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Natural Killer-Cell Lymphoma Involving the Gynecologic Tract.

Involvement of the female genital tract by systemic non-Hodgkin lymphoma (NHL) is not uncommon, and is often detected by radiologic staging studies or at the time of autopsy.[1-5] However, NHL arising within the female genital tract is rare.[2-4] Histologically, most NHL involving the female genital tract previously reported have been diffuse, aggressive, and most often of large-cell type.[1-5] Almost all reported cases studied have been of B-cell lineage.[1,2,5]

Natural killer (NK)-cell lymphomas usually occur in the nasal or nasopharyngeal region. Other sites also may be involved, such as the upper aerodigestive tract, skin, testis, gastrointestinal tract, soft tissue, and spleen.[6,7] However, we have not identified previous reports of primary or secondary involvement of the gynecologic tract by NK-cell lymphoma.

We report 2 cases of NK-cell lymphoma involving the female genital tract. Case 1 was a stage IE nasal-type NK-cell lymphoma arising in the cervix. Case 2 was a systemic blastoid NK-cell lymphoma/leukemia that involved the entire gynecologic tract.


Formalin-fixed, paraffin-embedded tissue sections derived from the uterine cervix and bone marrow of case 1 and the uterus, ovaries, fallopian tubes, lymph node, and bone marrow of case 2 were stained with hematoxylin-eosin.

Cytochemical and flow cytometry immunophenotypic studies were performed on bone marrow aspiration smears of case 2. Cytochemical studies were performed using standard methods. For immunophenotypic analysis, the blasts were gated using CD45 and side scatter. A panel of monoclonal antibodies was used specific for the following antigens: CD2, CD3, CD4, CD7, CD8, CD10, CD13, CD19, CD33, CD34, CD38, CD45 (LC, A), CD56, CD64, CD117 (c-kit), HLA-DR, and terminal deoxynucleotidyl transferase (TdT).

Immunohistochemical studies were performed using fixed, paraffin-embedded tissue sections and a variable panel of antibodies specific for the following antigens: CD3 (1:10); CD20 (1: 100); CD30 (1:30); CD43 (1:30); CD45 (1:80); CD56 (1:50); myeloperoxidase (1:500); Epstein-Barr virus latent membrane protein (EBV-LMP) (1:50) (Dako Corporation, Carpinteria, Calif); and TIA-1 (1:25) (Coulter Immunology, Hialeah, Fla). All antibodies were monoclonal with the exception of the anti-CD3 antibody.

In situ hybridization studies for Epstein-Barr virus (EBV) ribonucleic acid (RNA) were performed using a 30-base oligonucleotide probe complementary to a portion of the EBER1 gene and methods previously described by others.[8]

Molecular studies were performed using formalin-fixed, paraffin-embedded tissue of the cervical cone biopsy specimen of case 1, and lymph node and flesh bone marrow aspiration material of case 2. The DNA was prepared by standard proteinase K digestion and phenol/chloroform extraction. The T-cell receptor [Gamma] chain gene was analyzed using a polymerase chain reaction method and consensus variable and joining region primers as described previously by Theodorou et al.[9] The immunoglobulin heavy chain (IgH) gene was analyzed using a polymerase chain reaction method and consensus variable region framework 3 and joining region primers as described by others.[10]


Case 1

A 30-year-old Caucasian woman (gravida 5, para 2, and abortion 3) was admitted to the hospital complaining of lower abdominal pain and vaginal bleeding. Physical examination revealed a friable, necrotic uterine cervix without a well-defined mass. A complete blood count revealed the following values: hemoglobin, 126 g/L (normal, 140-180 g/L); platelet count, 183 x [10.sup.9]/L (normal 150-400 x [10.sup.9]/L); and white blood cell count, 3.5 x [10.sup.9]/L (normal, 4.5-12.0 x [10.sup.9]/L). A differential count revealed: 56% segmented neutrophils, 36% lymphocytes, 5% monocytes, 1% basophils, and 2% eosinophils. The patient was serologically positive for both hepatitis B and C. Computerized tomographic scan of the pelvis revealed a bulky cervix without evidence of lymph node enlargement (Figure 1). An abdominal CT scan, intravenous pyelography, and chest radiograph were unremarkable. A cone biopsy of the cervix was performed, followed by total abdominal hysterectomy and staging bone marrow aspirations and biopsies in the following few months.


Case 2

A 45-year-old African-American woman was admitted to the hospital, complaining of back and bone pain, increasing in frequency and intensity for the past 4 months. She had a long medical history of menorrhagia due to uterine fibroids, which resulted in symptomatic anemia. Physical examination revealed axillary, supraclavicular, and cervical lymphadenopathy. A complete blood count revealed the following values: hemoglobin, 95 g/L; platelet count, 173 x [10.sup.9]/L; and white blood cell count, 3.9 x [10.sup.9]/L, with a differential count of: 25% segmented neutrophils, 5% bands, 3% metamyelocytes, 2% myelocytes, 1% promyelocytes, 50% lymphocytes, 4% monocytes, and 9% unclassified blast forms. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Axillary lymph node biopsy and 2 bone marrow aspiration and biopsy specimens were subsequently obtained. The patient was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with an excellent clinical response following 1 cycle and continues on therapy.


Case 1

Grossly, the cervical cone biopsy specimen revealed a severely ulcerated, irregular 7-cm cervical cone biopsy specimen without a mass. Histologically, there was extensive necrosis, acute inflammation, and ulceration of the squamous epithelium. The cervical stroma was infiltrated by atypical, medium-sized lymphoid cells with irregular nuclear contours, scant to moderate cytoplasm, and vesicular nuclei. Several areas showed angiocentricity, where neoplastic lymphoid cells preferentially invaded and destroyed blood vessel walls (Figure 2).


Immunohistochemical studies showed that the neoplastic lymphoid cells were positive for CD3, CD56, and TIA-1 and were negative for CD20 and EBV-LMP1. In situ hybridization analysis for EBV RNA was negative. Polymerase chain reaction studies showed no evidence of monoclonal T-cell receptor [Gamma] chain or immunoglobulin heavy chain gene rearrangements.

The clinical, histologic, immunohistochemical, and molecular studies were interpreted as a stage IE N-K-cell lymphoma, nasal-type, arising in the cervix. A subsequent hysterectomy specimen consisted of a 103-g, 8.5 x 4.0 x 3.4-cm uterus. The endocervical canal, endometrium, and myometrium were grossly and histologically unremarkable. There was no evidence of malignant neoplasm.

Case 2

Grossly, the specimen consisted of a uterus, left and right fallopian tubes, and ovaries that weighed 400 g and measured 16 x 7.5 x 5.5 cm. Numerous well-circumscribed, intramural and submucosal, white leiomyomas were present, ranging in size from 1.5 cm to 0.3 cm. The ovaries and fallopian tubes were grossly unremarkable.

Histologic sections of the uterus, ovaries and fallopian tubes revealed extensive infiltration by malignant neoplasm, but a distinct mass was not formed (Figure 3). This neoplasm was composed of small to medium lymphoid cells with fine nuclear chromatin and a brisk mitotic rate (Figure 4). The axillary lymph node specimen was subtotally effaced by a histologically similar neoplasm, with a paracortical distribution in areas of subtotal replacement. The initial bone marrow biopsy specimen showed complete replacement of the medullary space by neoplastic cells similar to those found in the uterus and lymph node. Bone marrow touch preparations showed many neoplastic cells without prominent azurophilic granules. A repeat bone marrow aspiration and biopsy after 1 cycle of chemotherapy demonstrated persistent malignant neoplasm representing 10% of all cells.


Cytochemical studies on bone marrow aspiration smears of the second bone marrow specimen showed that the neoplastic cells were negative for myeloperoxidase and butyrate esterase. Flow cytometry immunophenotypic studies performed on both bone marrow aspiration specimens revealed that the neoplastic cells were positive for CD4, CD7, CD33, CD38, CD45, CD56, and HLA-DR, and were negative for CD2, surface CD3, CD8, CD10, CD13, CD19, CD34, CD64, CD117, and TdT.

Immunohistochemical stains performed on the uterus and lymph node showed that all of the neoplastic cells were positive for CD43, CD45, and CD56 (Figure 5). A subset of cells, approximately 40% to 50%, were positive for cytoplasmic CD3. The neoplastic cells were negative for CD20, CD30, CD45RO, myeloperoxidase, and TIA-1. In situ hybridization analysis for EBV RNA performed on the lymph node specimen was negative for EBV RNA. Molecular studies performed on lymph node and bone marrow aspiration specimens showed no evidence of monoclonal T-cell receptor [Gamma] chain or immunoglobulin heavy chain gene rearrangements.


The histologic, immunohistochemical, and molecular studies were interpreted as a stage IV blastoid NK-cell lymphoma/leukemia.


We report 2 cases of NK-cell lymphoma involving the gynecologic tract. We believe that both tumors are of NK-cell origin because they expressed CD56 and other NK-cell-associated antigens, such as cytoplasmic CD3, CD4, CDT, CD43, and TIA-1 (case 1), and were negative for surface CD3 (case 2) and T-cell receptor [Gamma] chain gene rearrangements. An argument might be made for considering case 2 a form of primitive acute myeloid leukemia, because this neoplasm weakly expressed CD33 and CD4. The markers CD7, CD43, and CD56 can be expressed by neoplastic myeloid cells,[11,12] leading others to postulate the existence of a common myeloid/NK-cell precursor.[12] However, CD33 can be expressed by immature NK cells,[13] the neoplasm was negative for all other myeloid, markers assessed (unlike CD56-positive acute myeloid leukemias reported previously[11,12]), and the neoplasm clinically and histologically responded well to the first cycle of CHOP chemotherapy. Thus, we believe that the sum of the evidence supports an NK-cell origin in this case.

Natural killer-cell lymphomas are heterogeneous and at least 3 types have been documented: nasal NK-cell lymphoma, nasal-type NK-cell lymphoma, and blastoid NK-cell leukemia/lymphoma.[14] Nasal NK-cell lymphomas usually involve the nasopharynx and midline structures, are more prevalent in Asian patients, and are strongly associated with EBV.[6,7,14,15] Nasal-type NK-cell lymphomas are histologically similar, but involve a variety of normasal sites. Nasal and nasal-type NK-cell lymphomas are characterized by prominent necrosis, often associated with vascular invasion. The neoplastic cells are positive for CD56 and may express cytoplasmic CD3, but are negative for surface CD3 and B-cell antigens. These tumors are also commonly positive for TIA-1, an antigen specific for NK-cells and cytotoxic T-cells.[16] Although most nasal NK-cell lymphomas are EBV-positive, some nasal-type NK-cell lymphomas (in nonnasal sites) are EBV-negative. These neoplasms do not show evidence of T-cell receptor or immunoglobulin gene rearrangements, as expected in tumors that arise from NK cells. Nasal-type NK-cell lymphoma may involve the gastrointestinal tract, skin, testis, and central nervous system, most often as part of systemic involvement, but rarely the tumor can be localized to these sites.[6,7,17-19] We believe that case 1 in this study is an example of a nasal-type NK-cell lymphoma involving the cervix.

For NHL to be considered to arise in the cervix, it should fulfill stringent criteria, such as those previously proposed by Fox and More.[20] The lesion must be confined to the cervix at the time of diagnosis and usually there is no evidence of NHL elsewhere for at least several months. Case 1 of this study fulfills these criteria. Primary cervical NHL is rare and there are few large series of cases reported from any single institution.[5,21] Almost all reported cervical NHL have been of B-cell lineage.[5,21] Case 1 in our study appears to be unique, as nasal-type NK-cell lymphoma arising in the cervix has not been described previously.

We believe that case 2 in this study is an example of systemic blastoid NK-cell lymphoma/leukemia secondarily involving the gynecologic tract. Blastoid NK-cell lymphoma/leukemia is clinically and histologically different from nasal or nasal-type NK-cell lymphoma, and relatively few well-documented cases have been reported in the literature.[7,22-24] Unlike nasal or nasal-type NK-cell lymphoma, the neoplastic cells of blastoid NK-cell lymphoma/ leukemia have finer nuclear chromatin and a high mitotic rate.[22] These tumors are CD56-positive and may express other T cell,associated antigens such as TIA-1, CD2, cytoplasmic CD3, and CD4, but are negative for surface CD3 and lack T-cell receptor or immunoglobulin gene rearrangements. Most cases reported to date have been EBV-negative.[23] However, at least 2 cases reported by Natkunam et al[24] were positive for EBV. Blastoid NK-cell lymphoma/leukemias are clinically aggressive and are usually resistant to chemotherapy.

Unlike nasal or nasal-type NK-cell lymphomas, blastoid NK-cell lymphoma/leukemia tumors rarely involve the nasal or nasopharyngeal regions, and instead involve a wide variety of nodal and extranodal sites.[22] A leukemic phase is common and therefore it is not surprising that blastoid NK-cell lymphoma/leukemia can widely infiltrate the female genital tract, as occurred in case 2 of this study. However, we are not aware of cases of blastoid NK-cell lymphoma/leukemia involving the female genital tract previously reported in the literature.

In summary, we have reported 2 cases of NK-cell lymphoma involving the gynecologic tract, including 1 stage IE case. Pathologists need to consider NK-cell tumors in the differential diagnosis of lymphoid lesions of the gynecologic tract.


[1.] Liang R, Chiu E, Luke SL. Non-Hodgkin's lymphomas involving the female genital tract. Hematol Oncol. 1990;8:295-299.

[2.] Monterroso V, Jaffe ES, Merino MJ, Medeiros LJ. Malignant lymphomas involving the ovary: a clinicopathologic analysis of 39 cases. Am J Surg Pathol. 1993;17:154-170.

[3.] Aozasa K, Saeki K, Ohsawa M, Horiuchi K, Mishima K, Tsujimoto M. Malignant lymphoma of the uterus. Cancer. 1993;72:1959-1964.

[4.] Harris NL, Scully RE. Malignant lymphoma and granulocytic sarcoma of the uterus and vagina: a clinicopathologic analysis of 27 cases. Cancer. 1984;53: 2530-2545.

[5.] Muntz HG, Ferry JA, Flynn D, Fuller AF, Tarraza HM. Stage IE primary malignant lymphomas of the uterine cervix. Cancer. 1991;68:2023-2032.

[6.] Nakamura S, Suchi T, Koshikawa T, et al. Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract. Am J Surg Pathol. 1995;19:284-296.

[7.] Chan JKC, Sin VC, Wong KF, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997;89:4501-4513.

[8.] Wu T-C, Mann RB, Epstein JI, et al. Abundant expression of EBER1 small nuclear RNA in nasopharyngeal carcinoma. A morphologically distinctive target for detection of Epstein-Barr virus in formalin-fixed paraffin-embedded carcinoma specimens. Am J Pathol. 1991;138:1461-1469.

[9.] Theodorou I, Delfau-Larue M-H, Birgorgne C, et al. Cutaneous T-cell infiltrates: analysis of T-cell receptor gamma gene rearrangement by polymerase chain reaction and denaturing gradient gel electrophoresis. Blood. 1995;86:305-310.

[10.] McCarthy KP, Sloane JP, Wiedemann LM. Rapid method for distinguishing clonal from polyclonal B cell populations in surgical biopsy specimens. J Clin Pathol. 1990;43:429-432.

[11.] Scott AA, Head DR, Kopecky KJ, et al. HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3. Blood. 1994;84:244-255.

[12.] Suzuki R, Yamamoto K, Seto M, et al. CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: a distinct hematolymphoid disease entity. Blood. 1997;90:2417-2428.

[13.] Spits H, Lanier LL, Phillips JH. Development of human T and natural killer cells. Blood. 1995;8,9:2654-2670.

[14.] Jaffe E. Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood. 1996;87:1207-1210.

[15.] Chan JKC, Yip TTC, Tsang WYW, et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol. 1994; 18:938-946.

[16.] Felgar RE, Macon WR, Kinney MC, Roberts S, Pasha T, Salhany KE. TIA-1 expression in lymphoid neoplasms. Identification of subsets with cytotoxic T-lymphocyte or natural killer cell differentiation. Am J Pathol. 1997;150:1893-1900.

[17.] Yeh K-H, Lien H-C, Hsu S-M, Chang A-L. Quiescent nasal T/NK cell lymphoma manifested as primary central nervous system lymphoma. Am J Hematol. 1999;60:161-163.

[18.] Kato N, Yasukawa K, Onozuka T, Kikuta H. Nasal and nasal-type T/NK lymphoma with cutaneous involvement. J Am Acad Dermatol. 1999;40:850-856.

[19.] Chan JKC, Tsang WYW, Lau W-H, et al. Aggressive T/natural killer cell lymphoma presenting as testicular tumor. Cancer. 1996;77:1198-1205.

[20.] Fox H, More JRS. Primary malignant lymphoma of the uterus. J Clin Pathol. 1965;18:1699-1704.

[21.] Komaki R, Cox JD, Hansen RM, Gunn WG, Greenberg M. Malignant lymphoma of the uterine cervix. Cancer. 1984;54:1699-1704.

[22.] DiGiuseppe JA, Louie DC, Williams JE, et al. Blastic natural killer leukemia/lymphoma: a clinicopathologic study. Am J Surg Pathol. 1997;21:1223-1230.

[23.] Kobashi Y, Nakamura S, Sasajima Y, et al. Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract. Histopathology. 1996;28: 111-120.

[24.] Natkunam Y, Smoller BR, Zehnder JL, Dorfman RF, Warnke RA. Aggressive cutaneous NK and NK-like T-cell lymphomas: clinicopathologic, immunohistochemical, and molecular analyses of 12 cases. Am J Surg Pathol. 1999;23:571-581.

Accepted for publication March 14, 2000.

From the Departments of Pathology (Drs Mhawech and Shahab) and Obstetrics and Gynecology (Drs Coffey and Gei), Baylor College of Medicine, Houston, Tex, and the Division of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Tex (Drs Medeiros and Bueso-Ramos). Dr Gei is currently a fellow in the Department of Obstetrics and Gynecology at The University of Texas Medical Branch, Calveston, Tex.

Reprints: L. Jeffrey Medeiros, MD, Department of Pathology, University of Texas, M.D. Anderson Medical Center, Houston, TX 77030 (email:
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Author:Mhawech, Paulette; Medeiros, L. Jeffrey; Bueso-Ramos, Carlos; Coffey, Donna M.; Gei, Alfredo F.; Sha
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2000
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