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AimsThe prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined.MethodsModel development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines were followed. PD-L1+ and CD30+ tumoral Reed-Sternberg cells were quantified through whole slide imaging and digital image analysis in 155 digital histopathological slides of cHL. Univariate and multivariate survival analyses were performed. The analyses were reproduced for patients with advanced stages (IIB, III and IV) using the Advanced-stage cHL International Prognostic Index.ResultsThe PD-L1/CD30 ratio was statistically significantly associated with survival outcomes. Patients with a PD-L1/CD30 ratio above 47.1 presented a shorter overall survival (mean OS: 53.7 months; 95% CI: 28.7 to 78.7) in comparison with patients below this threshold (mean OS: 105.4 months; 95% CI: 89.6 to 121.3) (p=0.04). When adjusted for covariates, the PD-L1/CD30 ratio retained prognostic impact, both for the OS (HR: 1.005; 95% CI: 1.002 to 1.008; p=0.000) and the progression-free survival (HR: 3.442; 95% CI: 1.045 to 11.340; p=0.04) in a clinical and histopathological multivariate model including the male sex (HR: 3.551; 95% CI: 0.986 to 12.786; p=0.05), a percentage of tumoral cells ≥10.1% (HR: 1.044; 95% CI: 1.003 to 1.087; p=0.03) and high risk International Prognostic Score (≥3 points) (HR: 6.453; 95% CI: 1.970 to 21.134; p=0.002).ConclusionsThe PD-L1/CD30 ratio identifies a group of cHL patients with an increased risk of treatment failure. Its clinical application can be performed as it constitutes an easy to implement pathological information in the diagnostic work-up of patients with cHL.

Follicular T cell lymphoma is derived from follicular T-helper cells. In many cases, neoplastic T cells form rosettes around Hodgkin–Reed–Sternberg-like cells, which can lead to the misdiagnosis of classical Hodgkin lymphoma. The aim of the present study was to obtain a better understanding of this rosetting phenomenon and to recognize features that are helpful in the differential diagnosis of classical Hodgkin lymphoma. Sixteen mostly elderly follicular T cell lymphoma patients (mean 66 years) were analyzed. Fifteen of the 16 follicular T cell lymphoma cases presented with Hodgkin–Reed–Sternberg-like cells, which were CD20-positive in 27% of the cases and Epstein–Barr virus-infected in nearly all cases. Frequently, the immunophenotype of rosetting neoplastic T cells differed from the bulk neoplastic cells with less numerous T-follicular helper cell markers expressed, suggesting a modulation of T-follicular helper cell marker expression in the neoplastic T cells. In 75% of the cases, variable CD30 expression was encountered in the neoplastic T cells, likely reflecting an activation state in these cells. Hodgkin–Reed–Sternberg-like cells were positive for CCL17, and follicular T cell lymphoma tumor cells expressed its receptor CCR4 at variable intensity, thus potentially explaining the phenomenon of the tumor cells’ rosetting around Hodgkin–Reed–Sternberg-like cells. In summary, this study confirms the presence of Hodgkin–Reed–Sternberg-like cells in a high number of cases of follicular T cell lymphoma, suggesting that Hodgkin–Reed–Sternberg-like cells may contribute to the development of this lymphoma. Hodgkin–Reed–Sternberg-like cells in follicular T cell lymphoma cannot reliably be differentiated from the Hodgkin–Reed–Sternberg cells of classical Hodgkin lymphoma based on their immunophenotype. In contrast, demonstration of a T-follicular helper cell phenotype with CD10 and frequent CD30 expression in the neoplastic T cell population can help to establish the diagnosis of follicular T cell lymphoma, and may even indicate CD30 as a therapeutic target for these patients.

ObjectiveIt has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA.MethodsThe expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα.ResultsCD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg).ConclusionsCD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

Systemic mastocytosis either presents as aggressive neoplasm with short survival time or indolent systemic mastocytosis with normal life expectancy. In both instances, neoplastic mast cells usually harbor the D816V-mutated variant of KIT. Phenotypically, mast cells in systemic mastocytosis usually express CD25. However, no robust marker that discriminates between aggressive and indolent variants of systemic mastocytosis has been identified yet. We here report that CD30, also known as Ki-1 antigen, is expressed in neoplastic mast cells in a majority of patients with advanced systemic mastocytosis (11/13, 85%), whereas in most patients with indolent systemic mastocytosis (12/45, 27%; P <0.001), only a few if any mast cells stained positive for CD30. These results could be confirmed by TissueFAXS analysis in subsets of patients with indolent systemic mastocytosis ( n =7) and advanced systemic mastocytosis ( n =4; P =0.008). The mast cell leukemia cell line HMC-1, derived from a patient with aggressive systemic mastocytosis also expressed the CD30 protein. In addition, we were able to detect CD30 mRNA in HMC-1 cells as well as in bone marrow biopsy samples in patients with systemic mastocytosis. In contrast, CD30 transcripts could not be detected in bone marrow biopsies in cases of reactive mast cell hyperplasia and in various other myeloid neoplasms. In conclusion, CD30 is preferentially expressed in neoplastic mast cells in advanced mast cell neoplasms. Upregulated expression of CD30 in advanced systemic mastocytosis may thus be employed as a potential marker for grading systemic mastocytosis in hematopathology.

Breast implant anaplastic large cell lymphoma is an entity recently recognized by the World Health Organization. The tumor arises around textured-surface breast implants and is usually confined to the surrounding fibrous capsule. Currently, there are no recommendations for handling and sampling of capsules from patients with suspected breast implant anaplastic large cell lymphoma without a grossly identifiable tumor. We analyzed complete capsulectomies without distinct gross lesions from patients with breast implant anaplastic large cell lymphoma. The gross appearance of the capsules as well as the presence, extent and depth of tumor cells on the luminal side and number of sections involved by lymphoma were determined by review of routine stains and CD30 immunohistochemistry. We then used a mathematical model that included the extent of tumor cells and number of positive sections to calculate the minimum number of sections required to identify 95% of randomly distributed lesions. We identified 50 patients with breast implant anaplastic large cell lymphoma who had complete capsulectomies. The implants were textured in all 32 (100%) cases with available information. Anaplastic large cell lymphoma was found in 44/50 (88%) capsules; no tumor was found in six (12%) patients who had lymphoma cells only in the effusion. The median number of sections reviewed was 20 (range, 2–240), the median percentage of sections involved by tumor was 6% (range, 0–90%), and the median percentage of sections involved by lymphoma was 10% (range, 0–90%). Invasion deep into or through the capsule was identified in 18/50 (36%) patients. In patients with breast implant anaplastic large cell lymphoma without a grossly identifiable tumor we identified a spectrum of involvement and we propose a protocol for handling, sampling and reporting these cases. The number of sections to exclude the presence of lymphoma with more than 95% certainty was supported by a mathematic rationale.

Brentuximab vedotin (BV), a CD30-targeted antibody–drug conjugate, has shown significant efficacy in CD30-positive lymphoma. However, the relationships between CD30 expression levels and BV efficacy remains unclear. In this study, we first evaluated the reliability of CD30 detection by immunohistochemistry (IHC) and found that flow cytometry (FCM) offers higher sensitivity and accuracy in assessing CD30 expression. Therefore, FCM may serve as a more effective method for evaluating CD30 levels. Furthermore, we confirmed a positive correlation between CD30 expression levels and BV efficacy. However, even when BV was applied to tumor cells with 100% CD30 expression, its anti-tumor activity did not reach complete eradication, highlighting the need for synergistic combination therapies. To address this, we conducted high-throughput screening (HTS) and identified auranofin and napabucasin as synergistic agents that enhance the efficacy of BV. These findings not only highlight the advantages of FCM for CD30 detection, but also provide valuable insights into combination strategies to optimize the therapeutic potential of BV.

Background It is important to confirm CD30 expression in T-cell lymphoma cases, but immunohistochemical staining for CD30 is not commonly performed and no comparison has been done between the results of flow cytometry (FCM) and immunohistochemical staining for CD30. Therefore, we devised a notation that we termed proportion of immunoreactivity/expression for FCM (PRIME-F notation), based on the cellular proportion showing different antigen-antibody reactivity. Methods We retrospectively compiled 211 cases of T-cell lymphoma, assessed via FCM, from major hospitals in Miyagi Prefecture from January 2012 to January 2019, and compared 52 of these cases with the immunohistochemical immunoreactive (IR) pattern of CD30 (PRIME-I notation). The PRIME-F notation was divided into five levels: notations starting with “-” followed by 3, 2, and 1 “>” correspond to level-I, level-II, or level-III; notations starting with “(dim)+” correspond to level-IV; and those starting with “+” or “(bright)+” correspond to level-V. Results The 52 cases of PRIME-F notation with “+” included 16 cases of peripheral T-cell lymphoma (PTCL/NOS), 3 of follicular T-cell lymphoma (FTL), 3 of angioimmunoblastic T-cell lymphoma (AITL), 6 of extranodal NK/T-cell lymphoma/nasal type (ENKL), 18 of adult T-cell lymphoma (ATL), and 6 cases of anaplastic large cell lymphoma (ALCL). Eight of the 52 cases were immunohistochemically CD30-negative. In the PRIME-F level-I to III group (excluding false-positive cases), 21.7% (5 out of 23 cases) were < 10% positive for CD30 upon immunohistochemistry (IHC). Contrarily, in the level-IV & -V group, no CD30 positivity rate of < 10% upon IHC was found (0%) ( p  = 0.0497). In level-IV, 42.9% of cases presented a CD30 negative rate  >  1/3 upon IHC, while in level-V, only 7.1% (one out of 14 cases) did. The CD30 negative rate tended to be low ( p  = 0.0877) in level-V. Conclusions To our knowledge, this is the first report describing the correspondence between FCM and immunohistochemistry findings for CD30 through newly proposed notations. The PRIME-F and PRIME-I notations for CD30 showed a minor positive correlation. The PRIME notation is considered universally applicable to antibodies, and notations of both FCM and IHC show great potential for big data.

Gonadal germ cell tumors continue to be the cause of diverse, diagnostically challenging issues for the pathologist, and their correct resolution often has major important therapeutic and prognostic implications. They are academically interesting because of the biological diversity exhibited in the two gonads and variation in frequency of certain neoplasms. The most dramatic examples of the latter are the frequency of dermoid cyst in the ovary compared to the testis and the reverse pertaining to embryonal carcinoma. Within the teratoma group, there is strong evidence that ovarian and prepubertal testicular teratomas are derived from benign germ cells, a pathogenesis that likely applies also to the rare dermoid cysts and uncommon epidermoid cysts of the testis. In contrast, postpubertal testicular teratomas derive from malignant germ cells, specifically representing differentiation within a preexistent nonteratomatous cancer. As expected, given the foregoing, teratomas in boys are clinically benign, whereas in postpubertal males they are malignant, independent of their degree of immaturity. On the other hand, immaturity is an important finding in ovarian teratomas, irrespective of age, although its significance in children has recently been challenged. It is usually recognized on the basis of embryonic-appearing neuroepithelium, which shows mitotic activity and apoptosis in contrast to differentiated neuroepithelial tissues, which may occur in mature ovarian teratomas. Rarely it is based on the presence of cellular, mitotically active glial tissue. Fetal-type tissues alone are not sufficient for a diagnosis of immature teratoma. Further differences between the teratomatous tumors in the two gonads are the relative frequency of monodermal teratomas in the ovary in contrast to the testis, where only one subset, carcinoids, is seen with any frequency. When uncommon somatic-type malignancies (usually squamous cell carcinoma) occur in mature cystic teratomas of the ovary, this is a de novo form of malignant transformation; similar tumors in the testis, a very rare event, represent overgrowth of teratomatous elements that originated from malignant, nonteratomatous germ cell tumors and, therefore, had previously undergone malignant transformation. Germinomas may have several unusual features in each gonad; these include microcystic arrangements that suggest yolk sac tumor, tubular patterns that mimic Sertoli cell tumor, apparent increased cytological atypia that causes concern for embryonal carcinoma, and prominent syncytiotrophoblast giant cells that suggest choriocarcinoma. Awareness of these variants, good technical preparations, the retained typical cytological features of germinoma cells, and the judicious use of tailored panels of immunohistochemical stains resolve these dilemmas in virtually all instances. Two aspects of germinomas are unique to the testis. Firstly, intertubular growth of small seminomas may cause them to be overlooked. Secondly, the distinctive spermatocytic seminoma occurs only in the testis. A newly recognized aspect of this tumor is the propensity for some to be relatively monomorphic, making them apt to be mistaken for usual seminoma or embryonal carcinoma, although the characteristic polymorphic appearance in some foci, absence of intratubular germ cell neoplasia, unclassified type, and immunohistochemical stains should prevent this error. Cytoplasmic membrane immunoreactivity for placental alkaline phosphatase and CD117, with usual negativity for AE1/AE3 cytokeratins, is helpful in the diagnosis of germinoma. The recently described marker, OCT3/4, a nuclear transcription factor, is especially helpful in the differential of germinoma and embryonal carcinoma with other neoplasms. Yolk sac tumor continues to be confused occasionally with clear cell carcinoma of the ovary. Glandular (‘endometrioid-like') yolk sac tumors mimic endometrioid carcinomas; predominant or pure hepatoid yolk sac tumors cause concern for metastatic hepatocellular carcinoma or, in the ovary, primary hepatoid carcinoma, and solid patterns, especially in limited samplings, may be misinterpreted as germinoma. The usually younger age of patients with yolk sac tumors helps with the differential considerations with the nongerm cell tumors, as do other clinical and microscopic features and selected immunohistochemical stains. Choriocarcinoma is rare in both gonads, and those in the ovary must be distinguished from metastatic tumors of placental origin. Syncytiotrophoblast cells alone, admixed with other forms of germ cell tumor, still are confused with choriocarcinoma, but this phenomenon, which is much more frequent than choriocarcinoma, lacks the plexiform arrangement of different trophoblast cell types that typifies the latter. Mixed germ cell tumors (which may show almost any combination of components) are common in the testis but rare in the ovary. A separately categorized, rare form of mixed germ cell tumor seen in both gonads is the polyembryoma. It is perhaps the most photogenic of all gonadal germ cell tumors and is also intriguing because of its distinctive, organized arrangement of yolk sac tumor and embryonal carcinoma elements and recapitulation of very early embryonic development, even to the extent of having in its fundamental unit, the embryoid body, a miniature yolk sac, and amniotic cavity. These tumors, which are constituted by innumerable embryoid bodies, almost always contain teratomatous glands in minor amounts, and one way of viewing the polyembryoma is to consider it the most immature form of teratoma. Embryoid bodies are also common as a minor component of many mixed germ cell tumors, particularly in the testis, and the diffuse embryoma is another variant that has a particular arrangement of yolk sac tumor and embryonal carcinoma elements. Regression of gonadal germ cell tumors is a phenomenon restricted to the testis, for unknown reasons. These so-called ‘burnt-out' germ cell tumors can be recognized by a distinctive constellation of findings, including sometimes minor foci of residual recognizable germ cell neoplasia, a well-defined zone of scarring (often having residual ghost tubules), associated lymphoplasmacytic infiltrate, intratubular calcification and, in about 50%, of in situ germ cell neoplasia.

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC₅₀ values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.