American Journal of Obstetrics and Gynecology (2005) 193, 866–72
www.ajog.org
Clinicopathologic features of six cases of primary cervical lymphoma John K. Chan, MD,a,* Vera Loizzi, MD,b Alessandra Magistris, MD,b Mark I. Hunter, MD,b Joanne Rutgers, MD,c Philip J. DiSaia, MD,b Michael L. Berman, MDb Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Center, Stanford University School of Medicine,a Stanford, CA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center,b Orange, CA; Department of Pathology, Long Beach Memorial Medical Center,c Long Beach, CA Received for publication December 17, 2004; revised March 13, 2005
KEY WORDS Cervix Lymphoma
Objective: Primary lymphoma of the uterine cervix is rare, with less than 60 cases reported. We present a series of 6 patients with cervical lymphoma and review the literature. Study design: Between 1988 and 2003, we identified 6 women with primary lymphoma of the uterine cervix treated at our institutions. Data for analysis were obtained from hospital charts, office records, and tumor registry files. We also reviewed 20 published reports on cervical lymphoma, providing information on 58 additional patients. Results: The median age at diagnosis was 52 years (range 40-76). Three patients had an abnormal Papanicolaou test within 6 months of the diagnosis. Mean tumor size was 8.3 cm (range 3-14 cm). On the basis of the Ann Arbor system of staging where ‘‘E’’ denotes extranodal tumor origin, 2 patients had stage IE, 1 had stage IIIE, and 3 had stage IVE disease. The median follow-up for these 6 women was 33 months (range 12-120). Adding the 6 patients in our series to the 58 patients obtained from published reports, 43 had stage IE, 14 had stage IIE, 2 had stage IIIE, and 5 had stage IVE disease. There was no consistent pattern of treatment identified from our literature review. Conclusion: Primary lymphoma of the uterine cervix is a rare malignancy. Most patients present with stage IE disease. Women with localized disease typically respond to various combinations of surgery, chemotherapy, and radiotherapy. Combination chemotherapy with tailored radiotherapy appears to be the preferred treatment option in women with advanced disease. Ó 2005 Mosby, Inc. All rights reserved.
* Reprint requests: John K. Chan, MD, Stanford University Medical Center, Department of Obstetrics and Gynecology, Division of Gynecology Oncology, 300 Pasteur Dr HH333, Stanford, CA 94305-5317. E-mail:
[email protected] 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.04.044
Primary malignant lymphoma of the genital tract is a rare disease accounting for only 1% of extranodal lymphomas.1 Of these genital tract lymphomas, only 0.6% arise from the uterine cervix.2-4 Freeman et al5 reported a series of 1467 patients with extranodal lymphomas and found only 3 cases of primary cervical
Chan et al Table I
867 International working formulation for classification of Non-Hodgkin’s lymphoma
Low grade A
B
C
Malignant lymphoma Small lymphocytic Consistent with chronic lymphocytic leukemia Plasmocytoid Malignant lymphoma follicular, predominantly small cleaved cell Diffuse areas Sclerosis Malignant lymphoma follicular, mixed small cleaved cell and large cell Diffuse areas Sclerosis
Intermediate grade D
E F G
Malignant lymphoma, follicular Predominantly large cell Diffuse areas Sclerosis Malignant lymphoma, diffuse small cleaved cell Malignant lymphoma, diffuse mixed-, small- and large-cell sclerosis Epithelioid component Malignant lymphoma, diffuse Large cell Cleaved cell Noncleaved cell Sclerosis
High grade H
I
J
Malignant lymphoma, large cell, immunoblastic Plasmacytoid Clear cell Polymorphus Epithelioid component Malignant lymphoma lymphoblastic Convoluted cell Nonconvoluted cell Malignant lymphoma, small noncleaved cell Burkitt’s Follicular area
lymphoma. Over the last 25 years, less than 60 cases of cervical lymphoma have been reported in the literature. The clinical presentation of primary cervical lymphoma often is similar to that of squamous cell carcinoma of the cervix. Most patients experience abnormal bleeding and have a large, bulky cervix on pelvic examination. Because cervical lymphomas typically arise within the cervical stroma rather than the mucosa, cytology is not a sensitive screening tool. Histologically, cervical lymphoma appears similar to lymphomas arising in other sites. It is important to make the correct diagnosis of this uncommon disease because the treatment for cervical lymphomas differs from more common cervical cancers. We report a series of 6 patients and provide a review of the literature on primary lymphoma of the uterine cervix.
Methods Between December 1988 and January 2003, 6 women with primary malignant lymphoma of the cervix were diagnosed and treated at University of California, Irvine Medical Center and Long Beach Memorial Medical Center. After Institutional Review Board approvals from both institutions, these patients were identified from tumor registry databases. All patients underwent staging with bilateral trephine marrow biopsy and computer tomography of the thorax, abdomen, and pelvis. On the basis of the Ann Arbor staging classification for extranodal lymphomas,6 stage IE is defined as the involvement of a single extra-lymphatic organ or site, stage IIE as a localized involvement of extra-lymphatic organ or site and of 1 or more lymph node regions on the same
868 Table II
Chan et al Clinicopathologic features and outcome of 6 cases of primary cervical lymphoma
Patients no.
1
2
3
4
5
6
Age (y) Race Menopausal status HRT Presenting complaints
62 White Yes
40 White No
41 White No
49 White No
76 Asian Yes
52 Asian Yes
Yes Vaginal discharge
No Vaginal bleeding
No Severe weakness
No Vaginal bleeding
No Vaginal bleeding
Yes Vaginal bleeding, weight loss and fatigue
Pelvic pain
Abdominal pain
Abdominal pain
Normal
Not available
Abdominal pain, weight loss, fever, night sweats ASCUS
Normal
ASCUS
CIS
6 cm cervical mass IEA
12 cm pelvic mass IVEA
12 cm barrelshaped cervix IIIEB
6 cm cervical mass IVEA
3 cm cervical mass IEA
14 cm pelvic mass IVEB
J (high-grade, small cell, non-Burkitt)
G (intermediate, large cell, diffuse)
G (intermediate to high, large cell, diffuse)
I (high, lymphoblastic)
G (intermediate, large cell, diffuse)
Cervical cytology Clinical findings Ann Arbor stage IWF histology
D (intermediate, predominantly large cell)
HRT, Hormone replacement therapy; ASCUS, atypical cells of undetermined significance; CIS, carcinoma in situ.
side of the diaphragm, stage IIIE as a localized involvement of extra-lymphatic organ or site and of lymph node regions on both sides of the diaphragm, and stage IVE as a diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or without associated lymph node involvement. Furthermore, lymphomas are classified histologically according to the International Working Formulation (IWF) for non-Hodgkin’s lymphomas (Table I).7 Specimens were reviewed by the pathologists at the institutions where the patients were treated. To confirm the diagnosis of lymphoma, all pathologic specimens were subjected to immunohistochemical and molecular studies to identify the cellular lineage, in particular, to differentiate B-cell and T-cell lymphomas. The clinical presentation, stage of disease, medical/surgical treatment, recurrence, and survival data were collected from hospital charts, office records, and tumor registry files. We performed a review of the literature with 58 additional patients from 20 published reports using a Medline search.
Results We identified 6 women with cervical lymphoma among 1330 treated for cervical cancers at the 2 institutions from 1988 and 2003. The patients’ characteristics are summarized in Table II. The median age at diagnosis was 52 years (range: 40-76). Of the 6 women, the median parity was 2. One patient used tobacco in the past. Two
women had a previous history of gynecologic tract infection; one with genital herpes and the other with syphilis. Both women were treated without sequelae. The most common presenting symptom was abnormal vaginal bleeding, occurring in 4 of 6 patients. Two women had 1 or more B symptoms typically associated with lymphomas, which include weight loss, weakness, night sweats, and fever. Three women also had history of an abnormal Papanicolaou (Pap) test within 6 months of diagnosis, 2 with atypical squamous cells of undetermined significance and 1 with cytologic features of carcinoma in situ. All 6 patients had either a cervical or cervicopelvic mass ranging from 3 to 14 cm. The diagnoses of lymphoma were made based on cervical punch biopsies in 3 of 6 patients. Of 2 women with cervical biopsy specimens not showing a malignancy, one had a computer tomography–guided biopsy of the cervicopelvic mass and the other underwent an exploratory laparotomy, bilateral salpingo-oophorectomy to make the diagnoses of primary cervical lymphoma. The remaining patient had a cervical biopsy showing a poorly differentiated carcinoma and underwent a radical trachelectomy and pelvic lymphadenectomy. The correct diagnosis of lymphoma was made on the excised cervix. All patients underwent a metastatic workup that included chest x-ray film, computer tomography or gallium scan of the abdomen and pelvis, and bone morrow biopsy. The median time from initial presentation to diagnosis was 5 months (range: 1 to 8 months).
Chan et al Table III
869 Clinical outcome of patients in published literature based on Ann Arbor stage and histology
Author
No. patients
Ann Arbor and histology group
Steinfield et al16 Tunca et al17 Volpe et al18 Harris et al9
1 1 1 17
IEA IEA IIEA 4 IEA
9 IEA
1 IEA 3 IIEA
Komaki et al8
3
3 IIEA
Taki et al19 Gharpure et al20 Bar et al21 Mann et al22 Andrews et al23 Muntz et al11
1 1 1 1 1 5
IEA IEA IEA IEA IVE IEA
Perren et al10
2
Awwad et al24 Stroh et al14
1 7
1 IIEA 1 IIEB IEA 4 IEA
1 IIEA 1 IIIEB
Papadopoulos et al25 Biswal et al26 Nasu et al27 Lee et al15
1 1 1 2
1 IVA IEB 1 IE IEA 2 IEA
Therapy
Surgery
radiation
Chemotherapy
Recurrence
Survival
Pelvis Pelvis None Pelvis None Pelvis None None Pelvis Pelvis PelvisCPA None
None Vincristine CHOP (6) None None None None Yes None None None None
None None 6 mo None None None None None None None None None
NED 9 mo NED 2.5 y DOD 3 y NED 2 y NED 14 y NED 13 y NED 4 y NED ! 1 y NED 3.3 y NED 9 y NED 6.3 y NED 9 y
G G G
H BSO None None H BSO H BSO H BSO H RSO H BSO H BSO None None H vaginectomy H BSO H H BSO
None None None
None None 13 mo
NED 7.1 y NED 2.2 y NED 6 y
G H G H H F G G G G G J J B G G G G F F G G G G G G G
H BSO H H H H BSO None None None H BSO None H BSO H BSO None H BSO RH BSO PLD None Staging lap H BSO PLD Staging lap None None None None None None None None
CVP None None None 1 cycle None None None None None CHOP (6) None CVM None None None None None None CHOP (6) None CHOP-bleo CHOP-bleo CHOP ASAP CHOP-bleo CHOP-bleo
NA None None 2 mo NA None 4y None 5 mo 6 wks 10 mo 6 mo 6 mo None None None None None None None 6 mos None None None NA None None
DOD ! 1 y NED 11 y NED 3 y DOD 10 mo DOD 10 mo NED 3 y NED 11 y NED 7 y DOD 7 mo DOD 8 mo DOD 10 mo DOD 10 mo DOD 6 mo NED 4.5 y NED 10 y NED 5 y NED 5 y NED 4.5 y DOO 18 y NED 6 y DOD 7 mo NED 14.4 y NED 13.7 y NED 5 y DOD 1 y NED 11.8 y NED 9.7 y
G H G G G G
None H None None H BSO PLD H BSO PLD
Pelvis Pelvis Pelvis, vagina, kidney None PelvisCPA None Pelvis None PelvisCPA Pelvis, abdomen PelvisCPA Pelvis Pelvis None Pelvis None PelvisCPA Pelvis PelvisCPA Pelvis Pelvis PelvisCPA None Pelvis Pelvis, inguinals Pelvis, abdomen Pelvis Pelvis Pelvis Pelvis, abdomen, inguinals None Pelvis Pelvis None Pelvis Pelvis
CHOP-bleo CHOP (8) CHOP (3) THP-COP None None
Never free None None None None None
DOD 4 mo NED 4 y NED 5 mo NED 1.5 y NED (NA) NED (NA)
G G E B C C C D D G G G
870 Table III
Chan et al (Continued)
Author
No. patients
Ann Arbor and histology group
Vang et al4
9
6 IE
3 IIE
Yokoyama et al28 Chan et al, 2004
1 6
IIEA 2IEA 1IIIEB 2IVEA 1IVEB
Therapy
G G E G G G G G B G G J G G I D
Surgery
radiation
Chemotherapy
Recurrence
Survival
None H BSO Conization None Conization Conization None None H BSO None H BSO PLD TRACH PLD None None H BSO PLD None
Pelvis None None None None None Pelvis Pelvis Pelvis Pelvis Pelvis None None Pelvis None None
Yes None None Yes Yes None Yes Yes Yes CEOP (3) None None CHOP (8) CHOP (8) CHOP (9) CHOP
None None None Yes None None None None None None None 3 mo 29 mo None None None
NED 7 mo NED 4.5 y NED (NA) DOD 1 y NED 5 y DOC 9 y NED 10 y NED 5 y NED 6 y NED 1 y NED 1 y DOO 6 y DOD 3 y NED 10 y NED 2.5 y NED 1 y
ASAP, Doxorubicin, solumedrol, araC, cisplatin; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; CHOP-bleo, CHOP and bleomycin; CVP, cyclophosphamide, vincristine, prednisolone; DOD, dead of disease; DOO, died of other causes; H, hysterectomy; NED, no evidence of disease; NA, not assessed; PA, para-aortic nodes; PLD, pelvic lymphadenectomy; RH, radical hysterectomy; RSO, residual salpingo-oophorectomy; TRACH, trachelectomy; BSO, bilateral salpingo-oophorectomy; THP-CHOP, pirarubicin and CHOP.
Of the 6 patients, 2 had stage IE, 1 had stage IIIE, and 3 had stage IVE disease. Two patients, with stage IIIE and IVE disease, presented with B symptoms. According to the IWF classification, 4 women had intermediate grade B-cell lymphomas, 3 with group G (diffuse, large cell), and 1 with group D (large cell). Moreover, 2 patients had high-grade B-cell lymphomas, 1 with group I (lymphoblastic) and 1 with group J (small cell, non-Burkitt).7 Of the 2 patients with stage IE disease, one had a cervical biopsy specimen that revealed a poorly differentiated carcinoma. Because she had a previous subtotal hysterectomy for leiomyoma, she underwent a trachelectomy with bilateral pelvic lymphadenectomy. The final diagnosis was consistent with a high-grade, small cell, non-Burkitt B-cell lymphoma. Adjuvant chemotherapy was delayed secondary to postoperative complications, including a distal colonic obstruction requiring a transverse loop colostomy and an acute cholecystitis for which she underwent a cholecystectomy. Three months after the primary surgery for her lymphoma, she experienced an intra-abdominal recurrence to the liver and spleen. She received 6 courses of bleomycin, doxorubicin, cyclophosphamide, and vincristine (BACOD) and remained free of disease for more than 6 years. She subsequently died of causes unrelated to her lymphoma. The other patient with stage IE lymphoma underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. She received adjuvant pelvic radiotherapy and remains free of disease 14 months after her diagnosis.
The patient with stage IIIEB disease underwent 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). She had a disease-free interval of 29 months and recurred in the abdominal retroperitoneal lymph nodes. She was treated with CHOP and rituxan for her recurrence but died 11 months later. All 3 patients with stage IVE disease received combination chemotherapy. One was diagnosed with an intermediate grade (group G) disease and received 8 courses of CHOP with pelvic radiotherapy for a 12-cm pelvic tumor. She is disease free 10 years after her diagnosis. The other one with intermediate grade (group D) disease received 8 cycles of CHOP with rituxan and is alive without disease 1 year after her treatment. The remaining patient had high-grade (group I) disease for which she received 5 cycles of CHOP with rituxan. Because of persistent, bulky, cervical disease, she underwent a total abdominal hysterectomy. Postoperatively, she was treated with an additional 3 cycles of chemotherapy and is alive without disease 3 years after her diagnosis. Immunohistochemical data were available in all 6 patients. All cases stained positive for CD-20. BCL-2 and monotypic immunoglobulin lambda light chain was found to be positive in 4 speicmens and CD-19 in 3 specimens. In addition, 1 tumor sample was positive for CD-10, CD-23, and CD43. We obtained information on 58 additional patients from 20 published reports using a Medline search. Including the 6 patients in our series, 43 patients had stage IE, 14 had stage IIE, 2 had stage IIIE, and 5 had stage IVE disease. There was no consistent
Chan et al pattern of treatment identified from the published reports (Table III).
Comment Lymphoma of the uterine cervix is an uncommon disease that provides a diagnostic challenge for the clinician and the pathologist. Because the majority of patients present with abnormal vaginal bleeding, a gynecologist usually performs the initial evaluation and treatment.8-11 Because cervical lymphomas typically originate from the cervical stroma, the superficial squamous epithelium is often preserved, leading to a falsenegative cytologic smear.11-13 Of 5 patients who had cytologic smears in our series, 2 were normal, 2 had atypical cells of undetermined significance, and the remaining 1 showed carcinoma in situ. Similarly, Harris et al9 found that only 5 of 10 patients in their study had a positive cytologic smear showing malignant cells. Although the Pap smear test can show false-negative results in patients with cervical lymphoma, 3 of 6 women in our study had an abnormal Pap smear test. The diagnosis of cervical lymphoma is typically made with a histologic analysis of a deep cervical biopsy. Harris et al9 reported that up to 67% of these tumors presented with a subepithelial mass without obvious ulceration or epithelial abnormality. The authors recommended a deep incisional or excisional biopsy to establish a definitive diagnosis when the initial biopsy is nondiagnostic. In such instance, the initial biopsy usually contains atypical epithelial cells coexisting with lymphoid infiltrates. The authors recognize that the Ann Arbor staging system has been replaced by the Word Health Organization classification. Because the majority of case reports provided in this extensive literature review used the Ann Arbor staging system, we reported our series as such to provide a standard for comparison of the therapeutic outcome. Primary cervical lymphomas have a rapid growth pattern. Six patients had a normal pelvic examination within the past year but presented with a 6-cm or greater cervical lesion. Muntz et al11 reviewed a series of patients with stage IE cervical lymphomas and found that half of these women had tumors larger than 4 cm at presentation. Because cervical lymphoma is an uncommon malignancy, the standard treatment has not been established. Some authors have recommended primary surgical treatment for stage IE disease, whereas others have suggested combination chemotherapy with or without radiotherapy.11,14 Muntz et al11 advocated primary surgery, followed by individualized radiation therapy for those with stage IE disease localized in the pelvis. For women with stage IE diffuse bulky disease, they recommended high-dose radiotherapy with brachyther-
871 apy. On the other hand, others have suggested combination CHOP chemotherapy with radiation, particularly in patients with bulky stage I to II disease.14 Because the survival rates in patients with earlier stage cervical lymphomas are excellent with either surgery, chemotherapy, or radiotherapy, young women who desire to retain their fertility will benefit from combination chemotherapy.10 On the basis of previous studies of patients with extranodal non-Hodgkin’s lymphoma, combination chemotherapy has been used in treating patients with disease that is more advanced than stage IE, with CHOP as the most common regimen used.15 All 4 women with stage IIIE to IV disease in our series received the CHOP regimen, with or without surgery or radiotherapy. Three are alive without any evidence of disease at 1, 2.5, and 10 years after their diagnosis. The patient who died from her disease received CHOP after a disease-free interval of 29 months and died 11 months after her recurrence despite further treatment. Lastly, chemotherapy alone may not be sufficient in the treatment of stage II to IV disease with bulky tumors in the pelvis. Some authors have advocated surgery or radiotherapy in addition to combination chemotherapy to decrease the risk of central recurrence.10,14 Malignant lymphoma of the uterine cervix is a rare disease. The diagnosis is typically made with a histologic analysis of a deep cervical biopsy. Patients with localized stage IE disease with nonbulky lesions often will respond to primary surgery, chemotherapy, or radiotherapy alone; however, combined therapy seems to be favored in many centers. Combination chemotherapy with tailored radiotherapy is the preferred treatment option in women with more advanced disease.
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