How I Diagnose Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Sarah L. Ondrejka, DO; German Ott, MD

Disclosures

Am J Clin Pathol. 2021;156(4):497-512. 

In This Article

Cases

Case 1: Primary Mediastinal (Thymic) Large B-cell Lymphoma

A 53-year-old woman with an 18 pack-year smoking history developed pleuritic chest pain, cough, and chest pressure. Evaluation included computed tomography (CT) of the chest with intravenous contrast, which revealed a large soft tissue mass of the anterior mediastinum suspicious of lymphoma. The mass bordered the pericardium and encased the pulmonary arteries. The patient was taken to the operating room for a robotic mediastinal mass resection. Histologic sections showed a dominant mass lesion composed of a diffuse infiltrate of intermediate to large lymphocytes with irregular nuclear contours, vesicular chromatin, and multiple nucleoli Figure 1. The infiltrate showed frequent interstitial sclerosis. Adjacent to the dominant mass lesion were fragments of thymus, with focal clusters of large atypical cells, both binucleate and lacunar forms, with prominent eosinophilic nucleoli (Figure 1 and Figure 2).

Figure 1.

Case 1. A, The majority of the mass demonstrated a diffuse infiltrate of tumor cells with fine sclerosis (×200). There were occasional areas of residual thymus at the periphery of the tumor (inset, ×20). B, The lymphoma cells were diffusely positive for CD20 (×200).

Figure 2.

Case 1. Few isolated clusters of apparent Hodgkin-like cells were identified in the medullary region of neighboring preserved thymic parenchyma (A and B, ×500). These cells were positive for CD30 (C, ×500) and only weakly positive for PAX5 (D, ×500).

Flow cytometric analysis identified an abnormal B-cell population expressing CD19, CD20 (bright), CD10 (dim), CD38, CD45, and FMC7 and lacking surface immunoglobulin expression. Immunohistochemistry (IHC) showed that the dominant lesion was composed of CD20-positive large cells, expressing PAX5, CD30 (dim), BCL-6, MUM1, MAL, CD23, OCT2, and BOB1 Figure 3. The large B cells were negative for CD15, TdT, and EBER in situ hybridization. The Ki-67 proliferative index was 60%. Cytokeratin AE1/3 highlighted thymic epithelium. The atypical cells in the nodules of thymic tissue outside the dominant mass had the following immunophenotype: positive for CD30, PAX5, MUM1, and MAL and negative for CD20, OCT2, and BOB1 (Figure 2).

Figure 3.

Case 1. Primary mediastinal (thymic) large B-cell lymphoma demonstrating large lymphoid cells (A, ×500) and positivity for OCT2 (B, ×500), BOB1 (C, ×500), and CD23 (D, ×500).

These features were diagnostic of PMBL. The majority of the sampled tissue (>95%) was representative of typical histology and immunophenotype. The thymic nodules outside the main mass lesion with limited clusters of atypical cells were favored to represent the Hodgkin/Reed-Sternberg–like (HRS-like) cells that are often seen in mediastinal large B-cell lymphoma rather than the small foci of a composite CHL. Notably, an inflammatory and destructive background typical of CHL was absent in these focal areas of individual HRS-like cells.

After cardiothoracic surgery, the patient underwent staging positron emission topography-CT (PET-CT), which showed a 5.3 soft tissue density in the anterior mediastinum that was read as likely reflective of residual thymic lymphoma. There was no evidence of systemic involvement or lymphadenopathy, consistent with stage IA disease. The lactate dehydrogenase (LDH) level was 347 U/L. The patient received 6 cycles of dose-adjusted rituximab-etoposide-prednisone-vincristine-cyclophosphamide-doxorubicin (R-EPOCH) and achieved a complete response evaluated by end-of-treatment PET with a Deauville score of 1. She remains in complete remission 25 months after completion of chemotherapy.

Case 2: B-cell Lymphoma, Unclassifiable, With Features Intermediate Between DLBCL and CHL (MGZL)

A 79-year-old man arrived at the hospital from a skilled nursing facility with chest pain, nausea, and new-onset atrial fibrillation. His condition was debilitated because he had recently suffered dysphagia and poor nutrition. Physical examination revealed significant lymphadenopathy in the cervical lymph nodes. A CT scan of the chest and abdomen/pelvis revealed a mass-like conglomerate of mediastinal lymph nodes separate from the thymus, with paratracheal compression, as well as enlarged lymph nodes in the mesentery.

A needle biopsy of an enlarged lymph node in the right neck was performed. Histologic sections showed an abnormal lymphoid infiltrate diffusely involving multiple needle core biopsies with areas of necrosis. The malignant cells were large, with ovoid nuclei, vesicular chromatin, prominent nucleoli, and areas of pleomorphism. IHC showed that the cells were positive for CD30 (subset), CD79a (variable), OCT2, PAX5, MUM1, and BCL2 and negative for CD20, CD45, ALK1, BOB1, and EBER in situ hybridization. The findings were concerning for a gray zone lymphoma, although the possibility of an undersampled CHL could not be excluded and an incisional biopsy was suggested for further classification.

A right neck excisional biopsy was performed Figure 4 that showed effacement by an essentially diffuse proliferation of large transformed mononuclear cells with moderate cytoplasm. Scattered throughout were large multinucleate and hyperchromatic forms. Interstitial sclerosis separated the infiltrate into trabeculae. Rare lacunar forms of Hodgkin-like cells were identified.

Figure 4.

Case 2. Mediastinal gray zone lymphoma: sheets of pleomorphic tumor cells (A, ×500) with occasional anaplastic forms (B, ×500).

Flow cytometry was negative for a monotypic B-cell population. IHC identified the same phenotype as was present in the needle biopsy, uniformly positive for PAX5 and OCT2 and negative for CD20, BOB1, and CD15 Figure 5. CD30 was positive in a subset of the cells. Fluorescence in situ hybridization (FISH) studies were negative for translocations involving BCL2, BCL6, or MYC. Polysomy of the BCL2 and MYC loci was noted. A final diagnosis of "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma" was rendered.

Figure 5.

Case 2. Mediastinal gray zone lymphoma immunophenotype positive for CD30 (A, ×500), weak CD79a (B, ×500), and PAX5 (E, ×500) and negative for CD19 (C, ×500), CD20 (D, ×500), and BOB1 (F, ×500).

Unfortunately, the patient could not be stabilized to receive intensive chemotherapy, and he died in the hospital before plans for outpatient brentuximab infusions could be initiated.

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