Anaplastic large cell lymphoma (ALCL), a type of lymphoma, was first described by Stain in 1985 and included in non-Hodgkin lymphoma according to REAL classification since 1998. In the absence of necrosis, neutrophils infiltration in non-Hodgkin lymphoma is uncommon. Mann et al1 had previously reported neutrophil rich ALCL as a variant of ALCL. In this paper, we describe a neutrophil rich, anaplastic large cell lymphoma (ALCL) which presented as cutaneous nodules in an adolescent.
A 15-year-old female presented with multiple, tender nodules all over her body for previous 14 days. Physical examination revealed distinct erythematous cutaneous nodules (0.5 cm - 2 cm in diameter) and subcutaneous tumours (2 cm - 4 cm) predominantly located in the trunk and lower extremities. A 2 cm × 2 cm nodule with cystic lesion in the centre was noted in the right parietotemporal site. All lesions were tender on palpation. Some nodules became superficially ulcerated, suppurated and desquamated gradually. Bilateral axillary lymphoadenopathy (3 cm × 4 cm) were noted. There was no hepatosplenomegaly.
Peripheral white blood cell count was 13.3×109/L - 15.5×109/L with 77% - 90% segmented cells, 3% - 6% band cells and 10% - 23% lymphocytes. Haemoglobin was 104 - 112 g/L, platelet 315×109/L - 422×109/L and ESR 84 mm/h. The B ultrasound scan showed splenomegaly with 4.26 cm in thickness. No lymph node was noted in posterior peritoneum. Multiple, very high density, nodules in both lungs were observed in chest CT scan. Bone marrow aspiration and biopsy showed hyperplasia without malignant lymphoma infiltration. Neutrophil alkaline phosphatase (NAP) scored 311 and 90% cells were positive. Polymerase chain reaction analysis demonstrated a monoclonal population with rearrangement of T-cell receptors.
The histology of cutaneous nodules and axillary lymph nodes was similar. The resected nodules were about 1-3 cm and contained entire dermis and the upper portion of subcutaneous tissue. The cellular infiltration of the dermis was extensive and disseminated. It mainly contained large neoplastic cells with abundant cytoplasm and folded, horseshoe or kidney shaped nucleus. Karyokinesis was observed occasionally. The numerous neutrophils mixed with neoplastic cells and concealed some neoplastic cells (Figure 1). However, coagulative necrosis was absent. There was no evidence of increased cell number of myeloid precursors or immature neutrophils. The structure of axillary lymph node was destroyed and infiltrated with a large number of neoplastic cells with the characteristic described previously. Similarly, the lymph nodes had significant neutrophil infiltration in the absence of necrosis.
The immunohistochemical studies revealed that all the neoplastic cells were positive for LCA, CD2, CD8, CD30 (Figure 2), ALK (Figure 3), CD43 and CD45 (leukocyte common antigen), but negative for EMA, CD3, CD4, CD5, CD15, CD20, CD79a, S-100, CD68 and MPO. Previous description indicated an anaplastic, large cell lymphoma, primary systemic subtype with T-cell lineage phenotype.
The nodules gradually enlarged over 10 days after the patient was admitted. The surfaces of some nodules ulcerated, suppurated and desquamated gradually. Meantime, the patient had continuous fever with the temperature above 39°C. The blood culture was negative in three tests and the patient had no response to antibiotic treatment. Since the definite diagnosis was made at that time, the patient received CHOP (cyclophosphamide 0.7 g, intravenously injection on day 1, vindesine 4 mg, intravenously injection on day 1, prednisone 30 mg, per os, bid, on days 1-7) chemotherapy. All the nodules showed shrink and scabs after the second day of chemotherapy. The temperature also returned to normal without relapse. However, the nodules reoccurred in the chest, back and neck 15 days later. These symptoms improved again after the second cycle of chemotherapy using standard CHOP regimen. Before the third cycle of chemotherapy, the patient developed continuous headache, vomiting, and blurry vision in the right eye. CT and MRI scans of skull revealed alteration of meninges. Intracranial pressure was 220 mm H2O and cerebrospinal fluid revealed white blood cell 8×106/L, red blood cell 10×106/L, protein 19.4 g/L, glucose 2.5 mmol/L, chloride 117 mmol/L and positive Pandy test. However, no neoplastic cell was found. Considering lymphoma infiltration in the central nervous system, injected MTX and DXM were conducted intrathecally. After that, the patient gave up hospilazation despite doctor’s advice and died a few days later.
ALCL represents a category of large cell lymphoma defined by anaplastic cytology and strong expression of the cytokine receptor CD30 on all or most neoplastic cells. It has been included in REAL classification. ALCL is divided clinically into primary and secondary subtypes. The de novo type is further classified into systemic, cutaneous and HIV related types. All the types strongly express CD30 antigen on the cell membrane.
Primary systemic ALCL is the most common subtype and accounts for 2% to 8% of non-Hodgkin lymphoma in adults and approximately 20% - 30% of large cell lymphoma in children. Primary systemic ALCL is associated with advanced stage at presentation and rapid deterioration. Systemic symptoms are observed in 75% of patients, with fever as the most common symptom. These patients developed lesions involving skin, bone, soft tissues, lung, liver and rarely gastrointestinal tract and central nervous system. The patient first presented scalp nodules and then the lesions spread to the whole body, lung and central nervous system. Fever was also noted when the disease progressed.
The patient also had neutrophilia in peripheral blood and skin nodules, but there was no evidence of infection despite the high score of NAP. No bacterial or fugal organisms were identified by blood, sputum or pustule culture. The patient was given antibiotics, but the symptoms did not improve. Although the presence of neutrophil is a morphological feature that may be shared by some cases of lymphomatous papulosis and Hodgkin disease, it is rare in ALCL. Mann et al1 first described this special type of neutrophil rich anaplastic large cell lymphoma and considered it a distinct subgroup of ALCL. However, Badve et al2 thought that anaplastic large cell lymphoma related tissue neutrophilia was only a transient phenomenon. According to this case, neutrophilia was present during the whole month of disease. It is consistent with the conclusion of Mann et al. Although this patient responded to chemotherapy, the disease relapsed in a very short time and then infiltrated to central nervous system. Mann at al1 considered that neutrophil rich ALCL might be more malignant than other types of lymphoma. It is still uncertain whether neutrophil rich ALCL with skin involvement has poorer prognosis.
The pathogenesis of tissue neutrophilia in ALCL remained unclear. It may be an inflammatory response to the neoplasm or neutrophil chemoattractant released by endothelial cells or tumour cells. It has been reported that interleukin 8 is likely involved in the presence of neutrophilia.3
Among the six cases in Mann’s report,1 1 patient was HIV positive and had skin and muscle involvement. Jhala et al4 reported two cases of neutrophil rich ALCL of T-cell lineage involving the scalp of HIV positive men. It seemed that the neutrophil rich ALCL is more likely to occur in those patients with immune deficiency and often involves skin. Therefore, the pathogenesis of ALCL might be related to the patient’s immunity.
T-cell/null-cell ALCL is often associated with translocation t (2; 5) (p23; q35) that results in the formation of protein, P80 NPM/ALK, with the resultant overexpression of ALK.4 Despite the similarity of histopathological features, t (2; 5) “+” and t (2; 5) “-” large cell lymphomas are distinct biological entities.4 P80-positive ALCL has been found to occur mostly during childhood or adolescence and has a far better prognosis.5 Jhala et al4 reported that two HIV-negative neutrophil rich ALCL cases were negative for ALK.4 Both patients died from infectious complications within 6 months. It was a pity that we did not perform the cytogenetic examination on this patient. To our knowledge, the longest survival time any patient with neutrophil rich ALCL was less than 1 year.
In summary, whether the presentations, pathological features or prognosis of neutrophil rich ALCL are different from the common ALCL and whether it is an independent subgroup of ALCL need further investigation.
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