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Extreme neutrophil granulocytosis in a patient with anaplastic large cell lymphoma of t-cell lineage

APMIS 115: 778–83, 2007 C 2007 The Authors Printed in Denmark . All rights reserved Journal Compilation C 2007 APMIS ISSN 0903-4641 Extreme neutrophil granulocytosis in a patient with
anaplastic large cell lymphoma of T-cell lineage
Case report FREDERIK NEESS ENGSIG,1 MICHAEL BOE MØLLER,2 HANS K. HASSELBALCH,3 BASSAM MAHDI4 and NIELS OBEL1 Departments of 1Infectious Diseases, 2Pathology, 3Haematology and 4Radiology, Odense University Hospital, Denmark Engsig FN, Møller MB, Hasselbalch HK, Mahdi B, Obel N. Extreme neutrophil granulocytosis in apatient with anaplastic large cell lymphoma of T-cell lineage. Case report. 2005;115:778–83.
We describe a 47-year-old male admitted with fever and extreme neutrophil granulocytosis (up to80¿109/L). All microbiology tests and test for autoimmune disease were negative. CT scan showedpulmonary infiltrates bilaterally, mediastinal lymphadenopathy and splenomegaly. Conventional path-ological examination of bone marrow and lymph node biopsies did not demonstrate malignant cellsand inflammatory disease was suspected. The patient died of multiorgan failure 23 days after admis-sion. Autopsy showed neutrophil infiltration of several organs. Immunohistochemistry and cyto-genetics postmortem led to a diagnosis of anaplastic large cell lymphoma (ALCL) of T-cell lineage.
Involvement of peripheral blood with leukemoid reaction is a rare manifestation of ALCL. This caseemphasizes the importance of immunophenotyping in unexplained extreme granulocytosis.
Key words: Leukemoid reaction; immunohistochemical staining; ALCL; infection.
Frederik Neess Engsig, Department of Infectious Diseases, Odense University Hospital, Sdr. Boul-evard 29, DK-5000 Odense C, Denmark. e-mail: fren74/gmail.com Fever and neutrophil granulocytosis are com- until 2 weeks previously. The patient had been treated mon findings in patients with severe bacterial with V-penicillin and doxycycline prior to admission infection. However, several non-infectious dis- but with no clinical effect. On admission the patientpresented with bilateral small sore angular lymph eases may induce these two essential clinical glands, oral candidiasis, moderate hypoxia and di- stigmata and therefore the clinician may be pre- arrhea. Neurological examination was normal. The sented with a major differential diagnostic chal- patient had neutrophil leukocytosis (33¿109/L; nor- lenge. We describe a patient with anaplastic mal range 3–10¿109/L), increased CRP (530 mg/l; large cell lymphoma (ALCL) of T-cell lineage normal range⬍10 mg/ml), and slightly elevated liver and extreme neutrophil granulocytosis.
enzymes. Bence Jones protein in blood and urine andtests for autoimmune diseases were all negative. Allmicrobiology tests were negative, including HIV,Epstein Barr and cytomegalovirus serology, PCR of sputum for legionella, mycoplasma and chlamydia,and cultures of bronchoalveolar lavage fluid. CT-scan A 47-year-old previously healthy male was admitted of the head and neck showed a left parietal cerebral with diarrhea, nausea and fever. He had been well tumor, 2¿2.5 cm, supposedly an oligodendroglioma,which was considered an incidental finding. CT scansof the abdomen and chest showed pulmonary infil- Received 29 August 2007.
trates bilaterally with small exudates, discrete Accepted 5 February 2007.
mediastinal lymphadenopathy not suspected of repre-


GRANULOCYTOSIS IN ANAPLASTIC LYMPHOMA senting malignancy, and splenomegaly. The followingtests initially showed no abnormality: Chest X-ray,direct laryngoscopy, ultrasound of the neck, dentalexamination, echocardiography, ventilation/perfusionscintigraphy and leukocyte scintigraphy. A bloodsmear showed leukemoid reaction, but there was nosuspicion of malignant hematological disease. A bonemarrow biopsy performed after 1 week was hypercel-lular, consistent with inflammation but without signsof hematological malignancy, which is why immuno-histochemistry and cytogenetic tests were not per-formed. Microscopy of pleural fluid showed acuteand chronic inflammatory cells and reactive meso-thelial cells.
The patient developed respiratory insufficiency and exanthema on the thighs and trunk along with he-morrhagic chemosis. Repeated chest X rays showed Fig. 1. CT scan of the abdomen 3 weeks after admis- increasing infiltration in both lungs.
sion, showing––besides liver and spleen enlarge- Bacterial infection was initially suspected and ment––lymphadenophathy (indicated by arrow).
treated with intravenous meropenem (1 g TID), cip-roxin (400 mg BID) and capsule fluconazole (50 mgQD), supplemented with clindamycin. In spite of the results of the cytogenetic analysis, including spec- antibiotic treatment, leukocyte count rose to 57¿109/ tral karyotyping, of the last ante mortem bone mar- L. After 9 days, treatment with Solumedrol (1 mg/ row aspiration showed t(2;17)(p23;q23) in 11 of 30 kg) was initiated and the patient responded with im- metaphases, including a subclone with an additional proved respiratory function and regression of eye and t(3,8)(p21;q24) in 2 metaphases. No t(9;22) was iden- skin symptoms. 3 weeks after admission the patient was transferred to the intensive care unit. Leukocyte In the light of these findings, the two bone marrow count had increased to 80¿109/L. A new bone mar- biopsies, the clots from the two pleural fluid examina- row biopsy still showed leukemoid reaction but no tions and the skin biopsy were reviewed. By conven- signs of malignancy. Abdominal CT scan showed tional H&E staining and Giemsa staining both bone lymphadenopathy and moderate enlargement of the marrow biopsies were still without morphologically liver and spleen.
identifiable tumor cells or lymphoid aggregates (Fig.
3C). However, immunohistochemical staining showed The lymphadenopathy on the neck advanced, but scattered single lymphoma cells positive for CD30 fine-needle aspirations from these glands showed no and ALK (Fig. 3D). Similarly, single tumor cells were malignant cells. The patient ultimately developed identified by CD30 and ALK staining in the pleural multi-organ failure and died 23 days after admission.
fluids but not in the skin biopsy.
At autopsy the spleen was enlarged (weight 1700 g) with several small infarcts. The lymph nodes weregrossly normal. The lungs were consolidated butwithout overt tumor formation. In the left cerebral hemisphere a tumor measuring 4¿4.5¿5 cm wasidentified and shown to be a protoplasmic astrocyto- Primary systemic ALCL is mainly of T-cell lin- ma. Spleen, lungs, brain, kidneys, heart and bone eage and characterized by large pleomorphic marrow were sampled for microscopic analysis.
cells with abundant cytoplasm, expression of Lungs and spleen were diffusely infiltrated with me- CD30 and anaplastic lymphoma kinase (ALK).
dium-to-large tumor cells with moderate to abundantcytoplasm (Fig. 2). Focally, the background showed Translocation t(2;5) is commonly found in pri- increased neutrophils. The tumor cells expressed mary systemic subtypes and along with other CD30, ALK (finely granular cytoplasmic pattern), translocations associated with the ALK gene. In CD4, CD2 (weak) and CD25. They failed to express our patient a variant translocation was found CD3, CD5, CD8, CD20, CD79a and PAX5.
(t(2;17)), which is observed in about 2–5% of Similar tumor cells were infiltrating the myocar- patients with ALCL, giving rise to the particu- dium, kidneys, bone marrow and brain, including the lar granular ALK expression pattern. As op- astrocytoma, as solitary single cells (Fig. 3A). Vascu-lar transsections often showed intravascular ALK- posed to the indolent and progressive cutaneous positive tumor cells among the neutrophils (Fig. 3B).
type, systemic ALCL is aggressive and often A diagnosis of ALK-positive anaplastic large cell located in extranodal sites such as the lungs and lymphoma of T-cell lineage was made. Concurrently, liver (1, 2). The disease infrequently involves pe-


ENGSIG et al. Fig. 2. Microscopic and immunophenotypic findings in the enlarged spleen. (A) The spleen shows a loosestroma with a fibrous quality. Larger atypical lymphoid cells are dispersed in the stroma, ¿200. (B) Theneoplastic cells strongly express CD30 with granular cytoplasmic and Golgi region pattern, ¿200 (insert,¿630). (C) There is strong ALK staining of the lymphoma cells with a granular cytoplasmic pattern. There isno membranous or nuclear staining, ¿200 (insert, ¿1000). (D) The lymphoma cells are also strongly CD25positive, ¿200. (E) The large atypical tumor cells are variably CD4 positive, ¿400. (F) There are a very smallnumber of scattered CD79a-positive small B-lymphocytes, ¿200.


GRANULOCYTOSIS IN ANAPLASTIC LYMPHOMA Fig. 3. (A) Myocardium section shows single cell infiltration of lymphoma cells (arrows) that is difficult todetect by conventional hematoxylin eosin staining, ¿200. (B) In the same area, extra- (arrows) and intravascular(arrowheads) ALK-positive tumor cells become apparent by immunohistochemistry, ¿200. (C) Hematoxylineosin staining of the second bone marrow biopsy shows hypercellularity, ¿200. (D) Occult tumor cells (arrows)can only be distinguished from immature hematopoietic cells by immunohistochemistry demonstrating ALK-positive cells, ¿200.
ripheral blood (3), but in our case the patient nant cells were not demonstrated by conven- presented with massive neutrophil granulo- tional pathological examination, which explains cytosis. In addition, several organs showed focal why immunophenotyping was performed late neutrophil infiltration in the absence of necrosis and diagnosis of ALCL was delayed. In a paper and infection, and thus resembled the so-called by Fraga et al. only 17% of ALCL patients were neutrophil-rich ALCL albeit with fewer infilt- found to have bone marrow infiltration on con- rating neutrophils than described in the original ventional examination, but after immunohisto- publication of this rare morphological ALCL chemical analysis for CD30, 40% of the patients variant (4).
had infiltration of the bone marrow (6). Thus, The importance of immunophenotyping has more than half the patients with bone marrow been emphasized in the diagnosis of this rare disease had occult tumor cells detectable only but highly aggressive T-cell lymphoma, which may otherwise be misdiagnosed as an inflam- Regarding the cause of the neutrophil-rich in- matory disease (5). In the present case, malig- filtrates, interleukin-8 has previously been sus- ENGSIG et al. pected of inducing neutrophil granulocytosis ness of these clinical associations is of the utmost and neutrophil infiltration in lymphomas. How- importance if clinicians and pathologists are to ever, Foss et al. (7) reported that only a few cells employ the relevant diagnostic tools.
showed IL-8 expression in Hodgkin and non-Hodgkin lymphomas, and they proposed thatother cytokines such as G-CSF and MG-CSFmay be responsible for the neutrophil acti- vation. In fact, a markedly elevated G-CSF hasbeen observed in some ALCL patients (8) and 1. Pileri SA, Piccaluga A, Poggi S, Sabattini E, Pic- caluga PP, De Vivo A, et al. Anaplastic large cell has been proposed to be produced by the tumor lymphoma: update of findings. Leuk Lymphoma cell line (9).
Studies by Reding et al. (10) showed that in 2. Falini B, Pileri S, Zinzani PL, Carbone A, Zago- 100 patients with extreme leukocytosis, defined nel V, Wolf-Peeters C, et al. ALKπ lymphoma: as more than 25¿109/l, 48% of the cases were clinico-pathological findings and outcome. Blood attributed to infection and 13% to malig- 3. Dalal BI, Chhanabhai M, Horsman DE, LeHu- nancy––mainly malignant melanomas, lym- quet J, Coupland R. Anaplastic large-cell phomas and CML. The remaining 39% were lymphoma presenting as acute leukaemia. Am J attributed to various causes, such as glucocort- icoid therapy, hemorrhage and G-CSF therapy.
4. Mann KP, Hall B, Kamino H, Borowitz MJ, Ra- The treatment with glucocorticoid may have tech H. Neutrophil-rich, Ki-1 anaplastic large raised the neutrocyte count further but cannot cell malignant lymphoma. Am J Surg Pathol explain the leukemoid reaction seen in the pres- 5. Tamiolakis D, Georgiou G, Prassopoulos P, Sim- ent case. Common infectious causes of leuke- opoulos C, Venizelos J, Papadopoulos N. Neu- moid reactions are miliary tuberculosis, pneu- trophil-rich anaplastic large cell lymphoma (NR- monia, meningitis and abscesses. In our case, all ALCL) mimicking lymphadenitis: a study by cultures, microscopy and PCR were negative fine-needle aspiration biopsy. Leuk Lymphoma and antimicrobial therapy was without effect.
We therefore conclude that the leukemoid reac- 6. Fraga M, Brousset P, Schlaifer D, Payen C, Rob- tion was caused by ALCL. Neutrophilia is not ert A, Rubie H, et al. Bone marrow involvementin anaplastic large cell lymphoma. Immunohisto- uncommon in neutrophil-rich ALCL (11, 12); chemical detection of minimal disease and its however, presentation of ALCL with a leuke- prognostic significance. Am J Clin Pathol 1995; moid reaction––as in this report––is highly un- usual, though it has been described casuistically 7. Foss HD, Herbst H, Gottstein S, Demel G, Arau- jo I, Stein H. Interleukin-8 in Hodgkin's disease.
Neutrophil dermatosis (Sweet's syndrome) is Preferential expression by reactive cells and as-sociation with neutrophil density. Am J Pathol defined as sudden onset of fever, leukocytosis and tender erythematous plaques showing neu- 8. Yuji Harada Y, Yamada S, Murakami S, Mine S, trophil infiltrations. Sweet's syndrome is associ- Momosaka Y, Tsukada J, et al. Ki-1 lymphoma ated with leukemoid reactions and in 20–25% of with nodular involvement in liver and spleen: the cases with hematological and non-hematol- possible role of cytokines in systemic manifes- ogical malignancies. Although the present pa- tation of fever and leucocytosis. Dig Dis Sci tient had skin manifestations, biopsies from 9. Nishihira H, Tanaka Y, Kigasawa H, Sasaki Y, these lesions showed minimal neutrophil infil- Fujimoto J. Ki-1 lymphoma producing G-CSF.
Br J Haematol 1992;80:556–7.
In conclusion, the present case demonstrates 10. Reding MT, Hibbs JR, Morrison VA, Swaim that ALCL is an important differential diagnosis WR, Filice GA. Diagnosis and outcome of 100 in patients with an unexplained leukemoid reac- consecutive patients with extreme granulocytic tion. Immunohistochemistry and cytogenetics leukocytosis. Am J Med 1998;105:359.
11. Hirano H, Ichimura T, Hanibuchi M, Nakagawa are important ancillary tools in the diagnosis of M, Maekura R, Ito M. Anaplastic large-cell these patients as bone marrow infiltration often lymphoma (Ki-1 lymphoma): ultrastructural and is too subtle to establish the diagnosis by conven- immunohistochemical studies. Med Electron tional bone marrow examination. Thus, aware- GRANULOCYTOSIS IN ANAPLASTIC LYMPHOMA 12. Mira JA, Fernandez-Alonso J, Macias J, Saez C, 13. Irani L, Hilliquin P, Dreyfus F, Renoux M, Lou- Japon MA, Pereda T. Bone involvement and ab- vel G, Menkes CJ. Paget disease, complicated by cess formation by neutrophil-rich CD30π anapl- Ki-1 lymphoma with G-CSF growth factor secre- astic large-cell lymphoma mimicking skeletal in- tion. Rev Rhum Ed Fr 1994;61:641–4.
fection in an AIDS patient. J Infect 2003;47:73–6.

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