.4%). There were unignorable cases of DF with negative β-catenin immunostaining despite a definitive clinical and pathological diagnosis of DF and/or positive CTNNB1 mutation.