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Small cell carcinoma of the cervix
Clinical Oncology(1996) 8:102-105 © 1996The RoyalCollegeof Radiologists
Clinical Oncology
Original Article Small Cell C a r c i n o m a of the Cervix E. Sheridan, P. C. Lorigan, J. Goepel, D. J. Radstone and R. E. Coleman YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK
Abstract. Small cell carcinoma of the cervix represents an uncommon variant of cervical cancer with a particularly poor prognosis. Traditionally, the diagnosis was established from routine histopathological sections, but there has been a trend to refer to this tumour as neuroendocrine carcinoma, with a requirement to demonstrate cytoplasmic granules. Five patients are described, who share the clinical features of young age of onset, early metastasis in the presence of apparently low stage disease, early failure of appropriate local treatment, and extreme chemosensitivity (features that are quite distinct from those seen in squamous cell cancer of the cervix). Light microscopy suggested a diagnosis of small cell cancer in all five tumours, but not all showed evidence of neuroendocrine differentiation. It is proposed that the present criteria for the diagnosis of cervical small cell carcinoma are too strict. The diagnosis should rely on the light microscopy of haemotoxylin and eosin sections and the distinctive clinical behaviour. The absence of neuroendocrine differentiation should not exclude the diagnosis, it does not appear to influence the clinical behaviour. The appropriate management of small cell carcinoma of the cervix is systemic, with chemotherapy as the first line of treatment. Surgery and radiotherapy may improve control of local disease but are unlikely significantly to influence the overall prognosis. Keywords: Cervical cancer; Chemosensitivity; Neuroendocrine markers; Small cell carcinoma
INTRODUCTION The natural history of cervical small cell carcinoma is of an aggressive, poor prognosis lesion with a high incidence of metastases outside the pelvis at, or shortly after, diagnosis, and a poor response to treatment. Long term survival is not common and early relapse seems to be the rule. The histological features were defined by Reagan Correspondence and offprint requests to: Dr R. E. Coleman, Senior Lecturer and Consultant Medical Oncologist, YCRC Department of Clinical Oncology,Weston Park Hospital, Sheffield $10 2SJ, UK.
et al. and may be summarized as the presence of sheets of small cells with coarsely granular nuclei, a fairly uniform size and shape, poorly defined cytoplasmic outline, and a high nuclear to cytoplasmic ratio [1,2]. Histologically, these lesions may be indistinguishable from the small cell carcinomas of the lung. It is known that small cell lung cancer (SCLC) may show neuroendocrine differentiation, with granules demonstrable by electron microscopy, silver stains and immunohistochemistry. Similar observations on cervical tumours have been reflected in alternative names such as neuroendocrine carcinoma or argyrophilic carcinoma of the cervix. The purpose of this study was to report five patients with tumours having the original morphological features of small cell carcinoma of the cervix, and to document the clinical outcome to see if it varied between tumours with and without immunohistochemical evidence of neuroendocrine differentiation.
MATERIALS AND METHODS Five patients, with a median age of 37 years (range 29-41), were referred with signs and symptoms of cervical cancer during 1991 and 1992 to local gynaecology departments. The symptoms included abnormal vaginal bleeding; one patient presented in the third trimester of pregnancy. All patients had had a normal cervical smear in the previous 2 years. In two patients, the tumours were initially classified pathologically as poorly differentiated squamous carcinoma, and appropriate local treatment with radical surgery and pelvic radiotherapy was performed. Subsquently, both these patients developed metastases and were referred to us for medical management. The other three patients were referred to the multidisciplinary gynaecological oncology clinic with a diagnosis of small cell carcinoma, for advice on primary management. All surgical specimens from the five patients have been reviewed by one of the authors (JG). In addition to routine light microscopy, immunohistochemical staining was performed to characterize the tumours more fully. Sections were stained using the avidin-biotin method and a panel of primary antibodies, comprising CAM5.2 for cytokeratins,
Small Cell Carcinoma of the Cervix
epithelial membrane antigen (EMA), and the neuroendocrine markers, neurone specific enolase (NSE), chromogranin A and synaptophysin. Two patients were treated by primary combination chemotherapy, receiving a combination of doxorubicin, cyclophosphamide and etoposide (ACE) intravenously every 3 weeks. After three courses, these patients had definitive local treatment (Wertheim's hysterectomy in one and radical radiotherapy with caesium insertions and external beam treatment to the pelvis in the other). This was then followed by a further three courses of chemotherapy to consolidate the excellent local response documented at surgery and examination under anaesthetic respectively. Dose reductions of 25% were needed to avoid severe bone marrow suppression after the local therapy. A third patient was treated initially by radiotherapy with two caesium insertions to stop bleeding, followed by a simpler chemotherapy combination of etoposide and vincristine. All chemotherapy was given in the outpatient clinic, with appropriate antiemetic cover and haematological monitoring. Chemotherapy was delayed for a week if the bone marrow function had not recovered adequately. In the other two patients, the initial histological diagnosis was of squamous cell carcinoma; consequently, they were treated with surgery and radiotherapy, as appropriate for an early stage squamous lesion. They relapsed unexpectedly early (2 and 5 months after local treatment) and were referred to us for chemotherapy of their metastatic disease. One had widespread lung metastases causing severe dyspnoea and the other painful liver and splenic metastases. Neither patient showed the typical pattern of pelvic relapse associated with squamous carcinoma of the cervix. Combination chemotherapy using cisplatin, methotrexate and bleomycin was prescribed in accordance with our standard practice for palliative therapy of advanced squamous carcinoma of the cervix. Treatment was given as inpatients with standard pre- and post-cisplatin hydration. The small cell classification of these two lesions only became apparent after review of the histology. In the patient with lung metastases, the chemotherapy was changed to ACE after four cycles because of cisplatin-induced tinnitus.
RESULTS All tumours had the classical histology of small cell carcinoma, but the immunohistochemical profile was variable, as shown in Table 1. Three patients had evidence of neuroendocrine differentiation, with chromogranin positivity in three and NSE in two. However, the other two tumours failed to stain with neuroendocrine markers. None was positive for synaptophysin. Three tumours were positive for EMA and two for cytokeratin. The morphology was similar, irrespective of whether stains for neuroendocrine differentiation were positive or negative (Fig. 1). All five patients achieved a rapid response to
103 Table 1. Histological features Patient
Morphology
NSE
C R G SYN
CYTO
EMA
1 2 3 4 5
Small Small Small Small Small
+ + .
+ + + -
+ + .
+ + +
cell cell cell cell cell
.
.
.
NSE, neurone specific enolase; C R G , chromogranin; SYN, synaptophysin; C Y T O , cytokeratin; EMA, epithelial m e m b r a n e antigen; + , positive immunohistochemical staining; - , negative immunohistochemical staining.
Fig. 1. Patient 1: small cell carcinoma of the cervix. This t u m o u r was positive for chromogranin A and neurone specific enolase. There was identical histology in the t u m o u r s that were negative for neuroendocrine granules. ( H & E × 400)
systemic treatment, usually with a marked reduction in tumour bulk after the first course of chemotherapy, accompanied by a dramatic relief of symptoms (Table 2). A complete response was achieved in the two patients with metastatic disease, but both have relapsed, one in the brain after 27 weeks and the other in the liver after 39 weeks, and subsequently died. The three patients with localized disease at presentation achieved rapid, and in two patients, durable, local control. However, all three have since relapsed and died. One relapsed in bone and supraclavicular lymph nodes after 38 weeks, another in bone after 74 weeks, and the third, both locally in the Table 2. Response and duration of response to c h e m o t h e r a p y Patient
Chemotherapy regimen
Response
Time to progression (weeks)
Survival (weeks)
1a 2 3 4 ~'b 5b
PMB ACE EV PMB/ACE ACE
CR CR CR CR CR
39 38 113 27 74
47 62 124 28 84
a D e n o t e s initially misdiagnosed, b D e n o t e s negative for neuroendocrine markers. P, cisplatin; M, methotrexate; B, bleomycin; A , doxorubicin (adriamycin); C, cyclophosphamide; E, etoposide; V, vincristine; CR, complete remission.
104
E. Sheridan et al.
pelvis and with widespread metastases, after more than 2 years.
DISCUSSION
Small cell carcinoma of the cervix is an uncommon condition. In the last 5 years, there were only five patients registered in this region, which has a population of over 4.5 million. Approximately 250 patients have been reported in 23 papers in the English language literature since 1984. The more important series are summarized in Table 3 [3-5]. Although the diagnosis of small cell carcinoma of the cervix is uncommon, the morphological features are well documented and were the basis of the diagnoses in the patients described. The differential diagnosis is from poorly differentiated squamous carcinoma or adenocarcinoma, particularly those with carcinoid features. If there is less than 10% of the tumour with recognizable squamous or glandular differentiation, then small cell carcinoma may be the best categorization [6]. Non-Hodgkin's lymphoma also needs to be considered, and will be recognized by a positive reaction for the leukocyte common antigen (CD45). Several investigators interpret the presence of neuroendocrine differentiation within the malignant cells as evidence for their origin from endocervical argyrophil cells or their precursors, the multipotential neuroendocrine stem cells [7,8]. In the patients reported here, however, only three tumours showed immunohistochemical evidence of neuroendocrine origin. The view that small cell cancers of the cervix require evidence of neuroendocrine differentiation for diagnosis is thus open to doubt. In addition to our report, another recent study using similar immunohistochemical markers showed evidence for neuroendocrine differentiation in only 33% of tumours [9]. The three patients in our series who had positive immunohistochemical markers Table 3. Summaryof published series of small cell carcinomaof the cervix Author [ref.]
No. patients
Main findings
Abeler et al. [12] Chang et al. [20]
26 28
Gershell et al. [10]
15
5-year survival 14% Adjuvant CAV/PE after hysterectomy superior to PVB Poor prognosis;median survival 11 months Poor prognosis; 3/7 showed neurosecretory granules Predominantly early stage; treated with chemotherapy, XRT and surgery; median survival 28 months Often locally advanced at presentation; median survival 9 months 14 turnouts positive for HPV 18 Neuroendocrine differentiation in 15 tumours Median survival 12 months
Groben et al. [3]
7
Morris et al. [19]
10
Miller et al. [2]
14
Stoler et al. [4] Silva [5]
20 33
Walker et al. [11]
14
survived 47, 62 and 124 weeks from the start of treatment. This includes one patient who was initially treated with surgery as having squamous cell carcinoma and who later re-presented with metastatic disease. The two patients with negative immunohistochemical markers survived 28 and 84 weeks. The patients with the poorest survival were those who were initially misdiagnosed and did not receive appropriate chemotherapy at presentation. While little can be said from such a small series, immunohistochemical markers did not appear to add any prognostic information. Gershell et al. reviewed 15 patients with small cell carcinoma of the cervix [10]. All of the 13 patients examined expressed one or more epithelial markers and at least one of the eight neuroendocrine markers used, but considerable heterogeneity of expression existed. The outcome was predictably poor. The disease desseminated early and was often widely metastatic at presentation. Median survival was 11 months. Similarly, Walker et al. reviewed 14 patients with small cell carcinoma of the cervix [11]. They noted that the majority presented with bleeding or a discharge. Eleven died of tumour, with a median survival of 12.5 months. Abeler reported a series of 26 patients [12]; the 5-year survival was just 14%. In two of the patients described here, the precise nature of the lesion did not become apparent until formal review of the histology when those with apparently early stage disease relapsed and were referred for consideration of chemotherapy. Two of the patients were therefore treated with platinum based chemotherapy, as appropriate for the palliation of advanced squamous cell cancer of the cervix. However, the other patients received primary treatment with etoposide-containing combination chemotherapy, as would be prescribed for young fit patients with small cell lung cancer. Small cell lung cancer shows similar heterogeneity of immunohistochemical staining for neuroendocrine differentiation, with a proportion of tumours positive for one or more of NSE, chromogranin A and synaptophysin [13]. Despite this, it is likely that SCLC arises from bronchial epithelium reserve cells, rather than from committed neuroendocrine cells. In contrast to SCLC, cervical small cell carcinoma is only very rarely associated with paraneoplastic endocrine syndromes [14]. None of our patients showed evidence of ectopic hormone production. There can be little doubt of the biological aggressiveness of cervical small cell cancer, and clearly this is a variant of cervical disease that metastasizes early, and is reminiscent of SCLC and of other small cell tumours. It is well recognized that SCLC is an extremely chemosensitive tumour, and that worthwhile responses with the maintenance of a good quality of life can be achieved by the use of approp r i a t e chemotherapy [15]. It has previously been assumed that cervical lesions are not as chemosensitive as SCLC, although there are several reports of cervical small cell cancer responding to chemotherapy that would refute this [16-18]. The chemotherapy used in our patients reflects the treatment in use in the U K for SCLC and should be the starting point for the treatment of this condition.
Small Cell Carcinoma of the Cervix
Morris et al. reported a median survival of 28 months in ten patients with predominantly early stage disease treated with cisplatin, doxorubicin and etoposide [19]. Chang et al. reported that adjuvant therapy with cyclophosphamide, adriamycin and vincristine, alternating with cisplatin and etoposide (CAV/PE), was superior to the PVB regimen (cisplatin, vinblastine, bleomycin), ,;vhich is widely used for squamous carcinoma of the cervix [20]. As in SCLC, cure may be rare, even with systemic treatment, but this appears to be the most effective form of palliation, with occasional long term remissions in those patients with small volume chemosensitive disease. In comparison, a response rate of only 37% to pelvic radiotherapy was reported by van Nagell et al. [16]. These responses were short lived, with early metastatic recurrence. While cervical small cell carcinomas seem to be a histologically heterogeneous group of turnouts, only some of which have immunohistochemical evidence of neuroendocrine differentiation, they appear to behave as a clinically distinct entity. If the diagnosis of small cell carcinoma of the cervix was to rest upon the demonstration of neuroendocrine differentiation, then our experience indicates that some patients may not be offered appropriate systemic treatment. We propose that the diagnosis of cervical small cell cancer should be dependent on the morphological features of poorly defined cytoplasmic outlines and high nuclear to cytoplasmic ratios. Precise nuclear morphometry may allow confirmation of the diagnosis but it should not depend upon the demonstration of neuroendocrine differentiation. The total number of patients reported is small and the treatments used are diverse. It is generally agreed that the treatment of this disease should be combination chemotherapy, using similar drugs to those known to be active in SCLC. Surgery and radiotherapy should be used to improve local control during or after the chemotherapy and as palliative treatment for recurrent disease. The small number of patients with this condition will make randomized studies impossible, but they should be treated on well defined SCLC protocols. Areas for research in the future will include dose intensification or sequential high dose chemotherapy as treatment approaches, and the role of autocrine growth factors and human papillomavirus in the aetiology of these tumours.
Acknowledgement. We
wish to thank the Trent Cancer Registry for providing the cancer registry data.
105
References 1. Regan JW, Hamonic MJ, Wentz WB. Analytical study of the cells in cervical squamous cancer. Lab Invest 1957;6:241-50. 2. Miller B, Dockter M, E1 Torky M. et al. Small cell carcinoma of the cervix: A clinical and flow cytometric study. Gynecol Oncol 1991;42:27-33. 3. Groben P, Reddick R, Askin F. The pathologic spectrum of small cell carcinoma of the cervix. Int J Gynecol Pathol 1985;4:42-57. 4. Stoler MH, Mills SE, Gersell DJ, et al. Small-cell neuroendocrine carcinoma of the cervix. A human papillomavirus type 18 associated cancer. Am J Surg Pathol 1991;15:28-32. 5. Silva EG. Small cell tumours of the uterine cervix: pathology [abstract]. The University of Texas MD Anderson Hospital and Tumor Institute at Houston Twenty-ninth Annual Clinical Conference on Cancer: Diagnosis and treatment strategies for gynecologic cancer; 1985 November 13-16:21-2. 6. Kurman RJ, Norris HJ, Wilkinson E. Tumours of the cervix, vagina and vulva. Atlas of tumour pathology, 3rd series (Fascicle 4). Washington DC: Armed Forces Institute of Pathology, 1992. 7. Yamasaki M, Tateishi R, Hongo J, et al. Argyrophil small cell carcinomas of the uterine cervix. Int J Gynecol Pathol 1984 ;3:146-52. 8. Pazdur R, Bonomi P, Slayton R. Neuroendocrine carcinoma of the cervix: Implications for staging and therapy. Gynecol Oncol 1981;12:120-8. 9. Van Nagell JR, Powell DE, GaUion HH, et al. Small cell carcinoma of the uterine cervix. Cancer 1988;62:1586-93. 10. Gershell D J, Mazoujian G, Mutch DG, et al. Small-cell undifferentiated carcinoma of the cervix: A clinicopathologic, ultrastructural, and immunocytochemical study of 15 cases. Am J Surg Pathol 1988;12:684-98. 11. Walker AN, Mills SE, Taylor PT. Cervical Neuroendocrine carcinoma: A clinical and light microscopic study of 14 cases. fnt J Gynecol Pathol 1988;7:64-74. 12. Abeler VM, Holm R, Nesland JM, et al. Small cell carcinoma of the cervix: A clinicopathologic study of 26 patients. Cancer 1994:73:672-7. 13. Mackay B, Lukeman JM, Ordonez NG. Tumours of the lung (Major problems in pathology, vol. 24). Philadelphia: Saunders, 1991:219-24. 14. Albores-Saavedra J, Larraza O, Poucell S, et al. Carcinoid of the uterine cervix: Additional observations on a new tumour entity. Cancer 1976;38:2328-42. 15. Ruckdeschel JC. Therapeutic options for small cell and nosmall cell lung cancer. Curr Opin Oncol 1993:5:323-34. 16. Van Nagell JR, Donaldson ES, Parker JC. The prognostic significance of cell type and lesion size in patients with cervical cancer treated by radical surgery. Gynecol Oncol 1977;5:14251. 17. Jacobs AJ, Marchevsky A, Gordon RE, et al. Oat cell carcinoma of the uterine cervix in a pregnant women treated with cis-diamminedichloroplatinum. Gynecol Oncol 1980; 9:505-10. 18. Turner WA, Gallup DG, Talledo DE et al. Neuroendocrine carcinoma of the cervix complicated by pregnancy: Case report and review of the literature. Obstet Gynecol 1986;67:80s-83s. 19. Morris M, Gershenson DM, Eifel P, et al. Treatment of small cell cancer of the cervix with cisplatin, doxorubicin, and etoposide. Gynecol Oncol 1992;47:62-5. 20. Chang TC, Chang HC, Lai CH, et al. The biological behaviour of and adjuvant chemotherapies for small cell carcinoma of the cervix. Proceedings of the Fourth International Congress on Anti-cancer Chemotherapy; 1993 February 2-5; Paris, France:88.
Received for publication January 1995 Accepted following revision September 1995
Clinical Oncology
Original Article Small Cell C a r c i n o m a of the Cervix E. Sheridan, P. C. Lorigan, J. Goepel, D. J. Radstone and R. E. Coleman YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK
Abstract. Small cell carcinoma of the cervix represents an uncommon variant of cervical cancer with a particularly poor prognosis. Traditionally, the diagnosis was established from routine histopathological sections, but there has been a trend to refer to this tumour as neuroendocrine carcinoma, with a requirement to demonstrate cytoplasmic granules. Five patients are described, who share the clinical features of young age of onset, early metastasis in the presence of apparently low stage disease, early failure of appropriate local treatment, and extreme chemosensitivity (features that are quite distinct from those seen in squamous cell cancer of the cervix). Light microscopy suggested a diagnosis of small cell cancer in all five tumours, but not all showed evidence of neuroendocrine differentiation. It is proposed that the present criteria for the diagnosis of cervical small cell carcinoma are too strict. The diagnosis should rely on the light microscopy of haemotoxylin and eosin sections and the distinctive clinical behaviour. The absence of neuroendocrine differentiation should not exclude the diagnosis, it does not appear to influence the clinical behaviour. The appropriate management of small cell carcinoma of the cervix is systemic, with chemotherapy as the first line of treatment. Surgery and radiotherapy may improve control of local disease but are unlikely significantly to influence the overall prognosis. Keywords: Cervical cancer; Chemosensitivity; Neuroendocrine markers; Small cell carcinoma
INTRODUCTION The natural history of cervical small cell carcinoma is of an aggressive, poor prognosis lesion with a high incidence of metastases outside the pelvis at, or shortly after, diagnosis, and a poor response to treatment. Long term survival is not common and early relapse seems to be the rule. The histological features were defined by Reagan Correspondence and offprint requests to: Dr R. E. Coleman, Senior Lecturer and Consultant Medical Oncologist, YCRC Department of Clinical Oncology,Weston Park Hospital, Sheffield $10 2SJ, UK.
et al. and may be summarized as the presence of sheets of small cells with coarsely granular nuclei, a fairly uniform size and shape, poorly defined cytoplasmic outline, and a high nuclear to cytoplasmic ratio [1,2]. Histologically, these lesions may be indistinguishable from the small cell carcinomas of the lung. It is known that small cell lung cancer (SCLC) may show neuroendocrine differentiation, with granules demonstrable by electron microscopy, silver stains and immunohistochemistry. Similar observations on cervical tumours have been reflected in alternative names such as neuroendocrine carcinoma or argyrophilic carcinoma of the cervix. The purpose of this study was to report five patients with tumours having the original morphological features of small cell carcinoma of the cervix, and to document the clinical outcome to see if it varied between tumours with and without immunohistochemical evidence of neuroendocrine differentiation.
MATERIALS AND METHODS Five patients, with a median age of 37 years (range 29-41), were referred with signs and symptoms of cervical cancer during 1991 and 1992 to local gynaecology departments. The symptoms included abnormal vaginal bleeding; one patient presented in the third trimester of pregnancy. All patients had had a normal cervical smear in the previous 2 years. In two patients, the tumours were initially classified pathologically as poorly differentiated squamous carcinoma, and appropriate local treatment with radical surgery and pelvic radiotherapy was performed. Subsquently, both these patients developed metastases and were referred to us for medical management. The other three patients were referred to the multidisciplinary gynaecological oncology clinic with a diagnosis of small cell carcinoma, for advice on primary management. All surgical specimens from the five patients have been reviewed by one of the authors (JG). In addition to routine light microscopy, immunohistochemical staining was performed to characterize the tumours more fully. Sections were stained using the avidin-biotin method and a panel of primary antibodies, comprising CAM5.2 for cytokeratins,
Small Cell Carcinoma of the Cervix
epithelial membrane antigen (EMA), and the neuroendocrine markers, neurone specific enolase (NSE), chromogranin A and synaptophysin. Two patients were treated by primary combination chemotherapy, receiving a combination of doxorubicin, cyclophosphamide and etoposide (ACE) intravenously every 3 weeks. After three courses, these patients had definitive local treatment (Wertheim's hysterectomy in one and radical radiotherapy with caesium insertions and external beam treatment to the pelvis in the other). This was then followed by a further three courses of chemotherapy to consolidate the excellent local response documented at surgery and examination under anaesthetic respectively. Dose reductions of 25% were needed to avoid severe bone marrow suppression after the local therapy. A third patient was treated initially by radiotherapy with two caesium insertions to stop bleeding, followed by a simpler chemotherapy combination of etoposide and vincristine. All chemotherapy was given in the outpatient clinic, with appropriate antiemetic cover and haematological monitoring. Chemotherapy was delayed for a week if the bone marrow function had not recovered adequately. In the other two patients, the initial histological diagnosis was of squamous cell carcinoma; consequently, they were treated with surgery and radiotherapy, as appropriate for an early stage squamous lesion. They relapsed unexpectedly early (2 and 5 months after local treatment) and were referred to us for chemotherapy of their metastatic disease. One had widespread lung metastases causing severe dyspnoea and the other painful liver and splenic metastases. Neither patient showed the typical pattern of pelvic relapse associated with squamous carcinoma of the cervix. Combination chemotherapy using cisplatin, methotrexate and bleomycin was prescribed in accordance with our standard practice for palliative therapy of advanced squamous carcinoma of the cervix. Treatment was given as inpatients with standard pre- and post-cisplatin hydration. The small cell classification of these two lesions only became apparent after review of the histology. In the patient with lung metastases, the chemotherapy was changed to ACE after four cycles because of cisplatin-induced tinnitus.
RESULTS All tumours had the classical histology of small cell carcinoma, but the immunohistochemical profile was variable, as shown in Table 1. Three patients had evidence of neuroendocrine differentiation, with chromogranin positivity in three and NSE in two. However, the other two tumours failed to stain with neuroendocrine markers. None was positive for synaptophysin. Three tumours were positive for EMA and two for cytokeratin. The morphology was similar, irrespective of whether stains for neuroendocrine differentiation were positive or negative (Fig. 1). All five patients achieved a rapid response to
103 Table 1. Histological features Patient
Morphology
NSE
C R G SYN
CYTO
EMA
1 2 3 4 5
Small Small Small Small Small
+ + .
+ + + -
+ + .
+ + +
cell cell cell cell cell
.
.
.
NSE, neurone specific enolase; C R G , chromogranin; SYN, synaptophysin; C Y T O , cytokeratin; EMA, epithelial m e m b r a n e antigen; + , positive immunohistochemical staining; - , negative immunohistochemical staining.
Fig. 1. Patient 1: small cell carcinoma of the cervix. This t u m o u r was positive for chromogranin A and neurone specific enolase. There was identical histology in the t u m o u r s that were negative for neuroendocrine granules. ( H & E × 400)
systemic treatment, usually with a marked reduction in tumour bulk after the first course of chemotherapy, accompanied by a dramatic relief of symptoms (Table 2). A complete response was achieved in the two patients with metastatic disease, but both have relapsed, one in the brain after 27 weeks and the other in the liver after 39 weeks, and subsequently died. The three patients with localized disease at presentation achieved rapid, and in two patients, durable, local control. However, all three have since relapsed and died. One relapsed in bone and supraclavicular lymph nodes after 38 weeks, another in bone after 74 weeks, and the third, both locally in the Table 2. Response and duration of response to c h e m o t h e r a p y Patient
Chemotherapy regimen
Response
Time to progression (weeks)
Survival (weeks)
1a 2 3 4 ~'b 5b
PMB ACE EV PMB/ACE ACE
CR CR CR CR CR
39 38 113 27 74
47 62 124 28 84
a D e n o t e s initially misdiagnosed, b D e n o t e s negative for neuroendocrine markers. P, cisplatin; M, methotrexate; B, bleomycin; A , doxorubicin (adriamycin); C, cyclophosphamide; E, etoposide; V, vincristine; CR, complete remission.
104
E. Sheridan et al.
pelvis and with widespread metastases, after more than 2 years.
DISCUSSION
Small cell carcinoma of the cervix is an uncommon condition. In the last 5 years, there were only five patients registered in this region, which has a population of over 4.5 million. Approximately 250 patients have been reported in 23 papers in the English language literature since 1984. The more important series are summarized in Table 3 [3-5]. Although the diagnosis of small cell carcinoma of the cervix is uncommon, the morphological features are well documented and were the basis of the diagnoses in the patients described. The differential diagnosis is from poorly differentiated squamous carcinoma or adenocarcinoma, particularly those with carcinoid features. If there is less than 10% of the tumour with recognizable squamous or glandular differentiation, then small cell carcinoma may be the best categorization [6]. Non-Hodgkin's lymphoma also needs to be considered, and will be recognized by a positive reaction for the leukocyte common antigen (CD45). Several investigators interpret the presence of neuroendocrine differentiation within the malignant cells as evidence for their origin from endocervical argyrophil cells or their precursors, the multipotential neuroendocrine stem cells [7,8]. In the patients reported here, however, only three tumours showed immunohistochemical evidence of neuroendocrine origin. The view that small cell cancers of the cervix require evidence of neuroendocrine differentiation for diagnosis is thus open to doubt. In addition to our report, another recent study using similar immunohistochemical markers showed evidence for neuroendocrine differentiation in only 33% of tumours [9]. The three patients in our series who had positive immunohistochemical markers Table 3. Summaryof published series of small cell carcinomaof the cervix Author [ref.]
No. patients
Main findings
Abeler et al. [12] Chang et al. [20]
26 28
Gershell et al. [10]
15
5-year survival 14% Adjuvant CAV/PE after hysterectomy superior to PVB Poor prognosis;median survival 11 months Poor prognosis; 3/7 showed neurosecretory granules Predominantly early stage; treated with chemotherapy, XRT and surgery; median survival 28 months Often locally advanced at presentation; median survival 9 months 14 turnouts positive for HPV 18 Neuroendocrine differentiation in 15 tumours Median survival 12 months
Groben et al. [3]
7
Morris et al. [19]
10
Miller et al. [2]
14
Stoler et al. [4] Silva [5]
20 33
Walker et al. [11]
14
survived 47, 62 and 124 weeks from the start of treatment. This includes one patient who was initially treated with surgery as having squamous cell carcinoma and who later re-presented with metastatic disease. The two patients with negative immunohistochemical markers survived 28 and 84 weeks. The patients with the poorest survival were those who were initially misdiagnosed and did not receive appropriate chemotherapy at presentation. While little can be said from such a small series, immunohistochemical markers did not appear to add any prognostic information. Gershell et al. reviewed 15 patients with small cell carcinoma of the cervix [10]. All of the 13 patients examined expressed one or more epithelial markers and at least one of the eight neuroendocrine markers used, but considerable heterogeneity of expression existed. The outcome was predictably poor. The disease desseminated early and was often widely metastatic at presentation. Median survival was 11 months. Similarly, Walker et al. reviewed 14 patients with small cell carcinoma of the cervix [11]. They noted that the majority presented with bleeding or a discharge. Eleven died of tumour, with a median survival of 12.5 months. Abeler reported a series of 26 patients [12]; the 5-year survival was just 14%. In two of the patients described here, the precise nature of the lesion did not become apparent until formal review of the histology when those with apparently early stage disease relapsed and were referred for consideration of chemotherapy. Two of the patients were therefore treated with platinum based chemotherapy, as appropriate for the palliation of advanced squamous cell cancer of the cervix. However, the other patients received primary treatment with etoposide-containing combination chemotherapy, as would be prescribed for young fit patients with small cell lung cancer. Small cell lung cancer shows similar heterogeneity of immunohistochemical staining for neuroendocrine differentiation, with a proportion of tumours positive for one or more of NSE, chromogranin A and synaptophysin [13]. Despite this, it is likely that SCLC arises from bronchial epithelium reserve cells, rather than from committed neuroendocrine cells. In contrast to SCLC, cervical small cell carcinoma is only very rarely associated with paraneoplastic endocrine syndromes [14]. None of our patients showed evidence of ectopic hormone production. There can be little doubt of the biological aggressiveness of cervical small cell cancer, and clearly this is a variant of cervical disease that metastasizes early, and is reminiscent of SCLC and of other small cell tumours. It is well recognized that SCLC is an extremely chemosensitive tumour, and that worthwhile responses with the maintenance of a good quality of life can be achieved by the use of approp r i a t e chemotherapy [15]. It has previously been assumed that cervical lesions are not as chemosensitive as SCLC, although there are several reports of cervical small cell cancer responding to chemotherapy that would refute this [16-18]. The chemotherapy used in our patients reflects the treatment in use in the U K for SCLC and should be the starting point for the treatment of this condition.
Small Cell Carcinoma of the Cervix
Morris et al. reported a median survival of 28 months in ten patients with predominantly early stage disease treated with cisplatin, doxorubicin and etoposide [19]. Chang et al. reported that adjuvant therapy with cyclophosphamide, adriamycin and vincristine, alternating with cisplatin and etoposide (CAV/PE), was superior to the PVB regimen (cisplatin, vinblastine, bleomycin), ,;vhich is widely used for squamous carcinoma of the cervix [20]. As in SCLC, cure may be rare, even with systemic treatment, but this appears to be the most effective form of palliation, with occasional long term remissions in those patients with small volume chemosensitive disease. In comparison, a response rate of only 37% to pelvic radiotherapy was reported by van Nagell et al. [16]. These responses were short lived, with early metastatic recurrence. While cervical small cell carcinomas seem to be a histologically heterogeneous group of turnouts, only some of which have immunohistochemical evidence of neuroendocrine differentiation, they appear to behave as a clinically distinct entity. If the diagnosis of small cell carcinoma of the cervix was to rest upon the demonstration of neuroendocrine differentiation, then our experience indicates that some patients may not be offered appropriate systemic treatment. We propose that the diagnosis of cervical small cell cancer should be dependent on the morphological features of poorly defined cytoplasmic outlines and high nuclear to cytoplasmic ratios. Precise nuclear morphometry may allow confirmation of the diagnosis but it should not depend upon the demonstration of neuroendocrine differentiation. The total number of patients reported is small and the treatments used are diverse. It is generally agreed that the treatment of this disease should be combination chemotherapy, using similar drugs to those known to be active in SCLC. Surgery and radiotherapy should be used to improve local control during or after the chemotherapy and as palliative treatment for recurrent disease. The small number of patients with this condition will make randomized studies impossible, but they should be treated on well defined SCLC protocols. Areas for research in the future will include dose intensification or sequential high dose chemotherapy as treatment approaches, and the role of autocrine growth factors and human papillomavirus in the aetiology of these tumours.
Acknowledgement. We
wish to thank the Trent Cancer Registry for providing the cancer registry data.
105
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Received for publication January 1995 Accepted following revision September 1995