Primary extranodal NK/T cell lymphoma, nasal-type of uterus with adenomyosis: a case report

Natural killer (NK)/T cell lymphoma of the female genital tract is extremely rare. We here report a case of ‘nasal type ’ NK/T cell lymphoma arising in the uterus with adenomyosis in a 41-year-old woman with fever and hypogastralgia. The histologic analysis demonstrated a highly aggressive tumor with characteristic angiocentric/angiodestructive growth pattern and focal necrosis. The lymphoma cells displayed a CD3 ε/CD56/TIA-1/granzyme-B/Perforin-positive and CD20/CD79a/CD4/CD8-negative immunophenotype and positive for Epstein-Barr virus by EBER in situ hybridization. Clinically, the disease was limited to the uterus at the initial diagnosis, but progressed rapidly. The patient died on day 54 after hysterectomy, irrespective of intensive chemotherapy. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx. eu/vs/1323474831125945

Uterus, NK/T cell lymphoma, Extranasal type

Primary lymphoma of the female genital tract is uncom- mon with a frequency of only 0.002% in all patients with extranodal lymphomas [1]. The majority of these cases represent aggressive B-cell lymphomas. Involvement of the gynecological tract by NK/T cell lymphomas is con- sidered to be extremely rare and only 5 cases with pri- mary NK/T cell lymphoma involving the endometrium of the uterus has been reported in the English literature [2-5]. There was no report of such case in uterus associ- ated with adenomyosis. Here, we report the first case of primary NK/T cell lymphoma arising in the uterus with adenomyosis. Case presentation Clinical history A 41 year-old woman, without relevant previous anam- nesis, presented with fever and hypogastralgia for 2 months. Computer tomography and ultrasonography revealed en- largement of the uterus and multinodular intrauterine mass. A hysterectomy was performed. She was diag- nosed as extranodal NK/T cell lymphoma, nasal-type. After surgical resection, the patient was treated with CHOP chemotherapy (cyclophosphamide, vincristine, daunorubicin and dexamethasone). Despite extensive chemotherapy, the disease progressed rapidly; shortly follow-up radiological imaging showed the retroperi- toneal involvement. The p atient died on day 54 after surgical resection of the tumor. Pathological findings Macroscopic examination displayed a yellow, soft, poorly circumscribed mass that invaded about 4 cm in uterine wall (Figure 1). Histopathological evaluation revealed lym- phomatous infiltrate the endometrial gland (Figure 2A) and myometrium with well demarcated large areas of coagulative necrosis containing apoptotic nuclear deb- ris (Figure 2B). The tumor cells demonstrated a prom- inent angioinfiltrative gr owth pattern with concentric arrangement around small arteries (Figure 2C). The lymphoma cells were densely packed, with an abundant cytoplasm and enlarged nuclei with open chromatin and several large nucleoli. Mitotic figures were frequently seen. There was adenomyosis in myometrium without tumour involvement (Figure 2D). The tumor cells were positive for cytoplasmic CD3 and membranous CD56 (Figiures 3A and Figure 3B) but negative for CD4, CD5, CD8, CD20, CD79 α, CD30. Cyto- toxic proteins TIA-1 (Figure 3C), granzyme-B and Perforin displayed strong cytoplasmic granular staining pattern. * Correspondence: [email protected] Ningbo Diagnostic Pathology Center, Ningbo 315031, China © 2014 Fang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fang et al. Diagnostic Pathology 2014, 9:95 http://www.diagnosticpathology.org/content/9/1/95 EBER in situ hybridization demonstrated strong posi- tivities for all tumor cells (Figure 3D). Based on the overall morphological, i mmunophenotypical and EBV characteristics, the diagnos is of extranodal (uterine) NK-cell lymphoma, nasal-type was made.

Extranodal NK/T-cell lymphomas characteristically in- volve the upper aerodigestive tract, with the nasal cavity being the prototypic site [6]. Rarely, the tumour occurs in prostate, adrenal glands and lung [7-9]. Thus far, only a few cases of T- or NK/T-cell neoplasms involved uterus have been reported [2-5]. Like most of NK/T cell lymphoma in other anatomic sites, these lymphomas in the uterus usually are highly aggressive, and conven- tional prognostic factors usually fail to predict their outcome [10]. While clinical presentation of NK/T cell lymphoma in- volving the uterus may include vaginal bleeding, and abdom- inal or pelvic pain [11], our patient presented with fever and hypogastralgia with no evidence of vaginal bleeding. As the common pathological features of NK/T cell lymphoma defined by WHO classification, the current case dem- onstrated a highly aggressive tumor with characteristic angiocentric/angiodestruct ive growth pattern and asso- ciated focal necrosis. Interestingly, there is uterus adenomyosis present nearby the lymphoma in the current case; perhaps it might be an important factor contributing to the onset and process of the tumor. Occurrence of T cells and CD56+ NK cells within the normal endometrium has been described [12]. It seems to be established that uterine NK cells form a dynamic lymphoid pool in each menstruation cycle. One could expect that these cells may frequently undergo genetic and regulatory errors leading to malignant trans- formation [2]. For this reason it is difficult to understand, why uterine NK-cells transform to malignant lymphoma with such a low frequency. As one possible explanation, the relatively short duration of a menstrual cycle and the regular shed of the endometrium may prevent the expan- sion and malignant transformation of NK cells [2]. In the presented case, the presence of adenomyosis may prevent the normal NK cell duration and cycling in the uterus, perhaps provide the evidence that NK cells frequently Figure 1 Macroscopic view. Macroscopic examination displayed a yellow, soft, poorly circumscribed mass. Figure 2 Histological features of this case. A , Dense lymphomatous cells infiltrate endometrium,partially covered by intact columnar epithelium (HE, ×40 magnification).B, The lymphomatous proliferation was interrupted by coagulative necrotic areas (HE, ×200 magnification).C, Angiocentric and angiodestructive growth pattern is frequently present (HE, ×100 magnification).D, Adenomyosis in myometrium without lymphomatous infiltrate (HE, ×40 magnification). Fang et al. Diagnostic Pathology 2014, 9:95 Page 2 of 4 http://www.diagnosticpathology.org/content/9/1/95 remained in uterine corps undergo genetic and regulatory errors leading to malignant transformation. The associ- ation of adenomyosis with NK/T-cell lymphoma was largely not mentioned previously, because that the major- ity of cases reported with NK/T cell lymphoma in uterus often diagnosed by curettage, the way impossible to find adenomyosis. According the WHO criterion, the neoplastic lymphoid cells usually coexpress NK cell markers such as CD56 and T cell-associated antigens like CD3, CD2 with expression of cytotoxic markers such as TIA-1, Perforin and Granzyme-B [6]. The current case demonstrated the immuno charac- teristics of tumor cells are typical nasal-type NK/T cell lymphoma: CD3+, CD56+, TIA1+, Perforin+, Granzyme B+. As a hallmark of nasal type NK/T cell lymphoma, EBV in situ hybridization clearly supported EBV infec- tion of the lymphoma cells. TIA-1 and EBER were the two most sensitive markers of the disease. However PCR-based TCR gene rearrangement analysis might not be a useful technique for making diagnosis of NK/T cell lymphoma [13]. Latent membrane protein (LMP) 1 and LMP2A encoded by Epstein-Barr virus were associated with the development of malignancies. High expression of the two proteins could independently predict poor overall survival [14]. NK/T cell lymphomas were reported to have a median survival of only 0.28 years [15]. One case of NK/T cell lymphomas involved prostate was reported recently, the patient died within 4 months after diagnosis [7]. In an- other case of the lymphomas occurred in bilateral ad- renal glands, the patient died only 33 days after initial presentation [8]. In the present case, the patient died 54 days (0.15 year) after hysterectomy. Unfortunately, treatment experience is mostly limited to the upper aerodigestive tract disease. Extranodal NK/T cell lymph- omas of other sites are extremely rare and very limited data for optimal treatment strategies are currently available.

This case demonstrated a rare NK/T cell lymphoma pri- marily in the uterus, providing a diagnostic pitfall: pa- thologists and gynecologists should be aware of its existence and need to consider NK/T cell lymphomas within the spectrum of differential diagnosis of neoplas- tic tumor in the uterus. Because of the clinical aggres- siveness and dismal prognosis of the tumor, more effective therapeutic regimens should be actively looked. Consent Written informed consent was obtained from the fam- ily of the patient for publication of this case report and any accompanying images. A copy of the written con- sent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests. Authors’ contributions JC F analyzed the data and wrote the manuscript as a major contributor. ZX X, Z L helped to perform the immunochemical staining. J Z helped to revise the discussion section of this m anuscript. All authors have read and approved the final manuscript. Figure 3 Phenotypic characteristics of tumor cells. A , The lymphoma cells showed cytoplasmic CD3 ε B and C, Membranous CD56 and cytoplasmic granular TIA-1 positivity by immunohistochemistry (×200 magnification). D, In situ hybridization for EBER sequences clearly supported EBV infection of the lymphoma cells (×200 magnification). Fang et al. Diagnostic Pathology 2014, 9:95 Page 3 of 4 http://www.diagnosticpathology.org/content/9/1/95 Acknowledgment We thank Professor Qin Huang for checking and editing the manuscript for English. Received: 3 April 2014 Accepted: 11 May 2014 Published: 23 May 2014

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