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Background
This is a group of aggressive lymphomas that have marked propensity to occur in the nose and paranasal sinuses. They are also known as angiocentric lymphomas and CD56 lymphomas. They are more common in men and peak during the 5th decade. Localized disease may be treated with irradiation with a 77% complete remission rate. In patients relapsing, disseminated disease may involve the skin, regional lymph nodes, lungs, and brain.
Under the microscope, these tumors are composed of a polymorphous mixture of inflammatory cells admixed with atypical lymphocytes having hyperchromatic, enlarged, and convoluted nuclei. These cells have a marked propensity to infiltrate large blood vessels. The identifying trait is found by immunohistochemistry which shows strong immunopositivity for CD56, a marker for natural killer (NK) cell differentiation. Natural killer cells comprise 10-15% of the normal circulating lymphocytes in the peripheral blood and play an important role in the immune system by lysing tumor cells without prior sensitization. These NK cells were once called null cells since they lack most of the usual T and B cell surface antigens.
CD56 is found in a small population of normal T cells. However, other T cell markers including T cell receptor gene rearrangement studies are negative. Epstein-Barr virus is reliably demonstrated indicating a primary pathogenic role for this virus.
OUTLINE
EPIDEMIOLOGY CHARACTERISTIC SYNONYMS Sinonasal and extra-nasal NK/T-cell lymphoma Common in Asia and South and Central America
Hum Pathol. 2006 Jan;37(1):54-60. Abstract quote
Nasal natural killer/T-cell lymphoma (N-NK/T-L) is prevalent in China. To further characterize this neoplasm, 36 cases of N-NK/T-L from 304 cases of malignant lymphomas in the north China area were investigated by histopathology, immunophenotyping, and genomic analysis of c-kit, in comparison with 11 cases of B-cell lymphoma (BCL) at the same region and 5 cases of nodal peripheral T-cell lymphoma (PTCL) (unspecified).
Histopathologically, N-NK/T-L was characterized by coagulative necrosis, inflammatory background, and angiodestructive growth pattern. In 36 cases of N-NK/T-L, 27 cases (75.0%) were stained for CD45RO and 25 (72.2%) for CD3epsilon. Thirty cases (83.3%) were positive for T-cell intracellular antigen-1, 22 (61.1%) for granzyme B, 18 (50.0%) for CD56, and 11 (30.6%) for CD30, whereas none was positive for CD117. All 5 cases of PTCL displayed positive staining for CD45RO and T-cell intracellular antigen-1, 3 cases for CD3epsilon, but only 1 case for granzyme B. All 11 BCLs presented positive staining for CD20 and CD79a but negative for other antibodies. A significant relationship was observed between neoplastic cells pleomorphism and granzyme B expression (P < .05). Despite the fact that all cases were negative for CD117 staining, genomic sequences of c-kit 11 and exon 17 sequencing showed that 8 (26%) of 31 cases N-NK/T-L proved to contain genomic mutations, including 4 cases in exon 11 and 4 in exon 17. For the control group, only 1 (9%) of 11 BCLs and 1 (20%) of 5 cases of PTCL were detected to harbor mutations in exon 11. All mutations detected in 3 groups were missense by base substitution, and codes 571, 572, and 821 were hot spots.
The results suggested that, in addition to histological features and routine immunophenotyping, granzyme B expression should be a more reliable marker in correct diagnosis of N-NK/T-L, and genetic analysis of c-kit mutation should be helpful in the diagnosis of this tumor.Clinicopathologic and genotypic study of extranodal nasal-type natural killer/T-cell lymphoma and natural killer precursor lymphoma among Koreans.
Ko YH, Ree HJ, Kim WS, Choi WH, Moon WS, Kim SW.
Department of Diagnostic Pathology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
Cancer 2000 Nov 15;89(10):2106-16 Abstract quote
BACKGROUND: This study aimed to define genotypic profile and to describe the clinicopathologic features of nasal-type natural killer (NK)/T-cell lymphoma of nasal and extranasal origin and NK precursor lymphoma.
METHODS: NK/T-cell lymphomas from the upper aerodigestive tract (n = 45), skin (n = 2), gastrointestinal tract (n = 3), and soft tissue (n = 2) and NK precursor neoplasms (n = 3) were studied. Immunophenotype was analyzed by immunohistochemistry and flow cytometry. In situ hybridization with EBER 1/2 RNA probes was performed. T-Cell Receptor (TCR)-gamma gene rearrangement was analyzed by seminested polymerase chain reaction with heteroduplex analysis. Overall survival rate was correlated with clinicopathologic parameters and compared by Wilcoxon test.
RESULTS: Clonal TCR-gamma gene rearrangement was detected in 3 of 31 upper aerodigestive and 1 of 2 skin tumors. When immunostained using paraffin embedded tissue, 6 upper aerodigestive lymphomas were negative for CD56 in which 4 cases lacked clonal TCR gene rearrangement. Epstein-Barr virus (EBV) mRNA was detected in 33 upper aerodigestive tumors including 26 of 29 nasal tumors (90%), and 7 of 10 extranasal tumors (70%). There was no histologic, immunophenotypic, or genotypic differences according to the lineage and EBV association in upper aerodigestive lymphomas. Among the patients with upper aerodigestive tumors, overall 1-year survival rate was 41%, and correlated well with the stage (P < 0.05) but not with the size of tumor cells, EBV status, and lineage (P > 0.05). Median survival rate of lymphomas from other sites excluding upper aerodigestive tract was not significantly different from that of upper aerodigestive lymphomas with same stage (P > 0.05). Unlike nasal-type NK/T-cell lymphomas, NK precursor lymphoma involved the bone marrow and lymph nodes at initial presentation or in the course of disease. Tumor cells were positive for TdT in all and myeloid markers in two. TCR gene rearrangement was germ line.
CONCLUSIONS: Most upper aerodigestive nasal-type NK/T-cell lymphomas among Koreans are genotypically of NK derivation and few belong to T lineage. Presence or absence of EBV has no significant correlation with the histologic changes and the lineage of these lymphomas.
Sinonasal NK/T-cell Lymphomas in the United States
Karl Gaal, M.D.; Nora C. J. Sun, M.D.; Antonio M. Hernandez, M.D.; Daniel A. Arber, M.D.
From the Departments of Pathology at City of Hope National Medical Center, Duarte, California, (K.G., D.A.A.), Harbor UCLA Medical Center, Torrance, California (N.C.J.S.), and Kaiser Permanente, Los Angeles, California, U.S.A. (A.M.H.).
Am J Surg Pathol 2000;24:1511-1517 Abstract quote
Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized.
Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR- gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma.
Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.
HISTOLOGICAL
TYPESCHARACTERIZATION GENERAL Broad cytologic spectrum
Nuclei often irregular with granular chromatin
Moderate amount of pale to clear cytoplasm
Azurophilic granules in Giemsa touch preparations
Many admixed inflammatory cells
Angiocentric and angiodestructive growth common
Fibrinoid necrosis of blood vessels
Extensive coagulative necrosis and apoptosis common
Epithelium may be infiltrated by lymphoma cellsAm J Surg Pathol 1996;20:103-11.
Pathol Pattern 1999;111(Suppl 1):S46-S55.
Am J Surg Pathol 1997;21:242-8.
Am J Surg Pathol 1997;21:1223-30.
Am J Surg Pathol 1998;22:135-7.Three major groups of natural killer (NK) cell-associated hematolymphoid malignancy:
Nasal and nasal-type NK-cell lymphoma
Aggressive NK-cell lymphoma/leukemia
Blastic NK-cell lymphoma/leukemiaAm J Surg Pathol 1995;19:284-96.
Arch Dermatol 1996;132:550-3
Am J Surg Pathol 1999;23:137-46.
Another group of patients with unique immunohistochemical characteristics has been reported:
Express both the T helper/inducer cell marker CD4 and the NK-cell marker CD56
Suggest a T-cell origin, but the negativity of the CD3 (surface and cytoplasmic) and the other T-cell-related antigen, CD2, and the absence of clonal rearrangement of the T-cell receptor (TCR) gene are against this hypothesisANAPLASTIC
Department of Pathology and Laboratory Medicine, CB# 7525, UNC, Chapel Hill, NC 27599-7525, USA.
CONTEXT: Anaplastic large cell lymphomas (ALCLs) are a heterogeneous group of CD30+ large cell lymphomas that, according to the World Health Organization classification, are defined as being of T-cell origin, based on immunophenotype, and/or the finding of a T-cell gene rearrangement by molecular studies. Most cases express cytotoxic granule-associated proteins. Relatively recent data have suggested that some T-cell ALCLs are derived from cytolytic CD4+ cells, gammadelta T cells, or natural killer-like (CD56+ or CD57+) T cells.
We encountered a pediatric case of CD56+, anaplastic lymphoma kinase-positive ALCL of apparent natural killer-like T-cell origin (showing positivity for CD2, cytoplasmic CD3, surface CD3 partial positivity, CD7, CD8, CD56, TIA-1, and granzyme B). The patient had initial lymph node and multiple sites of cutaneous involvement and an aggressive clinical course with multiple recurrences after varying periods of complete remission.
OBJECTIVE: To review the current pediatric literature regarding the incidence, differential diagnosis, and clinical course of such cases.
DATA SOURCES: Relevant articles indexed in PubMed (National Library of Medicine) between 1975 and 2006.
CONCLUSIONS: Our review did not confirm a uniformly aggressive clinical course in pediatric cases of CD56+ ALCLs. Such cases suggest the usefulness of the analysis of CD56-positivity in additional cases of ALCL in an attempt to accrue additional information on this condition. Future accrual of such cases may address whether such cases should be treated more aggressively or with possible targeted therapeutic regimens.BLASTIC/BLASTOID (CD4+/CD56+)
From the *Departments of Pathology and Laboratory Medicine; and daggerDepartment of Dermatology, Indiana University, Indianapolis, IN.
We report a case of a 75-year-old man with a cutaneous CD4+CD56+ hematodermic neoplasm. CD4+CD56+ hematodermic neoplasms are rare and commonly present as cutaneous lesions.
This is an important diagnosis in the differential diagnosis of cutaneous hematologic malignancies because of the extremely poor prognosis.
- CD4(+) CD56(+) Lineage-Negative Malignancies Are Rare Tumors of Plasmacytoid Dendritic Cells.
Reichard KK, Burks EJ, Foucar MK, Wilson CS, Viswanatha DS, Hozier JC, Larson RS.
From the Department of Pathology, University of New Mexico, Albuquerque, NM.
Am J Surg Pathol. 2005 Oct;29(10):1274-83. Abstract quote
CD4(+) CD56(+) lineage-negative malignancies are difficult to diagnose and classify. Recent studies have suggested that these malignancies may derive from plasmacytoid dendritic cells (pDC).
In this report, we examine 10 cases of CD4+, CD56+ lineage-negative malignancies that presented in various tissue sites. The goal was to identify the morphologic, immunophenotypic, and genotypic findings to devise a diagnostic approach to tissue biopsies of these lesions and to confirm the proposed cell of origin.
The mean age was 66 years (range, 45-80 years) with a male predominance (8 males/2 females). Frequent sites of disease included skin (60%) and peripheral blood/bone marrow (70%). Tumor cells were positive for CD45, CD43, CD4, and CD56 (9 of 10). The pDC markers, CD123 (9 of 10) and CD45RA (10 of 10), were detected by immunoperoxidase staining. Also noted was CD2 positivity (1 case), weak CD7 positivity (4 of 8 cases), weak CD33 (4 of 9 cases), TdT (2 cases), and CD68 (2 cases). All cases were otherwise negative for EBV (EBER), B-cell, T-cell, myeloid, and NK cell markers. T-cell receptor-gamma gene rearrangement was negative in all cases. Complex structural chromosomal abnormalities were seen in 3 of 5 cases, a subset of which may be recurrent in pDC malignancy. Overall prognosis was poor despite multiagent chemotherapy and/or radiation.- Our study confirms that CD4+/CD56+ lineage-negative tumors are derived from pDC and have characteristic clinical, histopathologic, and immunophenotypic features. Furthermore, these rare neoplasms can be readily diagnosed using recently developed immunoperoxidase techniques.
Tony Petrella, MD, etal.
Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published.
In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed.
The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.
Non-B, non-T neoplasms with lymphoblast morphology: further clarification and classification.
Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Suefuji H, Suzumiya J, Harada M, Kikuchi M.
Am J Surg Pathol. 2003 Oct;27(10):1366-74 Abstract quote. SUMMARY: We studied the morphologic, immunohistochemical, and clinical characteristics of 158 cases of lymphoblastic lymphoma. Based on immunophenotyping and cell lineage, cases were classified into B-cell type (CD20,CD19 or CD79a+, n = 53), T-cell type (surface CD3+, n = 84), and non-B, non-T type (B cell marker- and surface CD3-, n = 21). The latter group was further divided based on immunohistochemistry into: 1) CD7+ stem cell lymphoma (CD7+SCL) [CD4-, CD7+, CD33+/-, CD56-], 2) blastic natural killer cell lymphoma (B-NKL) [CD4-, CD7+/-, CD33-, CD56+, CD123-], 3) myeloid/NK precursor cell leukemia (M/NKL) [CD4-, CD7+, CD33+, CD56+], and 4) CD4+CD56+ hematodermic malignancy (CD4+CD56+) type [CD4+, CD7+/-, CD33-, CD56+, CD123+]. The CD7+SCL and M/NKL types frequently exhibited bone marrow invasion and mediastinal masses. All CD4+CD56+ types were associated with skin lesions. B-NKL type is included into Blastic NK lymphoma in new World Health Organization classification with CD4+CD56+ type. But the cases of B-NKL were more reminiscent of CD7+SCL or M/NKL type than the CD4+CD56+ type, both clinically and histologically.
We propose that blastic NK lymphoma, a disease entity in the new WHO classification, should be divided into two types based on phenotypes and clinical features. The non-B, non-T lymphomas exhibited poorer prognoses, similar to that of B-cell lymphomas, than T-cell type tumors (P = 0.009).Among the 21 tumors, the prognosis of the four subtypes did not differ significantly; however, cases receiving aggressive chemotherapy and stem cell transplantation had a more favorable prognosis than those receiving only traditional chemotherapy and radiation therapy (P = 0.0089).
Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study.
DiGiuseppe JA, Louie DC, Williams JE, Miller DT, Griffin CA, Mann RB, Borowitz MJ.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6417, USA.
Am J Surg Pathol 1997 Oct;21(10):1223-30 Abstract quote
The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined.
We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase.
These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.
CD56+/CD4+ Lymphomas and Leukemias Are Morphologically, Immunophenotypically, Cytogenetically, and Clinically Diverse
Christiane K. Rakozy, MD,1 Anwar N. Mohamed, MD,1 Trieu D. Vo, PhD,2 Ghada Khatib, MD,1 P. Michael Long, PhD,1 David Eilender, MD,3 and Margarita Palutke, MD
Am J Clin Pathol 2001;116:168-176 Abstract quote
CD56, a neural adhesion molecule, is a marker of natural killer (NK) lymphocytes as well as a subgroup of CD8+ T cells. Normal lymphocytes with a CD56/CD4 phenotype are scarce. Physiologic increases may occur in patients with immunosuppression, chronic inflammation, and autoimmune disorders.
We report 4 cases of lymphomas/leukemias with the unusual CD56/CD4 phenotype. Two were of T-cell and 2 of true NK-cell origin. The T-cell lymphomas had large granular lymphocyte morphologic features and splenomegaly. One patients had a benign course; the other died within months of the leukemia diagnosis. The 2 NK cell lymphomas had blastic morphologic features, initially involved skin, and had a very aggressive clinical course; 1 patient died of acute leukemia, and 1 had recurrence after bone marrow transplantation. Cytogenetic analyses did not show a consistent pattern of abnormalities. The NK lymphoma with acute leukemia had a t(2;5) but was CD30– and anaplastic lymphoma kinase negative.
Although CD56+/CD4+ lymphomas/leukemias are a heterogeneous group, there may be a distinct subgroup of NK lymphoblastoid lymphomas of the skin, judging from our cases, as well as those previously reported.
Agranular CD4+CD56+ blastic natural killer leukemia/lymphoma.
Kimura S, Kakazu N, Kuroda J, Akaogi T, Hayashi H, Nishida K, Abe T.
Division of Hematology, Kyoto Second Red Cross Hospital, Japan.
Ann Hematol 2001 Apr;80(4):228-31 Abstract quote
Blastic natural killer cell leukemia/lymphoma (blastic NKL/L) is characterized by blastic morphology and a distinctive immunophenotype combining blastic features and cytologically resembling acute myeloid or lymphoid leukemia. The clinical, pathologic, and cytogenetic features of blastic NKL/L have not yet been systematically identified.
We report herein a case of blastic NKL/L with skin lesion, adenopathy, and systemic lymphoadenopathy. The identified tumor cells were positive for CD4 and CD56, and negative for T-cell, B-cell, and myeloid markers. T-cell receptor beta, gamma, delta, and immunoglobulin heavy chain genes in the bone marrow cells showed germ-line configurations. Southern blot analysis with a terminal probe did not reveal any Epstein-Barr virus infection.
Although patients diagnosed as blastic NKL/L have generally shown chemotherapy resistance and poor prognosis, our patient was treated with a combined chemotherapy, which is also used for acute lymphoblastic leukemia, and has maintained complete remission (CR) for more than 13 months. In addition to clinical investigations, we thoroughly analyzed his karyotype by using a combination of G-banding and a new technique, spectral karyotyping. The karyotype was described as 45, XY, der(1)t(1;20)(p32;q11.2), der(6) (1pter-->1p32:: 6p21.1-->6q13:: 7q11.2-->7qter), der(7) t(7;20)(q11.2;q11.2), t(13;14)(q14;q32), der(13)t(6;13) (p21.1; q14), -20.
Blastic Natural Killer Cell Lymphoma/Leukemia A Report of Seven Cases
Michael G. Bayerl, MD
Christiane K. Rakozy, MD
Anwar N. Mohamed, MD
Trieu D. Vo, PhD
Michael Long, PhD
David Eilender, MD
and Margarita Palutke, MDAm J Clin Pathol 2002;117:41-50 Abstract quote
Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American.
All cases exhibited blastic morphologic features and were CD3– and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4– cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene.
Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.
B-CELL ANTIGENS T-cell/natural killer cell lymphoblastic lymphoma with an unusual coexpression of B-cell antigens.
Gloeckner-Hofmann K, Ottesen K, Schmidt S, Nizze H, Feller AC, Merz H.
Institute of Pathology, Medical University of Luebeck, Germany.
Ann Hematol 2000 Nov;79(11):635-9 Abstract quote
Lymphoblastic lymphomas are usually B- or T-cell neoplasms. There exists a small group of T-cell lymphomas additionally coexpressing cytotoxic or natural killer (NK)-cell markers, supporting the hypothesis of a common T/NK-cell precursor and respective neoplasms. Clinically, lymphatic neoplasms of T/NK-cell phenotype are either extranodal lymphomas or acute leukemias. The clinical course of these T/NK neoplasms cannot be predicted by morphology and/or phenotype alone. However, the expression of a heterogeneous (T + NK or myeloid) marker profile or of "early" antigens (such as TdT, CD10, RAG1, RAG2) render them more likely to be in the acute leukemia group.
We present a case of a 63-year-old woman with a bone marrow infiltrate, enlarged lymph nodes, and B-symptoms. A cervical lymph node biopsy showed a monomorphic blastic infiltrate with a T-cell phenotype, coexpressing NK markers (CD56, CD57, NK1) and B-cell antigens (CD20, CD79).
To the best of our knowledge, this is a newly recognized phenotype that has not been reported before. T/NK-cell lymphomas, including blastic NK-cell leukemia/lymphoma and T-lymphoblastic lymphomas, have to be included in the differential diagnosis. Both groups have a different clinical behavior and prognosis. In particular, T/NK-cell lymphomas associated with an Epstein Barr virus infection are clinically very aggressive neoplasms.
J Am Acad Dermatol 2001;44:231-8
Japanese patient with a unique hematolymphoid malignancy characterized by an involvement of skin, nasopharyngeal region, bone marrow, lymph node, and a CD4+ CD43+ CD56+ CD2–CD3–CD8– and terminal deoxynucleotidyl transferase phenotype
Clinically, the cutaneous eruptions were purplish, hard, multiple nodules
Histologically, a massive proliferation of atypical pleomorphic cells with medium-sized nuclei were observed throughout the dermis
No clonal rearrangement of T-cell receptor (TCR)- gene or immunoglobulin heavy chain J gene was found, and no positive identification of EBV by in situ hybridization for EBV-encoded small nuclear RNA was found
Patient underwent high-dose chemotherapy with autografting of peripheral blood stem cells; however, the tumors quickly relapsed
Additional data from 17 cases of lymphoid malignancy from the literature sharing immunophenotypic and genotypic features similar to those of this case, including CD2–CD4+CD56+ and germline rearrangement of TCR
Although the cellular origin could not be decided, this malignancy was found to have 100% affinity for skin, a short course, and poor prognosis
CD30 POSITIVE
From the *Department of Dermatology, University Hospitals Case Medical Center, Cleveland, OH; daggerCase Western Reserve University School of Medicine, Cleveland, OH; and double daggerDivision of Hematology/Oncology, University Hospitals Case Medical Center; section signDepartment of Pathology, University Hospitals Case Medical Center, Cleveland, OH.
Extranodal nasal natural killer (NK)/T-cell lymphoma is a very rare lymphoma characterized by strong association with Epstein-Barr virus infection, very aggressive clinical behavior, and poor prognosis. The typical phenotype of neoplastic natural killer cells in this entity is as follows: CD2+, CD56+, surface CD3-, cytoplasmic CD3ϵ+, and cytotoxic granule-associated protein positive. CD30 expression, a phenotype characteristic of anaplastic large-cell lymphomas, is not a typical feature of nasal NK/T-cell lymphomas.
We describe the case of a 42-year-old woman with chronic nasal congestion and septal deviation who presented with progressive generalized tender erythematous plaques. A skin biopsy revealed an atypical angiocentric mononuclear cell infiltrate. Strong CD30 and CD3e immunoreactivities were noted in large atypical mononuclear cells within the infiltrate initially suggestive of a CD30+ T-cell lymphoma. However, flow cytometry of the skin lesion indicated that the cells were CD2+, CD4-, CD8-, and lacked surface CD3 more typical of a neoplasm of natural killer cells. Further studies revealed that the cells were CD56+, T-cell-restricted intracellular antigen-1+, and contained Epstein-Barr virus sequences consistent with a nasal-type NK/T-cell lymphoma. High titers of Epstein-Barr virus in the blood, evidence of sinonasal disease, and absence of a T-cell receptor gene rearrangement were additional features consistent with the diagnosis. The patient had a very aggressive clinical course and, despite combination chemotherapy, died 8 months after the onset of skin lesions.
This case represents an example of nasal-type NK/T-cell lymphoma with expression of CD30. When presenting in the skin, the phenotypic and morphologic features of this lymphoma may lead to an erroneous diagnosis of a CD30+ large-T-cell lymphoma.NORMAL HISTOLOGY
Nasal natural killer cell/t-cell lymphoma showing cellular morphology mimicking normal lymphocytes.Chinen K, Kaneko Y, Izumo T, Ohkura Y, Matsubara O, Tsuchiya E.
Departments of Pathology
(Drs Chinen, Izumo, Ohkura, and Tsuchiya) and Cancer Chemotherapy
(Dr Kaneko), Saitama Cancer Center, Ina-machi, Japan; and the Department of Pathology, National Defense Medical College, Tokorozawa City, Japan
(Dr Matsubara).Arch Pathol Lab Med 2002 May;126(5):602-5 Abstract quote We report the autopsy case of a 34-year-old Japanese man with a nasal natural killer (NK)-cell/T-cell lymphoma.
The patient developed the disease at 32 years of age, and a biopsy of the nasopharynx revealed pleomorphic lymphoma cell proliferation. Radiotherapy was performed, but the patient eventually died of respiratory failure. After radiotherapy, no histologic evidence of malignancy was obtained with biopsy materials featuring lymphocytic infiltration. Autopsy studies, including in situ hybridization for Epstein-Barr virus-encoded RNA, revealed generalized infiltration of normal lymphocyte-like, UCHL-1-positive, and Epstein-Barr virus-encoded RNA-positive lymphoma cells. Monoclonal proliferation of the Epstein-Barr virus-carrying cells was verified by means of Southern blot analysis.
Retrospectively, we concluded that the normal lymphocyte-like presentation of the lymphoma cells, probably influenced by radiotherapy, prevented pathologists from recognizing the lymphoma. The utility of in situ hybridization for Epstein-Barr virus-encoded RNA in identification of tumor cells is emphasized with respect to the present case.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains IMMUNO-
HISTOCHEMICAL MARKERRESULT + + + + + +
>90% of nasal type cases but figure may be lower in CaucasiansHigh proliferative rate, usually >80% Germline Immunoreactivity of B-cell markers (CD79a, L26) in rare cases of extranodal cytotoxic peripheral T- (NK/T-) cell lymphomas.
Blakolmer K, Vesely M, Kummer JA, Jurecka W, Mannhalter C, Chott A.
Department of Clinical Pathology, General Hospital Vienna, University of Vienna, Austria.
Mod Pathol 2000 Jul;13(7):766-72 Abstract quote
The monoclonal antibodies L26 (CD20) and CD79a are very useful reagents for the immunohistochemical assessment of B-cell lineage in lymphoproliferative disorders. Although very few CD20-positive peripheral T-cell lymphomas (PTL) have been reported, comprehensive analyses of CD79a reactivity in extranodal PTL and NK/T-cell lymphomas have not been performed previously.
This study investigated CD79a (clone JCB117) and CD20 reactivity in 94 extranodal non-B-cell lymphomas (enteropathy-type intestinal T-cell lymphoma [n = 52], nasal NK/T-cell lymphoma [n = 11], and primary cutaneous PTL [n = 31]) and in 17 cases of nodal PTL, unspecified.
In four cases (enteropathy-type intestinal T-cell lymphoma [n = 3] and nasal NK/T-cell lymphoma [n = 1]), the majority of tumor cells stained for CD79a (all CD20 negative) and one cutaneous PTL, unspecified, was CD20 positive (CD79a negative). Extensive immunophenotyping and polymerase chain reaction-based molecular analyses revealed that all five B-cell marker-positive extranodal lymphomas had a cytotoxic phenotype and did indeed represent monoclonal peripheral T-cell proliferations.
To minimize the risk of misinterpretation of lymphoma cell lineage, especially in cases of extranodal, lymphoproliferative disease, we suggest the use of both CD79a and CD20 in combination with a panel of antibodies reactive to T cells, such as betaF1 and CD5, and to T cells and NK cells, such as CD3, CD2, CD56, and TIA-1.
CHEMOKINE RECEPTORS
Chemokine Receptor Expression in Cutaneous T cell and NK/T-cell Lymphomas: Immunohistochemical Staining and In Vitro Chemotactic Assay.Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Japan.
Interactions between chemokines and chemokine receptors are involved in migration and invasion of lymphoma cells.
We investigated expression profiles of CXCR3 and CCR4 by immunohistochemistry and flow cytometry, and their biologic behaviors by real-time horizontal chemotaxis assay in cutaneous T cell and NK/T-cell lymphomas (TCLs). Tumor cells in mycosis fungoides (MF) constantly expressed CXCR3 at the patch stage, and expressed CCR4 at the tumor stage and in the folliculotropic variant of MF. Neoplastic cells at the plaque stage expressed CXCR3 and/or CCR4. Sezary cells in the dermis and circulation were positive for CCR4. Epidermotropic atypical cells in pagetoid reticulosis expressed CXCR3. CD30 cells exclusively expressed CCR4 in anaplastic large-cell lymphoma, and CXCR3 and/or CCR4 in lymphomatoid papulosis. In CD8TCL and extranodal NK/TCL characterized by extensive epidermotropism, tumor cells were positive for CXCR3. These data demonstrated preferential expression of CXCR3 in epidermotropic tumor cells, and of CCR4 in dermis-based lymphomas.
In chemotaxis assays, CCR4 tumor cells in MF and CXCR3 tumor cells in CD8TCL migrated to thymus and activation-regulated chemokine and inducible protein-10, respectively. Therefore, spatial and temporal interactions between chemokine receptors and their ligands seem to dictate recruitment and retention of lymphoma cells in the skin.Electron microscopy (EM) Comparative ultrastructural study of cytotoxic granules in nasal natural killer cell lymphoma, intestinal T-cell lymphoma, and anaplastic large cell lymphoma.
Sadahira Y, Akisada K, Sugihara T, Hata S, Uehira K, Muraki N, Manabe T.
Department of Pathology, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan.
Virchows Arch 2001 Mar;438(3):280-8 Abstract quote
Comparative immunohistochemical and ultrastructural studies were performed on five nasal natural killer (NK) cell lymphoma cases, two intestinal T-cell lymphoma cases, and eight anaplastic large cell lymphoma (ALCL) cases to clarify morphological differences in cytotoxic granules among these cytotoxic lymphomas.
Nasal NK-cell lymphomas and intestinal T-cell lymphomas had fine azurophilic granules and displayed dot-like immunostaining of granzyme B- and T-cell intracellular antigen 1 (TIA-1), predominantly in the central area of the cytoplasm. Ultrastructurally, these NK-cell lymphomas and intestinal T-cell lymphomas had two types of cytotoxic granules, type-I granules (dense core granules) and type-II granules (multivesicular bodies), which have been demonstrated in normal large granular lymphocytes in peripheral blood. However, ALCLs did not have azurophilic granules, and only type-II cytotoxic granules were found ultrastructurally, even though they showed similar dot-like immunostained patterns of granzyme B and TIA-1, as seen in NK-cell lymphomas and intestinal T-cell lymphomas. Immunoelectron microscopy revealed that TIA-1 was primarily located at the periphery of the cytoplasmic granules in the NK-cell lymphoma and ALCL cases.
These findings suggest that malignant lymphomas with a cytotoxic phenotype can be divided into two types, (azurophilic granule)+, (type-I granule)+, (type-II granule)+ lymphomas and (azurophilic granule)-, (type-I granule)-, (type-II granule)+ lymphomas.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES CD30+ ANAPLASTIC LYMPHOMA Solitary primary cutaneous CD30+ large cell lymphoma of natural killer cell phenotype bearing the t(2;5)(p23;q35) translocation and presenting in a child.
Gould JW, Eppes RB, Gilliam AC, Goldstein JA, Mikkola DL, Zaim MT, Wood GS.
Department of Dermatology, Case Western Reserve University, and the Veterans Administration Medical Center, Cleveland, Ohio 44106, USA.
Am J Dermatopathol 2000 Oct;22(5):422-8 Abstract quote
Primary cutaneous CD30+ large cell lymphoma is an unusual tumor most commonly seen in adults. Most of these lymphomas are of T-cell origin and carry a good prognosis.
We present the case of a 4-year-old girl with stage IEA CD30+ large cell lymphoma with a CD56+ natural killer cell phenotype and the t(2;5)(p23;q35) translocation. After excision, the patient has been free of disease for 44 months. Primary cutaneous CD30+ large cell lymphoma is uncommon in children. To our knowledge, primary cutaneous CD30+ natural killer type lymphoma has not been reported previously. The indolent behavior of this tumor indicates its similarity to other primary cutaneous CD30+ large cell lymphomas and its difference from other CD56+ lymphomas involving the skin, which often exhibit an aggressive clinical course.
Cases such as this one illustrate why the use of a single, or even a few, immunohistochemical stains can be misleading in regard to lymphoma classification and prognostication.
LYMPHOMATOID PAPULOSIS Lymphomatoid papulosis with a natural killer-cell phenotype.
Bekkenk MW, Kluin PM, Jansen PM, Meijer CJ, Willemze R.
Department of Dermatology, Leiden University Medical Centre, Albinusdreef 2, 2300 RC Leiden, the Netherlands.
Br J Dermatol 2001 Aug;145(2):318-22 Abstract quote
Lymphomatoid papulosis (LyP) is defined as a recurrent self-healing papulonodular eruption with the histological features of a (CD30+) cutaneous T-cell lymphoma. The atypical cells usually have a CD3+/-, CD4+/-, CD8-, CD30+, CD56- T-cell phenotype.
We report an unusual case of LyP, in which the atypical cells expressed a CD3-, CD4-, CD8-, CD30+, CD56+ phenotype. Detailed phenotypic and genotypic analysis confirmed that these cells had a natural killer (NK)-cell phenotype. Lymphomas with an NK-cell phenotype usually have a poor prognosis.
However, the waxing and waning of papular lesions for more than 20 years and the excellent response to low-dose oral methotrexate in this patient suggest similar clinical behaviour to LyP cases with a T-cell phenotype.
NK-CELL, ATYPICAL PROLIFERATION
- Atypical NK-cell Proliferation of the Gastrointestinal Tract in a Patient With Antigliadin Antibodies but not Celiac Disease.
Vega F, Chang CC, Schwartz MR, Preti HA, Younes M, Ewton A, Verm R, Jaffe ES.
*Department of Pathology, Baylor College of Medicine Departments of daggerPathology double daggerOncology, and section signGastroenterology, The Methodist Hospital, Houston, TX parallelLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
Am J Surg Pathol. 2006 Apr;30(4):539-544. Abstract quote
We describe a unique case of atypical natural killer (NK)-cell proliferation likely related to gluten sensitivity, mimicking NK-cell lymphoma. The patient, a 32-year-old man, has had persistent multiple erythematous bull-eye lesions in the stomach, small bowel, and large bowel for 3 years.
Histologically, the lesions were well circumscribed and relatively superficial, composed of atypical medium-sized to large-sized lymphocytes with slightly irregular nuclear contours, a dispersed chromatin pattern, and clear cytoplasm.
Immunohistochemistry and flow cytometry showed that the cells were NK cells expressing CD56 (aberrantly bright), T-cell intracellular antigen (TIA)-1, cytoplasmic CD3, and CD94, but not surface CD3, with bright aberrant expression of CD7 and a lack of other NK cell-associated markers. Polymerase chain reaction for rearrangement of the T-cell receptor-gamma chain gene showed no evidence of a clonal T-cell population, and in situ hybridization for Epstein-Barr virus encoded RNA was negative. There was no evidence of the involvement of peripheral blood or bone marrow. Although a diagnosis of extranodal NK/T-cell lymphoma was considered because of the atypical morphology and immunophenotypic aberrancy, no chemotherapy was given because of the relatively superficial nature of the infiltrates, lack of significant symptoms, and negativity for Epstein-Barr virus.
Two years after initial presentation, the patient was found to have high titers of antigliadin antibodies with no other evidence of celiac disease. After instituting a gluten-free diet, many of the lesions regressed, suggesting that this atypical NK-cell proliferation may be driven by an anomalous immune response. Awareness of this case may prevent pathologists from misdiagnosing similar lesions as NK/T-cell lymphomas.
It is as yet unknown whether this process occurs more commonly in patients with gluten sensitivity, or in other settings, and the pathogenesis is as yet undetermined.SMALL ROUND BLUE CELLS CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms.
Liu Q, Ohshima K, Sumie A, Suzushima H, Iwasaki H, Kikuchi M.
Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonanku, Fukuoka 814-01, Japan.
Virchows Arch 2001 Mar;438(3):271-9 Abstract quote
CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration.
Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas.
Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.
TREATMENT AND PROGNOSIS CHARACTERIZATION PROGNOSIS GENERAL Angiocentric nasal T/natural killer cell lymphoma: a single centre study of prognostic factors in 108 patients.
Aviles A, Diaz NR, Neri N, Cleto S, Talavera A.
Departament of Hematology, Oncology Hospital, National Medical Center, Mexico.
Clin Lab Haematol 2000 Aug;22(4):215-20 Abstract quote
Angiocentric T cell/natural killer (NK) nasal lymphoma remains a rare clinical presentation in North America and Europe but is more common in Asia and Latin America.
We have reviewed 108 cases of angiocentric T/NK cell lymphoma of the nasal cavity with a view to establishing prognostic factors. Most patients were high or high intermediate clinical risk and had additional poor prognostic factors such as bulky disease, high levels of beta 2 microglobulin, advanced stage and multiple extranodal involvement. At 8 years, overall survival was 82%, 90% and 84% for low-intermediate, high-intermediate and high clinical, respectively. Disease free survival was very similar: 79%, 83% and 80%, respectively.
Multivariate analysis did not identify any factor influencing overall survival and disease-free survival. There was no evidence that the international prognostic index (IPI) was applicable in these patients and it appears that angiocentric T/NK cell lymphoma is an independent prognostic factor itself.
Clinicopathological features of Epstein-Barr virus-associated nasal T/NK cell lymphomas in southern Japan.
Seki D, Ueno K, Kurono Y, Eizuru Y.
Department of Otolaryngology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
Auris Nasus Larynx 2001 Jan;28(1):61-70 Abstract quote
OBJECTIVE: Nasal T/natural killer cell lymphomas (NTCL) are highly prevalent among Oriental populations. However the characteristic immunophenotype of NTCL is still controversial and it can be difficult to make a firm histologic diagnosis of malignancy. Therefore, 14 cases of NTCL in patients from southern Japan were evaluated for clinicopathological features and immunophenotypic status. Furthermore, the genetic variations in the latent membrane protein 1 (LMP-1) gene of Epstein-Barr virus (EBV)-related NTCL were evaluated.
METHODS: Biopsy specimens were fixed in formalin and embedded in paraffin before examination using in situ hybridization for EBV-encoded RNA-1 (EBER-1) as well as immunohistochemical staining for CD3, CD3epsilon, CD4, CD8, CD43, CD45RA, and CD45RO. To detect genetic variations, single-strand conformation polymorphism (SSCP) analysis and DNA sequencing were applied.
RESULTS: Clinically, 14 cases were divided into two groups. The first group consisting of eight patients showed good prognosis. The other group consisting of six patients showed poor prognosis. The vast majority of neoplastic cells in NTCL were EBER-1 positive. These cells did not express CD4, CD8, or CD45RA, but often expressed CD43 and CD45RO. In addition, they were negative for CD3 when stained with a mouse monoclonal antibody but stained for CD3epsilon when a rabbit polyclonal was used. The 3'-terminal of LMP-1 gene of seven cases were amplified and all of them have 30 base pair (bp) deletion.
CONCLUSION: NTCL are a heterogeneous mix of cell types although EBV-associated NTCL in patients from southern Japan appear to originate from natural killer cells rather than T cells, and also prognosis is variable and not always poor. The ability to make a firm diagnosis can be enhanced through the combined use of in situ hybridization and immunohistochemistry. High prevalence of the 30-bp deletions of the LMP-1 gene in EBV-related NTCL may also reflect the prevalence of the deletion variant in the normal population in Japan.
BONE MARROW INVOLVEMENT Bone marrow involvement by nasal NK cell lymphoma at diagnosis is uncommon.
Wong KF, Chan JK, Cheung MM, So JC.
Dept of Pathology, Queen Elizabeth Hospital, 30 Gascoigne Rd, Kowloon, Hong Kong SAR, China.
Am J Clin Pathol 2001 Feb;115(2):266-70 Abstract quote
To look for subtle evidence of marrow involvement in nasal NK cell lymphoma at diagnosis, we retrospectively studied trephine biopsy specimens from 25 consecutive patients by 2 sensitive techniques: CD56 immunohistochemistry and Epstein-Barr virus-encoded RNA in situ hybridization (EBER ISH).
Only 2 patients had marrow involvement by NK cell lymphoma at diagnosis. In 3 additional patients, marrow involvement developed during or after systemic recurrence. All 5 positive cases were revealed by EBER ISH, but only 3 cases showed CD56 immunoreactivity. Among the 5 cases, only 2 were recognized by morphologic assessment. All 5 patients died, often within a short period, compared with a mortality of 50% for patients without demonstrable marrow involvement.
Marrow involvement is distinctly uncommon in nasal NK cell lymphoma at diagnosis, and EBER ISH is the most sensitive technique for the demonstration of occult NK cell lymphoma.
Despite the low frequency of marrow involvement in nasal NK cell lymphoma, EBER ISH is worthwhile to identify the minor subgroup of patients with a high likelihood of early death due to disease and when autologous bone marrow or peripheral blood stem cell transplantation is contemplated.
TREATMENT Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation.
Nawa Y, Takenaka K, Shinagawa K, Deguchi S, Matsumura N, Koyama S, Hiramatsu Y, Omoto E, Yoshino T, Harada M.
Second Department of Internal Medicine, Okayama University Medical School, Japan.
Bone Marrow Transplant 1999 Jun;23(12):1321-2 Abstract quote
CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical entity which is the prototype of the putative NK cell lymphomas.
A 16-year-old Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose chemotherapy supported with syngeneic peripheral blood stem cell transplantation (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional chemotherapy before transplantation, resulting in a partial response. PBSC were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She achieved complete remission and is now surviving in continuous complete remission for more than 30 months after syngeneic PBSCT.
Thus, marrow-ablative chemotherapy facilitated by autologous or allogeneic PBSCT should be considered as part of the primary therapy for poor prognosis NK cell lymphomas.
High-dose chemotherapy with peripheral blood stem cell rescue in blastoid natural killer cell lymphoma.
Mukai HY, Kojima H, Suzukawa K, Hori M, Komeno T, Hasegawa Y, Ninomiya H, Mori N, Nagasawa T.
Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Leuk Lymphoma 1999 Feb;32(5-6):583-8 Abstract quote
A 25-year-old man was referred because of skin rash, lymphadenopathy and anemia. Laboratory examinations revealed severe anemia (Hb, 4.8 g/dl) and elevated levels of GOT, GPT, LDH and soluble interleukin-2 receptor.
Work-up studies disclosed the involvement of lymphoma cells in lymph nodes, skin, bilateral kidneys and bone marrow. Lymph node biopsy revealed diffuse proliferation of medium- to large-sized lymphoblastic cells. Bone marrow aspiration showed massive infiltration of large blastic cells with no cytoplasmic granules. The lymphoma cells in bone marrow and lymph node showed surface CD3-, cytoplasmic CD3epsilon+, CD4+, CD8-, CD56+, CD57-, CD16- and CD43 (MT-1)+ phenotype. Analyses of T cell receptor beta and gamma genes showed germ line configurations. EBER-1 was not detectable in the lymphoma cells. He was diagnosed as having blastoid natural killer (NK) cell lymphoma. In spite of several courses of combination chemotherapy, the lymphoma was progressive. He was then treated with high-dose chemotherapy and peripheral blood stem cell rescue, achieving remission which has now lasted for more than 12 months.
We consider that blastoid NK cell lymphoma is an extremely aggressive subtype of CD56-positive lymphomas, and high-dose chemotherapy with peripheral blood stem cell rescue should be included for the choice of the treatment.
Successful treatment of disseminated nasal NK/T-cell lymphoma using double autologous peripheral blood stem cell transplantation.
Sasaki M, Matsue K, Takeuchi M, Mitome M, Hirose Y.
Department of Medicine, Kameda General Hospital, Kamogawa, Japan.
Int J Hematol 2000 Jan;71(1):75-8 Abstract quote
Nasal natural killer (NK)/T-cell lymphoma is a rare disease with an aggressive clinical course. Prognosis is generally poor and the disease is invariably fatal after systemic dissemination.
We report a patient with aggressive nasal NK/T-cell lymphoma who was resistant to therapy and developed systemic dissemination involving the intestine, skin, and stomach. Epstein-Barr virus (EBV) was detected by Southern blotting with EBV-terminal repeat probe and by in situ EBV-encoded small nuclear early region-1 hybridization. The patient was treated using double high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). Pretransplant conditioning for the first auto-PBSCT was MCVC (high-dose ranimustine, carboplatin, etoposide [VP16], and cyclophosphamide), and for the second auto-PBSCT, modified ICE (high-dose ifosfamide, VP16, and carboplatin). The patient obtained a complete remission and has been free of disease for 3.0 years since the second PBSCT.
These observations suggest that double high-dose chemotherapy with PBSCT support may be effective in resistant nasal NK/T-cell lymphoma.
Killer T-cell induction in patients with blastic natural killer cell lymphoma/leukaemia: implications for successful treatment and possible therapeutic strategies.
Yamada O, Ichikawa M, Okamoto T, Park C, Motoji T, Mizoguchi H, Shibuya A.
Department of Haematology, Tokyo Women's Medical University, Japan.
Br J Haematol 2001 Apr;113(1):153-60 Abstract quote
A rare form of putative natural killer (NK) cell lymphoma called blastic NK cell lymphoma appears to be clinicopathologically distinctive in showing a homogenous lymphoblast, variable expression of CD2, CD4, CD56 and TdT, negative for surface CD3, T-cell receptor antigen, CD16, CD34 and lack of association with Epstein-Barr virus (EBV).
We report two patients with blastic NK cell lymphoma and describe the interesting clinical studies. The patients presented with cutaneous plaques. Both patients had adenopathy, and one had marrow involvement at presentation. Unlike in many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent. They expressed intermediate density CD45. In addition, the cells were positive for HLA-DR, CD2, CD4, CD56 and TdT, and negative for EBV transcripts. In spite of the advanced clinical stage, complete remission was achieved by conventional chemotherapy.
After interleukin 2 expansion of tumour-infiltrating bone marrow and lymph node cells from the patients, cytotoxic T-cell lines with rearranged T-cell receptor genes were established. They showed specific killing activity against autologous tumour cells in an MHC-restricted fashion, with possible implications for treatment. In addition, upon cessation of maintenance chemotherapy, one patient developed overt leukaemia with blasts expressing CD33 antigens, suggesting a continuous spectrum of blastic NK cell lymphoma to myeloid/NK cell precursor acute leukaemia.
Natural killer cell lymphoma: report of two pediatric cases, therapeutic options, and review of the literature.
Shaw PH, Cohn SL, Morgan ER, Kovarik P, Haut PR, Kletzel M, Murphy SB.
Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois 60614, USA.
Cancer 2001 Feb 15;91(4):642-6 Abstract quote
BACKGROUND: Natural killer (NK) cell lymphomas are rapidly fatal malignancies that to the authors' knowledge are rare in children. In the current study, the authors report the cases of two boys with NK cell lymphomas with refractory disease who both were salvaged with high dose chemotherapy and stem cell transplantation and compare these patients with those in the published experience.
METHODS: A comprehensive literature review was performed to identify other cases of pediatric patients with NK cell lymphomas, their treatment, and outcome.
RESULTS: One of the patients in the current study developed two recurrences and the other patient experienced early disease progression during front-line treatment. Both then were treated with high dose chemotherapy followed by stem cell rescue. At last follow-up, the patients remained free of disease at 15 months and 16 months, respectively, after transplantation (48 months and 22 months, respectively, from the time of diagnosis). In addition to the 2 patients in the current study, the authors found 13 pediatric patients reported in the literature to date. Of the 7 patients with localized (Stage I-II) disease, 5 patients (71%) were reported to be alive 1-107 months after diagnosis. Of the 6 patients with Stage IV disease, only the 2 patients who received high dose chemotherapy and stem cell rescue (33%) were alive at the time of last follow-up (at 30 months and 12 months, respectively). Including the patients reported in the current study, 9 of 15 children with NK cell lymphoma (all stages) (60%) were reported to be alive at the time of last follow-up.
CONCLUSIONS: Although pediatric NK cell lymphomas rapidly can become fatal, it appears that high dose chemotherapy followed by stem cell transplantation is effective therapy, especially in patients with advanced or resistant disease. Further follow-up is needed to determine whether this treatment approach will be curative.
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