Steps Journal for Pathology and Laboratory Medicine (SJPLM)

The diffuse variant of NLPHL is an exceedingly rare variant, accounting for less than 25% of NLPHL cases, as described by Fan et al. The vast majority of cases typically affect young adults and children, showing a male predominance and an indolent clinical behaviour (Fan et al., 2003; Lee & LaCasce, 2009). In our case, the patient was a 39-year-old female. Contrary to the usual presentation of the diffuse variant at an advanced stage (Fan et al., 2003), our patient presented solely with an isolated swelling in the left axillary nodes, alongside a mildly elevated ESR, without any other abnormal results.

Ultrasonography is the primary radiologic method for evaluating axillary lymphadenopathy (Fujioka et al., 2021). In our patient, it revealed 6 enlarged lymph nodes within the left axilla, indicating signs of malignancy. Additionally, the ultrasound image allowed us to exclude metastatic breast cancer, which is primary differential diagnosis in cases of axillary lymphadenopathy.

The current guidelines recommend whole-body contrast-enhanced computerized tomography (CT) scan for assess the extent of malignancy (McKay et al., 2016). In our patient, a CT scan of the neck, chest, abdomen and pelvis revealed no abnormal findings.

Moreover, 18-F fluoro-deoxy-glucose-positron emission computerized tomography (FDG-PET/CT) is considered the gold standard technique for staging according to the ANN-ARBOR staging system (Lister et al., 1989). Accordingly, our patient underwent an FDG-PET/CT scan, which detected a small amount of metabolic activity in the left cervical lymph nodes, registering an SUV of 2.8, deemed benign with no further lesions indicated. Subsequently, the disease was classified as stage IA NLPHL.

Nevertheless, histological and immunohistochemical examinations remain the most reliable procedures to confirm the diagnosis of NLPHL. Typical histologic findings involve the effacement of the lymph node structure by a diffuse and mildly nodular proliferation of lymphocytes, histiocytes, dendritic reticulum cells, and the neoplastic LP cells. The latter are characterized by a popcorn-like nuclear contour, basophilic cytoplasm, and lobulated nuclei, as demonstrated in our case (Lee & LaCasce, 2009).

Immunohistochemical examination is crucial for confirming the diagnosis, characterized by the expression of CD20 along with CD45 and BCL6, while showing negativity for CD15 and CD30. Additionally, T cells, which form rosettes around LP cells, typically positive for CD57 and CD3 (Anagnostopoulos et al., 2000; Younes et al., 2021).

In our case, LP cells displayed positivity for CD45 and CD20 and negativity for CD15 and CD30. Scattered CD57-positive T cells were observed in the background surrounding LP cells. This immunostaining panel supports the diagnosis of a diffuse variant of NLPHL. Other immune stains, such as CD10, BCL-2, and BCL-6 yielded inconclusive results.

The main differential diagnosis includes the lymphocyte-rich subtype of CHL (LR-CHL), distinguished by small B-lymphocyte nodules within a rich inflammatory background.

However, unlike NLPHL nodules, LR-CHL nodules typically exhibit small germinal centers at their edges, a characteristic not observed in NLPHL. Additionally, CD30 and CD15 are expressed in approximately all cases of CHL, which contrasts with NLPHL.

T-cell/histiocyte-rich large B-cell lymphoma (THR-LBCL) presents a significant challenge as another differential diagnosis. Both diagnoses share similar histological and immunophenotypic characteristics, with a few malignant B cells dispersed within a reactive background of histiocytes and lymphocytes. Moreover, the neoplastic cells of THR-LBCL might exhibit popcorn-like nuclear contours resembling those observed in LP cells of NLPHL.

However, according to the latest edition of the Who classification, THR-LBCL is defined by a complete loss of nodular architecture and the absence of follicular dendritic cell (FDC) meshworks. Therefore, a detailed microscopic examination and the detection of even one nodule suffice to exclude the diagnosis of THR-LBCL (Anagnostopoulos et al., 2000; Hartmann & Eichenauer, 2020).

The treatment approach for NLPHL depends on the disease stage. According to the latest version of NCCN guidelines, involved-site radiation therapy (ISRT) is recommended for asymptomatic patients in early disease stages. This recommendation emphasizes that most deaths are related to secondary malignancies and chemotherapy-related toxicities rather than the disease itself (NCCN, 2021). However, this treatment approach is typically restricted to stage IA patients with a solitary lymph node involvement completely removed by biopsy which aligns with our patient’s case. Yet, the presence of histopathological variants may alter the treatment strategy.

Some studies advise against a ‘watch and wait’ strategy for patients with diffuse histological variants (Bessen et al., 2021). However, a recent study of two cases showed that these variants have not significantly influenced treatment decisions (Spinner et al., 2019).

This was the case of our patient who underwent treatment solely through complete excision of the affected lymph nodes despite the presence of the histological diffuse variant. The patient chose a ‘’watch and wait’’ approach due to planning for pregnancy, she was monitored regularly with PET scans at periodic intervals of 6 months. The most recent PET scan indicated complete remission of the disease.