Cutaneous Involvement in Systemic Diffuse Large B-Cell Lymphomas

Alejandro A. Gru

DEFINITION

The overall landscape of systemic B-cell lymphomas with a large-cell component has undergone major changes in the most recent World Health Organization (WHO) classification. At this stage, it is much speculated that subsequent modifications will occur in the next few years, with the advent of recent molecular and immunophenotypic studies. The paradigm of diffuse large-cell lymphoma as a distinct entity is altered by the numerous subcategories that can be potentially included under this term. It is important to emphasize that certain prognostic biomarkers have played a significant role in the distinction between germinal center types (GCT) and nongerminal center (activated B-cell type, ABC) using gene expression profiles. Diffuse large B-cell lymphoma (DLBCL) with GCT have a better prognosis than those of ABC.¹^,² It is now widely recommended that a panel of several markers must be performed upon the diagnosis of systemic DLBCL, even when there is cutaneous dissemination by the disease. Several algorithms have been employed and, among them, the Hans algorithm is one of the most widely used.³ Under the Hans algorithm, cases with CD10 expression, or CD10⁻, MUM1−, BCL-6+ are classified as GCT. Cases that are CD10⁻ and MUM1+ are categorized as ABC (Fig. 32-1). The use of such algorithm is, however, subject to potential misclassifications in approximately 15% to 20% of cases, when comparing with gene expression profiling.³ Other algorithms, such as the ones developed by Muris et al.⁴ and Choi et al.⁵ have been used with success. In addition to such markers, fluorescent in situ hybridization (FISH) also plays an important role, as cases with an MYC⁶^,⁷ or BCL-6⁸ rearrangements tend to have a more aggressive behavior and worse prognosis.

FIGURE 32-1. Hans algorithm for subclassification of GCT versus ABC in DLBCL.

In this chapter, emphasis will be placed in describing the more recent variants of large B-cell lymphomas, reported to have cutaneous dissemination, currently included in the most recent WHO classification of hematopoietic neoplasms.

CUTANEOUS EBV+ DIFFUSE LARGE B-CELL LYMPHOMA OF THE ELDERLY

EBV+ diffuse large B-cell lymphoma of the elderly (EBV-DLBCL) was recently introduced in the more recent WHO classification as a distinct entity that occurs in patients older than 50 years of age and without any known immunodeficiency or previous lymphoma diagnosis.⁹ It appears likely that changes in the immune-status related to the aging process are linked to this lymphoma subtype. EBV-DLBCL appears to be more common in certain areas of Asia and Mexico, and more infrequent in Western countries.¹⁰ The disease has a striking predilection for extranodal sites (70%), and particularly the skin, lung, tonsils, and stomach.¹⁰^,¹¹^,¹²^,¹³ In individuals 90 years of age or older, it represents 20% to 30% of all B-cell lymphomas.¹⁰ An important factor affecting the definition of such lymphoproliferative disorder is linked to the fact that the definition of this entity has struggled with different cutoff points for the number of EBV+ cells.¹⁰ Clinically, patients can present with lymphadenopathy and cutaneous plaques and tumors.⁹^,¹⁴ Lesions are usually nonulcerated. Because sometimes lesions can present in the legs, a diagnosis of DLBCL leg type (LT) is often entertained.

Histologically, EBV-DLBCL presents with two distinctive patterns: polymorphous and monomorphous types (Figs. 32-2 and 32-3), but often a combination of the two can be present.⁹ The polymorphous variant is classically associated with a mixture of immunoblasts, plasmablasts, centroblasts, and the presence of cells with Hodgkin or Hodgkin-like appearance. The background cells include small lymphocytes, histiocytes, and plasma cells. The monomorphic variant is characterized by the presence of sheets of immunoblastic-appearing cells. Classically, lymph nodes show areas of necrosis with a geographic pattern, but such phenomenon is less common in the skin.¹³ The tumor cells express B-cell antigens (CD20, CD19, CD79a, PAX5), but some cases can have loss of CD20, as opposed to the majority of the other systemic DLBCLs. EBV-DLBCL has a nongerminal center phenotype (activated B-cell type) with expression of MUM1, and lack of expression of CD10 and BCL-6. CD30 shows variable expression in the cells, but more frequently is seen in a high proportion of cases. The detection of EBV is a prerequisite for the diagnosis (Fig. 32-4). Some cases can show expression of LMP-1 and EBNA2, which suggest a latency III type of infection, similar to posttransplant lymphoproliferative disorders.¹³ EBV-DLBCL shows activation of the NF-κβ pathway and has a monoclonal immunoglobulin light chains restriction.

FIGURE 32-2. EBV-DLBCL. A and B (H&E, 10× and 20×). There is a vaguely nodular and diffuse infiltrate extending into the subcutaneous tissue with an area of deep dermal necrosis. The infiltrate shows sparing of the surface epidermis.

FIGURE 32-3. EBV-DLBCL. A and B (100× each) highlight the areas of necrosis. C (200×) illustrates focal areas with a vague granulomatous pattern. D (100×) shows the infiltrate in the adipose tissue. E and F (400× and 600×) show diffuse sheets of large cells with an immunoblastic appearance and prominent nucleoli.

FIGURE 32-4. EBV-DLBCL—IHC. The sheets of large cells are positive for the B-cell markers PAX-5 (A) and CD20 (B). C. Clusters of large cells are positive for CD30. D. MUM1 is positive in a subset of the large cells. E. Ki67 is markedly elevated within the larger cells (70% to 80%). F. EBER is diffusely positive in the malignant infiltrate.

The differential diagnosis includes DLBCL and DLBCL-LT, which typically do not show high levels of EBV expression. Cutaneous dissemination by Burkitt lymphoma (BL) can also be linked to high levels of EBV expression in the malignant cells. But, as opposed to EBV-DLBCL, the cells are smaller, are typically more homogeneous, have a germinal center phenotype (BCL-2–, BCL-6+, and CD10⁺), are CD30⁻, and have a more variable Ki67. Plasmablastic lymphoma (PBL) can also have significant overlap with EBV-DLBCL. In fact, some cases with a monomorphic plasmablastic morphology might be impossible to distinguish on the basis of the histologic or immunophenotypic profile.¹⁵ However, PBL has also diffuse EBV+, but is more frequently negative for B-cell markers such as CD20, CD19, and PAX5. It has been shown that such distinction might be an important one, as cases of EBV-DLBCL have a worse prognosis compared to PBL.¹⁵ Other lymphomas with a plasmablastic appearance such as primary serous effusion lymphoma and diffuse large B-cell lymphoma associated with Castleman disease can be distinguished on the basis of their association with human herpes virus-8 (HHV-8). ALK+-DLBCL also has a plasmablastic appearance, but invariably shows expression of ALK1 and a rearrangement of the gene. EBV+ mucocutaneous ulcers are also seen in association with immune-suppression, and in mucosal sites (oral cavity and anal region). Although they can share similarities with the polymorphous variant of EBV-DLBCL, they differ in the clinical context where the tumors occur.

Another variant of EBV+-associated large B-cell lymphoma represents the so-called pyothorax-associated lymphoma or diffuse large B-cell lymphoma associated with chronic inflammation. These patients typically have a longstanding history of pyothorax with associated respiratory symptoms and can present with a tumor in the chest wall. The interval between the onset of pyothorax and this lymphoma is ∼37 years. This subtype shares the immunophenotype with EBV-DLBCL and commonly has MYC amplification.

The prognosis of EBV-DLBCL is very poor with a median survival of ∼2 years.⁹^,¹⁰^,¹¹^,¹²^,¹³ The treatment of the disease is complicated further by the advanced age of this population and the limited tolerability of aggressive chemotherapeutic regimens. Most of the treatment modalities include anti-CD20 (rituximab), and some have used anti-CD30 with some success (brentuximab). Experimental protocols targeting the NF-κβ pathway with bortezomib are underway.

PLASMABLASTIC LYMPHOMA

Most cases of PBL typically present in the oral cavity of individuals in association with HIV infection.¹⁶^,¹⁷ However, PBL can also occur in the setting of immune-suppression,¹⁸ after transplant,¹⁹ and in older individuals.²⁰ It can also present in children.²¹ It is typically human herpesvirus 8 (HHV-8) negative. It manifests clinically as nodules and tumors in the oral cavity and less than 30 cases have been reported in cutaneous sites.²⁰^,²²^,²¹^,²²^,²³^,²⁴ When it does affect the skin, it presents as solitary or multiple skin-colored or violaceous nodules and papules in the trunk or limbs that range from 0.5 to 12 cm in size. Some cases can present clinically as DLBCL-LT. Particular factors related to the transplant setting are linked to a higher incidence in this population, and those include: younger age, higher rejection frequency, and high doses of cyclosporine therapy.

Histologically, PBL can have a range of morphologic differentiation (Figs. 32-5 and 32-6): the plasmablasts are immunoblastic-appearing cells with a moderate-to-abundant cytoplasm, and very prominent nucleoli. In some cases, the malignant cells can show a configuration of more mature plasma cells, with coarser chromatin, eccentrical nuclei and “clock-faced” chromatin, and smaller nucleoli. Multinucleated forms and bizarre-appearing malignant cells can also be seen.¹⁷^,²⁰^,²²^,²³^,²⁴ There are frequently a very brisk number of mitoses and apoptotic cells, which can show the configuration of a “starry-sky” similar to BL. Areas of necrosis can be present. The immunophenotype of the malignant cells is characterized by the expression of plasma cell markers (CD138, vCD38, or CD38) and lack of markers of differentiated B-cells (CD19, CD20, PAX-5). CD79a and CD30 are frequently expressed, as well as EMA. Variable expression of CD56 and CD10 is seen. EBV is positive in the vast majority of cases with a latency type III pattern. Most cases have a very high proliferation index (>90%). However, cases where the plasmablastic cells show a more “plasmacytic” appearance can be accompanied by lower indices. As previously mentioned, HHV-8 is negative and, if positive, a diagnosis of primary serous lymphoma with cutaneous extension should be favored or one in association with Castleman disease.²⁵ At a molecular level, PBL shows a rearrangement or amplification of the MYC gene (45% of cases)²⁶^,²⁷ and frequently high expression of MYC by immunohistochemistry (IHC).

FIGURE 32-5. Plasmablastic lymphoma with plasmacytic differentiation. A and B (20× and 40×) show a diffuse dermal-based infiltrate that spares the epidermis. C and D (100× and 200×) show that the infiltrate is composed of cells with a vague plasmacytoid appearance and abundance cytoplasm. E and F (400×) illustrate that the tumor cells have abundant cytoplasm and variable prominent nucleoli.

FIGURE 32-6. Plasmablastic lymphoma. A (200×) shows that the malignant infiltrate focally extends to the surface mucosa in a case of PBL presenting in an HIV patient. B and C (200× and 400×). A “starry-sky” pattern is present, with numerous medium-to-large cells with a plasmablastic appearance, numerous mitoses, apoptotic bodies, and admixed macrophages. The tumor cells are positive for CD138 (D) and EMA (E), and show a high (>90%) proliferation index by Ki67 (F).

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