Primary cutaneous diffuse large B-cell lymphoma of the upper limb: a fascinating entity.

Primary cutaneous lymphomas are defined as lymphoid neoplasms that present themselves clinically on the skin and do not have extra-cutaneous disease, when the diagnosis is made or even after 6 months of the diagnosis. Primary cutaneous lymphomas of B-cells are less frequent than lymphomas of T-cells. Primary B-cell lymphomas have a better prognosis than secondary B-cell lymphomas. Primary B-cell cutaneous lymphomas are classified into five types according to the World Health Organization and European Organization for Research and Treatment of Cancer classification. The primary diffuse large B-cell cutaneous lymphoma - leg type corresponds to approximately 5-10% of the B-cell cutaneous lymphomas. It is predominantly seen in elderly people and has a female preponderance. Skin lesions can be single, multiple, and even grouped. A 5-year survival rate ranges from 36 to 100% of the cases. The expression of Bcl-2, presence of multiple lesions, and involvement of both the upper limbs lead to a worse prognosis. Very few cases have been described in the literature.

What was known?

Primary B cell cutaneous lymphoma – leg type has a predominant female preponderance and occurs usually on the legs.

Introduction

Non-Hodgkin Lymphomas (NHL) are neoplasms of the lymphoreticular system and may originate from three lineages of lymphoid cells: B, T, and NK (natural killer). A variety of T and B-cell neoplasms can involve the skin, either primarily or secondarily. The term “primary cutaneous lymphoma” refers to cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas that present in the skin with no evidence of extra-cutaneous disease at the time of diagnosis or even after 6 months of the diagnosis. They show considerable variation in its clinical, histological, immunophenotypic presentation, and prognosis.[12] Primary cutaneous lymphomas of B-cells occur less frequently than primary CTCLs. B-cell lymphomas comprise 20-25% of all primary cutaneous lymphomas. From a dermatological point of view, they are characterized by few lesions, in general showing nodules or infiltrations of relatively fast growth that are different from the T lymphomas and have no itching. From a histopathological view, they are in general, monomorphic (large or small cell), and the neoplastic cell infiltrate is separated from the epidermis by a collagen band (Grenz zone). Rare cases show epidermotropism and can be confused with mycosis fungoides. Primary B-cell lymphomas have a better prognosis than the secondary B-cell lymphomas. Neoplastic B-cells express markers-CD19, CD20, and CD79a. As per the World Health Organization and European Organization for Research and Treatment of Cancer classification for primary B-cell cutaneous lymphomas, they are classified in five types: Marginal zone primary cutaneous B-cell lymphoma, Centrofollicular primary cutaneous lymphoma, Diffuse large B-cell primary cutaneous lymphoma – leg type, Large B-cell primary cutaneous lymphoma (NOS) and Intravascular large B-cell primary cutaneous lymphoma [Table 1]. The diagnosis is made by the clinicopathological correlation, immunohistochemical findings, and molecular pathology.[3] The primary diffuse large B-cell primary cutaneous lymphoma – leg type (PDLBCL-LT) comprise 5-10% of the B-cell cutaneous lymphomas, affecting the lower limbs more frequently, although they may also affect other areas. PDLBCL-LT is usually seen in elderly female subjects and often presents clinically as a solitary lesion. The 5-year survival rate of this variant of primary B-cell lymphoma is seen in 36 to 100% of the cases. The poor prognostic markers for PCLBCL-LT are – expression of Bcl-2 by neoplastic cells, presence of multiple lesions, and involvement of both the upper limbs.[4] There are very few cases described in literature from the West. We report our experience of one such case.

Table 1

Differences between the five types of primary cutaneous B-cell lymphomas

Case Report

A male patient, aged 82, retired accountant by profession, sought medical assistance in October 2011, complaining of a nodular skin swelling on the upper medial arm [Figure 1a]. The patient initially reported the appearance of small swellings in the right arm, which slowly progressed to a nodular growth over a period of many months. He denied any history of developing a rash, fever, night sweats, or weight loss. Clinical examination revealed a nodular swelling, reddish in appearance, mobile, non-tender, firm in consistency, and measuring 5 cm × 3 cm in size. Neither any axillary or generalized lymphadenopathy nor hepatosplenomegaly were detected. His systemic examination did not reveal any abnormality. Investigations revealed him to have a normal hematological profile, i.e., hemoglobin (13.9 g/dL), platelet count (2,20,000/mm3), ESR –11 mm fall at the end of 1st h, TLC (8,200/mm3), DLC P (64) L (32) M (01) E (03), and Prothrombin time 15/14 s. His biochemical parameters did not show any abnormality, i.e., blood urea – 56 mg/dL, serum creatinine-1.2 mg/dL, normal blood sugar profile, serum sodium – 139 mEq/L, potassium – 4 mEq/L, total bilirubin – 0.6 mg/dL, serum total proteins – 6.5 mg/dL, albumin – 4.3 mg/dL, globulin – 2.2 mg/dL, serum AST – 22 IU/L, and serum ALT – 16 IU/dL. He was found to be non-reactive for HBsAg, HCV, and HIV antigens. Urine routine and microscopic examination was unremarkable. He underwent a wide local excision of the lesion on 25 October 2011 at a civil hospital with a clinical diagnosis of an abscess. The histopathological review done at our center showed an unencapsulated tumor in the superficial dermis, with distortions of the natural architecture of the skin and destruction of the cutaneous appendages. The tumor was composed of large cells arranged in sheets. These cells were round to oval, had scant cytoplasm, pleomorphic vesicular nuclei, and prominent nucleoli [Figure 1b]. Dispersed among these large cells were few small lymphoid cells. An initial opinion of poorly differentiated round cell tumor was offered. Immunohistochemistry (IHC) was carried out using monoclonal antibodies against CD45, pancytokeratin (CK), human melanoma black (HMB) 45, Carcinoembryonic antigen (CEA) [Figure 1c and d], and S100 protein. The IHC was positive for CD45 [Figure 1e] and negative for CK, HMB 45, CEA, and S100, thereby proving the lymphoid origin of the tumor cells. The subtyping of the tumor by IHC showed the predominant large cells were positive for CD 20 [Figure 1f] with the intervening small cells staining for CD 3, thereby delineating the B-cell lineage of tumor cells. The tumor cells revealed Bcl2 [Figure 1g], Bcl6 positivity, and a high (Mindbomb homolog) MIB-1 labeling index [Figure 1h]. Co-relating histomorphology and immunohistochemistry, a final diagnosis of Primary cutaneous diffuse large B-cell lymphoma – leg type was made.

Figure 1

(a) Grossly 5 cm × 3 cm reddish nodule present over the medial aspect of right upper arm. (b) Diffuse round cell tumor in the dermis. Inset shows large cells with vesicular nucleus and prominent nucleoli (H and E, ×40). (c) Pancytokeratin (AE1/AE3)-negative tumor cells, with the diffuse positivity of the epidermis (immunohistochemistry [IHC], ×40). (d) human melanoma black-45 negative tumor cells (IHC, ×40). (e) Diffusely leukocyte common antigen-positive tumor cells confirming the lymphoid cell population (IHC, ×40). (f) Diffuse crisp membranous positive CD 20 cells confirm the B-cell lineage. Inset shows tumor cells to be negative for T-cell marker CD 3 (IHC, ×40). (g) Bcl-2 shows diffuse cytoplasmic positivity in the tumor cells (IHC, ×40). (h) High MIB-1 labeling index of the tumor cells (IHC, ×40)

Discussion

In the last decade, studies have proved an increase in the incidence of NHL in relation to the other subtypes of dermal neoplasms. Cutaneous lymphomas may be primary or secondary.[5] Primary lymphoma is exclusively cutaneous when diagnosed or even up to 6 months after diagnosis, as evidenced in our case by thorough examination and follow up. Despite being identical in morphological appearance, the lymphomas have different clinical behaviors. The primary lymphomas have a more indolent history when compared to the secondary lymphomas. It presents with local recurrence in up to 68% of the cases and with rare extra-cutaneous dissemination, with an average rate of 5-year survival varying from 89 to 96%.[5] The presentation of the diffuse large B-cell NHL is rare as a primary cutaneous manifestation. In this case, epidemiological factors of interest were added to this fact, i.e., gender (lower incidence in men) and atypical location (more commonly found in the lower limbs).[6] Histopathological diagnosis is essential for the correct characterization of the tumor. The IHC is fundamental and serves, initially, to differentiate between cutaneous neoplasms that are morphologically similar to lymphoma, such as the Merkel cell carcinoma (S-100 positive) and the malignant melanoma (Positive for S-100, HMB-45), and later, to define the subtype of lymphoma. It also serves as an important tool to exclude systemic lymphomas with secondary skin involvement.

What is new?

Primary cutaneous B-cell cutaneous lymphoma - leg type can also manifest (though rarely) in the upper limbs.