At present, pathologic features of A-DLBCL have not been fully clarified. A-DLBCL is a disease with rare B cell phenotype and genotype variation, which have overlapping clinicopathological features between gray zone lymphoma and classical Hodgkin lymphoma (CHL).5 The most of A-DLBCL occurs in lymph nodes but also can occur in any part outside of it, such as tonsil, testis, posterior nasal cavity, retroperitoneum, prostate, liver and intestine, pancreas, thyroid, thymus, central nervous system, pleura, skin, etc. Otherwise, lesions involved with extranodal organ or lymph node show the similar morphological characteristics, both were sinusoidal growth or diffuse adhesive cancer-like growth.[1], [2], 4, 6, 7–10 But there may be different features in patients that occurred in outside of lymph nodes, such as the primary central nervous system of A-DLBCL have unique genetic and biological characteristics, often with MYC/BCL2 double expression, accompanied by MYC, Bcl2 and/or Bcl6 gene abnormalities, besides, NF-κ B pathway is constitutively activated, so prognosis is also more worse than universal A-DLBCL. 11,12 In addition, A-DLBCL can also be transformed from low-grade mucosa associated lymphoid tissue gastric tissue lymphoma.13 It needs more research about whether A-DLBCL occurred in the skin, mucosa, and other sites have different characteristics.
In terms of morphology, the previously reported cases of A-DLBCL are sinusoidal growth, while our case provided in this paper are follicular or germinal-center-like growth. Due to the limitation of quantity, its mechanism is still unknown. The morphology of A-DLBCL is more diverse than ordinary DLBCL. A-DLBCL is often sinusoidal or solid, adherent, and characterized by large, bizarre cells. These cells mixed with common immunoblastic cells and centroblastic cells of DLBCL and have bizarre nuclei that can be HRS-like, horseshoe-shaped, kidney-shaped, doughnut-like, which is similar to tumor cells of anaplastic large cell lymphoma. At present, the diagnosis of A-DLBCL mainly depends on morphology, especially HRS-like cells, which always grow in sheets, in the study of professor Nirmeen A. Megahed2 and professor Zhe Wang et al4, the probability of HRS-like cells in A-DLBCL was 72% (13/18) and 51% (17/35) respectively, but whether the presence of HRS-like cells in A-DLBCL is related to the pathogenesis of A-DLBCL and CHL still needs further study. Some scholars believe that EBV may play a role in the pathogenesis of some of these tumors. 14
About treatment, for patients with DLBCL, approximately 60%-70% of them can be cured by standard therapy, which contains rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP). Although this patient was not accepted standard therapy, majority of tumor cells of this case are positive for CD30, it may demonstrate durable responses if treat with Brentuximab vedotin. Brentuximab vedotin is an antibody-drug conjugate that targets CD30 with significant effects approved for the treatment of relapsed, refractory non-Hodgkin disease, but Brentuximab vedotin also has toxicity and side effects, such as peripheral neuropathy, which is a major reason why Brentuximab vedotin cannot be used for a long time, but this lesion is reversible and can be recovered after discontinuation.15–17 Brentuximab vedotin was active in DLBCL with some level of CD30 expression, with an objective response in 44% of patients.18
In the study of biomarker of prognosis in DLBCL, CD30 has always been a research hotspot, which is of great significance for the diagnosis of A-DLBCL, but it is not a necessary condition. Compared with other immunophenotypes, the positive rate of CD30 of anaplastic variants are higher, which was often less than 90% .10 Moreover, its positive signal was always located in the tumor cell membrane, unlike the classic ALCL, it is more located in the tumor cell membrane and Golgi region. 19 In 2001, New Zealand scholars proposed that the expression of CD30 in A-DLBCL may be related to its anaplastic features and survival rate.20 In previous studies, it is still controversial about whether CD30 is related to the prognosis of patients. Hao et al21 believed that the expression of CD30 was related to B cell symptoms, non-germinal center immunophenotype and poor prognosis, Noorduyn LA et al22 thought that the expression of CD30 was not related to the survival rate of patients, while Hu23 and Slack et al24 reported that CD30 positive DLBCL had superior 5-year overall survival rate and progression free survival rate in GCB and N-GCB subtypes. Therefore, whether the expression of CD30 is related to prognosis remains to need further studied. But compared with CD30 negative A-DLBCL, CD30 positive A-DLBCL has a higher p53 mutation rate trend4, which may suggest that the expression of CD30 may have an adverse impact on the prognosis.
A-DLBCL has different genetic changes and biological characteristics from ordinary DLBCL. There are literature suggested that A-DLBCL may biologically mimic gray zone or intermediate lymphoma between DLBCL and classic Hodgkin lymphoma(CHL).25, 26The main prognostic factors of DLBCL are closely related to GCB type or non-GCB type, and prognosis of the former may be better.4, 27–29 About 30% of DLBCL cases have MYC and BCL2 overexpression, which is called double expression lymphoma, compared with MYC or BCL2 single or no overexpression, prognosis of the former is worse, while double expression lymphoma is more common in ABC subtype, which may affect the prognosis to some extent.30–33 However, patients of DLBCL with MYC and Bcl6 rearrangement or co-expression do not always have a poor prognosis.34 MYC protein plays an important role in a variety of cellular processes, including cell proliferation and differentiation, cell cycle progression, metabolism and apoptosis, and MYC is usually overexpressed in human cancer.35, 36 However, it has not been elucidated about whether MYC overexpression alone is associated with the prognosis of A-DLBCL. Prognostic factors for A-DLBCL may include the origin of tumor cells, genetic alterations, etc. Compared with ordinary DLBCL, A-DLBCL are more prone to have high-stage disease, extra-lymph nodes involvement, elevated serum LDH and high international prognostic indicators (IPI), however, the incidence of complete remission (CR) during chemotherapy is low (P < 0.05).4 Factors affecting the prognosis of A-DLBCL include the source of tumor cells, genetic changes, etc. Zhe Wang group in 2017 found that patients with A-DLBCL have a bigger probability to be non-GCB immunophenotype, have expression of CD30, p53 mutation, abnormalities of MYC, BCL2 and (or) BCL6 simultaneously (P < 0.05). 4 Overexpression of C-MYC and Bcl-2 protein, as well as TP53 mutation may lead to poor prognosis.4, 28 Expression of Bcl-6 may be related to the development of primary central nervous system lymphoma, but it is also a potential and independent favorable prognostic marker. 28 The prognosis of A-DLBCL and its factors need to be studied further.