Cutaneous B cell lymphomas: Report of two interesting cases.

Cutaneous B cell lymphomas can arise primarily from the skin or may occur due to secondary spread from nodal lymphomas. Primary lymphomas are confined to the skin without systemic spread and they differ from secondary lymphomas in their clinical behavior, treatment and prognosis. Cutaneous lymphomas being relatively rare, lack of precise definition and understanding of their clinical behavior diseases leads to pitfalls in the diagnosis. We report two cases of cutaneous B cell lymphomas who presented with fever of unknown origin initially and later found to have skin lesions. Hence, skin can be a potential diagnostic clue in the evaluation of patients with fever of unknown origin. The distinctions between the primary and the secondary lymphomas become important in choosing the treatment and assessing the prognosis.

What was known?

Cutaneous lymphomas are rare tumors of the skin. The clinical presentation and behavior of primary and secondary lymphomas differ with prognostic and therapeutic implications. The delineation between the primary and the secondary lymphomas is important while choosing treatment.

Introduction

Cutaneous lymphomas are a heterogeneous group of lymphomas representing clonal proliferation of lymphocytes and occasionally Natural Killer cells and plasmacytoid cells. B cell lymphomas constitute 22.5% of all cutaneous lymphomas. Skin is the second common site of extra nodal involvement next to the gastrointestinal tract.[1] Initially, B cell lymphomas of the skin were thought to be exclusively secondary to systemic involvement. Often non-Hodgkin's lymphoma (NHL) is found to be a cause of pyrexia of unknown origin (PUO) which raises a diagnostic difficulty.[2] We describe two cases of cutaneous B cell lymphomas with unique presentation emphasizing the importance of distinction between primary and secondary lymphomas, which has therapeutic and prognostic implications.

Case Reports

Case 1

A 58-years-old female patient was admitted with persistent fever for 2 months, night sweats, occasional lower abdominal pain, loss of appetite and weight loss of more than 6 kg. Complete evaluation of fever of unknown origin was carried out for tropical diseases, collagen vascular disease and malignancy with appropriate blood investigations and radiography, which were found to be normal. Clinical examination was also unremarkable. Later, the patient accidentally noticed few asymptomatic, small skin nodules over the thighs and neck for which dermatologist opinion was sought. An excision biopsy from the skin nodule was performed which showed sheets of atypical lymphoid cells in the dermis with vesicular nuclei, scanty cytoplasm and frequent mitotic figures were noted and immunohistochemical marker studies confirmed the presence of B cell lineage (CD20+; CD79a+; CD10+; CD3−; Ki-67 >95%; Bcl-2-positive; c-myc-negative) with high proliferation index (MIB 1 80-90%) [Figures 1 and 2]. Further staging evaluation was performed. Serum lactate dehydrogenase (LDH) and alkaline phosphatase was found to be elevated. Positron emission tomography (PET) computerized tomography (CT) showed extensive hypermetabolic subcutaneous nodules all over the body sparing the head and neck region [Figure 3]. There were also increased fluorodeoxyglucose (FDG) uptake in mesenteric, paraaortic, bilateral external iliac, inguinal and axillary lymph nodes. She was diagnosed to have diffused large B cell lymphoma. Subsequently, she was given eight cycles of R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine) and Prednisolone) chemotherapy regimen. PET scan showed complete resolution of skin nodules after chemotherapy. At 3 months after completion of chemotherapy, the patient complained of headache and was evaluated with lumbar puncture and radiography. There was evidence of metastasis in the brain, which was treated with a combination of chemotherapy (intrathecal methotrexate along with cytarabine and hydrocortisone) and radiotherapy but the patient succumbed to the disease shortly.

Figure 1

Histology showing large sheets of atypical cells in the dermis (H and E, ×100) and atypical cells with vesicular nuclei and mitotic figures (H and E, ×400)

Figure 2

Immunohistochemical panel consistent with diffuse large cell lymphoma

Figure 3

Positron emission tomography computerized tomography showing extensive “shower of lesions” in the subcutaneous tissue

Case 2

A 59-year-old male patient presented with intermittent fever, night sweats and weight loss for 3 months duration. All investigations done for identifying the cause of fever were non-contributory. Few weeks later, he noticed asymptomatic skin nodules over the neck and trunk [Figure 4]. He also had swelling on both the legs, difficulty in swallowing and multiple oral ulcers. Biopsy and immunohistochemistry were consistent with diffuse large B cell lymphoma. His serum LDH, uric acid and renal parameters were elevated. PET CT showed hypermetabolic cervical, axillary, hilar, subpectoral, abdominal and popliteal nodes along with diffuse subcutaneous deposits. The patient is currently on R-CHOP chemotherapy regimen.

Figure 4

Asymptomatic skin nodules over the neck and trunk

In both cases, bone marrow aspiration showed mildly hypercellular marrow with focal atypical lymphoid infiltrate. No chromosomal abnormalities were detected on cytogentic studies. Fluroscent in situ hybridization technique for the presence of Igh/c-myc translocation was negative. Bcl-2 was positive.

Discussion

Cutaneous B cell lymphomas can be primary or secondary to systemic lymphomas. Primary cutaneous B cell lymphomas are defined as tumors that are confined to the skin with no evidence of dissemination at presentation and remains so for at least 6 months. In contrast to the systemic counterpart, primary cutaneous lymphomas are more indolent in nature and the chances of dissemination are rare. They are also less aggressive and have a better prognosis.[34]

In our first patient, despite carrying out multiple investigations, the diagnosis was not evident. Surprisingly, an excision biopsy of a skin nodule clinched the diagnosis of B cell lymphoma. Subsequent staging workup using FDG-PET revealed “shower of lesions” with subcutaneous hypermetabolic foci all over the body sparing the head and neck region which was disproportionate to the palpable lesions. Lymphoma patients presenting with PUO are known to have aggressive disease with rapid progression and poor prognosis.[4] The presence of extensive skin lesions and “B” symptoms (fever, night sweats and weight loss) concurrently at presentation, raises greater diagnostic difficulty in determining the origin of lymphoma. Owing to the presence of widespread cutaneous lesions compared to systemic involvement in this patient, there is a possibility of primary cutaneous B cell lymphoma that has long been unnoticed now presenting with disseminated disease. However, bcl-2 expression of the tumor cells suggests systemic diffuse B cell lymphoma presenting with predominant skin nodules and B symptoms.

Diffuse large cell lymphomas are the most frequent (31%) of all NHL with aggressive clinical course. Our second patient had widespread systemic disease involving the liver and kidneys along with noticeable skin lesions. Extensive cutaneous infiltration along with clinically evident involvement of liver, muscle and cranial nerves at presentation has been reported in systemic diffuse large B cell lymphoma.[56] The involvement of skin as a clue in the presence of disseminated lymphomas is of considerable interest. There are reports of cases with disseminated follicular lymphoma with skin lesions as the first clinical manifestation.[7] Both cases described are systemic diffuse B cell lymphomas with cutaneous presentation. Patients with skin involvement in systemic lymphomas develop brain metastasis eventually. Further studies in the larger group may help us delineate primary cutaneous B cell lymphomas from disseminated B cell lymphomas.

A patient diagnosed with cutaneous nodule suggestive of B cell lymphoma should undergo a staging evaluation for NHL with complete physical examination, laboratory investigations like serum LDH, beta-2 microglobulin and serum electrophoresis in addition to routine tests. Radiographic studies such as CT abdomen, thorax and PET scan provide additional clues. Chromosomal translocations as in systemic lymphomas are usually not detected in primary cutaneous lymphomas. Primary follicular cell lymphoma lack t (14:18) translocation and do not rarely express bcl-2 protein. Diffuse large B cell lymphoma of leg type expresses bcl-2 protein. Systemic B cell lymphoma with bcl-2 expression has a high rate of relapse. Mantle cell lymphomas mostly involve the skin secondarily.

Our report has provided several insights in clinical problem solving in a patient with lymphoma. Systemic diffuse large cell lymphomas can have predominant cutaneous involvement in addition to systemic symptoms. Skin can be a “potential diagnostic clue” in the evaluation of fever of unknown origin. A proper dermatological examination and skin biopsy from the suspicious skin lesions should be included in the structured algorithm in evaluating a patient with fever of unknown origin.

What is new?

Skin can be a potential diagnostic clue in the evaluation of patients with fever of unknown origin. In some clinical scenarios, the origin of lymphomas is a hardest riddle to crack. Further studies in a larger number of cases would help us to delineate primary from secondary cutaneous lymphomas.