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Liposomal Doxorubicin for Treatment of Metastatic Chemorefractory Vulvar Adenocarcinoma
Gynecologic Oncology 87, 313–318 (2002) doi:10.1006/gyno.2002.6830
CASE REPORT Liposomal Doxorubicin for Treatment of Metastatic Chemorefractory Vulvar Adenocarcinoma Gloria S. Huang, M.D.,* Margrit Juretzka, M.D.,* Giuseppe Ciaravino, M.D.,* Sabine Kohler, M.D.,† and Nelson N. H. Teng, M.D., Ph.D.* ,1 *Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94303; and †Department of Pathology, Stanford University School of Medicine, Stanford, CA 94303 Received March 12, 2002
Background. Primary adenocarcinoma of the vulva is a rare entity, and for widely metastatic vulvar adenocarcinoma, no effective treatment has been established. Case. A 65-year-old woman was diagnosed with regionally advanced vulvar adenocarcinoma, with bulky involvement of bilateral groin lymph nodes, and associated extramammary Paget’s disease. Initial therapy consisted of multiagent chemotherapy and vulvar and groin irradiation, followed by radical vulvectomy with groin and pelvic lymph node dissection. She subsequently developed widely metastatic disease including brain, pulmonary, hepatic, osseus, and subcutaneous lesions. Treatment with liposomal doxorubicin (Doxil) resulted in dramatic regression of metastatic lesions and marked improvement in quality-of-life. She remains clinically well, greater than 1 year since initiating Doxil treatment for widely metastatic vulvar adenocarcinoma, and has surpassed 5 years of survival since her initial diagnosis. Conclusions. We report the first case of Doxil used for the treatment of metastatic chemorefractory vulvar adenocarcinoma. We observed that Doxil was a well-tolerated and effective agent for this gynecologic malignancy, and warrants further investigation. © 2002 Elsevier Science (USA) Key Words: vulvar neoplasm; adenocarcinoma; extramammary Paget’s disease; doxorubicin; liposome.
INTRODUCTION Primary adenocarcinoma of the vulva is a rare entity, representing less than 10% of vulvar cancers [1]. Most commonly, vulvar adenocarcinomas arise from the Bartholin gland or from invasion of extramammary Paget’s cells [2–9]. Some vulvar adenocarcinomas appear to originate from vulvar sweat glands or anogenital “mammary-like glands,” or rarely, from sebaceous glands, aberrant breast tissue, cloacal remnants, paraure1 To whom correspondence and reprint requests should be addressed at: Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5317. Fax: 650.723.7448. E-mail: [email protected].
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thral glands, minor vestibular glands, or endometriosis [1, 10 –14]. The usual treatment for vulvar adenocarcinoma is patterned after the treatment for vulvar squamous carcinoma, which is primarily a surgical approach. However, for widely metastatic disease, no standard treatment has been established, and long-term survival is extremely rare. Here we report the first case of liposomal doxorubicin (Doxil, Alza Pharmaceuticals) for the treatment of metastatic vulvar adenocarcinoma with associated extramammary Paget’s disease. CASE REPORT The patient is a 65-year-old postmenopausal woman who presented with a 4-year history of vulvar irritation and erythema. A vulvar biopsy performed in May 1996 showed invasive vulvar adenocarcinoma, with extramammary Paget’s disease (EMP) of the overlying epidermis. Computerized tomography (CT) of the chest, abdomen, and pelvis confirmed inguinal lymphadenopathy, but no evidence of an internal malignancy. Mammography, bone scintigraphy, and cervical cytology were also negative. Due to her regionally advanced disease, she was initially treated with systemic multiagent chemotherapy, beginning in August 1996, consisting of three cycles of CAF (cyclophosphamide, adriamycin, and fluorouracil), three cycles of carboplatin/fluorouracil, followed by one additional cycle of CAF, without significant response clinically or by CT. She then received external beam radiotherapy consisting of 6040 cGy to the bilateral inguinal–femoral regions in 33 fractions, and a total of 7870 cGy to the vulva in 40 fractions over 65 days, completed in June 1997, with clinical improvement in her pagetoid skin changes. A follow-up CT December 1997 showed persistent inguinal lymphadenopathy. In April 1998, CT demonstrated enlarging right inguinal lymphadenopathy measuring 4 ⫻ 6 cm and development of new right iliac lymphadenopathy. The patient presented to our institution, where vulvar biopsy 0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
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FIG. 1. (A) Adenocarcinoma of the vulva deeply invading the dermis as large tumor nodules. The overlying epidermis is broadly ulcerated. (B) Adjacent intact epidermis shows tumor cells with prominent full thickness pagetoid spread. Focally tumor cells along the dermal– epidermal junction form glands. (C) Extensive angiolymphatic invasion in the papillary dermis. (D) Areas of mucinous differentiation with islands of tumor cells set in a background of mucin.
confirmed persistent invasive adenocarcinoma. She then underwent radical vulvectomy with advancing abdominal skin flap, bilateral groin lymph node dissection, and right pelvic lymph node dissection in August 1998. The vulvar specimen demonstrated invasive mucinous adenocarcinoma, with associated Paget’s disease of the overlying epidermis (Fig. 1). Bilateral groin lymph nodes as well as the right external iliac lymph nodes were extensively replaced by metastatic adenocarcinoma. Postoperatively, the patient received right pelvic irradiation consisting of 3600 cGy in 20 fractions. The patient’s subsequent chest radiograph demonstrated enlarging pulmonary nodules; a CT-guided fine needle aspiration of the lung in May 1999 was consistent with metastatic adenocarcinoma from her vulvar primary. She was treated with 4980 cGy external beam radiotherapy to her lung metastases (3980 cGy in 20 fractions to the right hilum and lower lobe mass and 1000 cGy to right hilum off cord), completed July 1999. Shortly thereafter, she developed subcutaneous nodules of the scalp and back, as well as supraclavicular adenopathy.
She pursued palliative therapy with a variety of agents including brief courses of tamoxifen, thalidomide, and Japanese mushrooms. In May 2000, she was hospitalized for nausea, vomiting, and generalized pain. Her left back and lower extremity pain was palliated with radiotherapy consisting of 4600 cGy to her left iliac metastases. During treatment, she developed a left lower extremity deep venous thrombosis requiring anticoagulation. In June 2000, evaluation of severe neck pain led to the discovery of extensive osseous metastases involving the cervical spine, skull, scapula, thoracic–lumbar vertebrae, left sacroiliac joint, and right femur. A head CT was notable for a 4-cm enhancing right frontal mass with surrounding edema and mass effect with midline shift of 7 mm, as well as erosion through the bone into the subcutaneous tissues (Fig. 2A). Abdominal/ pelvic CT demonstrated multiple pulmonary nodules in the lung bases, multiple hepatic nodules up to 4-cm diameter, and multiple subcutaneous nodules (Fig. 3, top). Due to the findings on head CT, treatment with dexamethasone and radiother-
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FIG. 2. (A) Head CT: 4-cm enhancing right frontal mass with surrounding edema and mass effect. (B) Head CT: Decrease in size of the right frontal mass following radiation therapy and one course of Doxil therapy. (C) Head CT: Resolution of right frontal mass at the time of cycle eight of Doxil therapy.
apy was initiated. She received 3084 cGy in 11 fractions to the whole brain on a German helmet field, completed in June 2000. Due to her advanced symptomatic disease, the patient was unable to ambulate and was residing in a skilled nursing facility, requiring morphine sulfate PCA for pain control. An abdominal/pelvic CT scan in July 2000 confirmed disease progression, with interval increase in size and number of numerous hepatic and subcutaneous nodules. The patient wished to pursue chemotherapeutic options and was offered treatment with Doxil. Selection of this agent was based on its dosing schedule and toxicity profile, as well as results of the tumor resistance assay performed on her radical vulvectomy specimen, which showed low drug-resistance to Doxil. In July 2000, she began Doxil therapy at a dosage of 30 mg/m 2 every 4 weeks. Within 1 month of initiating Doxil therapy, abdominal/pelvic CT demonstrated a decrease in tumor volume. Also, a head CT (Fig. 2B) in August 2000 showed a decrease in the
tumor volume of the intracranial mass, which could reflect a response to either radiation therapy or Doxil therapy or both. After five cycles of Doxil, she was able to live at home again and perform her activities of daily living. She was able to ambulate with a walker, and she noted improved energy and appetite. Examination demonstrated resolution of her supraclavicular lymphadenopathy and regression of her numerous subcutaneous nodules, with a single 2-cm subcutaneous nodule representing the only remaining palpable disease. Head CT in March 2001 was remarkable for resolution of her intracranial soft tissue mass (Fig. 2C). In addition, abdominal/pelvic CT in March 2001 showed marked decrease in size and number of her multiple pulmonary, hepatic, subcutaneous metastases, and slight decrease in size of bony and adrenal lesions, as well as resolution of pleural effusions and subcutaneous edema. For instance, the largest pulmonary mass, previously 2.8 cm in diameter, measured 9 mm, and the largest hepatic mass, pre-
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wall motion abnormality. The patient has remained clinically well, with residual disease (pulmonary, hepatic, bony, subcutaneous, and adrenal), now greater than 1 year since the finding of widely metastatic disease and 5 years since her original diagnosis of vulvar adenocarcinoma. DISCUSSION
FIG. 3. (Top) Abdominal CT: Multiple hepatic; pulmonary, and subcutaneous nodules. (Bottom) Abdominal CT: Regression of metastatic lesions following Doxil therapy.
viously 4 cm in diameter, decreased in size to 1.6 cm (Fig. 3, bottom). The patient completed her ninth cycle of Doxil therapy in April 2001, with a total dosage administered equal to 492 mg (270 mg/m 2). Possible chemotherapy-related toxicities encountered during her Doxil treatment included one hospitalization for nausea and vomiting following her first cycle of Doxil, as well as a treatment delay prior to her fourth cycle, due to port site erythema and desquamation necessitating removal of the Mediport for suspicion of infection. No cardiotoxicity was encountered; the patient’s follow-up MUGA scan (resting equilibrium gated nuclear angiocardiography) demonstrated normal left ventricular ejection fraction of 54% and no focal
Vulvar adenocarcinoma and extramammary Paget’s disease of the vulva are rare, but often associated conditions, whose origins have long been debated in the literature. Due to the lack of consensus in their etiologies and relationship to each other, the nomenclature and classification of these diseases have varied over the years. Extramammary Paget’s disease is characterized by epidermal infiltration by neoplastic cells showing apocrine and glandular differentiation and, as such, is traditionally considered an “apocrine adenocarcinoma in situ” [9, 15, 16]. At times, however, the Paget’s cells will invade the dermis producing either superficial dermal invasion or a fully invasive adenocarcinoma with metastatic capability. Conversely, extramammary Paget’s disease can arise secondarily from an underlying carcinoma, such as a primary vulvar adenocarcinoma, or be associated with an internal malignancy [4 – 8]. As for the etiology of vulvar adenocarcinoma, Bartholin gland carcinoma is one of the relatively more common types of vulvar adenocarcinoma, with more than 200 cases reported in the literature, including all histologic types [3]. Progression of EMP also accounts for some cases of vulvar adenocarcinoma; these cases are often referred to as “invasive Paget’s disease” or “metastatic Paget’s disease” [6 – 8] Additional types of vulvar adenocarcinoma include sweat gland carcinomas and other skin adnexal carcinoma, as well as those arising from ectopic breast tissue, cloacal remnants, paraurethral glands, minor vestibular glands, or endometriosis [1, 11–14]. It has also been proposed that there exists a special type of vulvar gland, called the anogenital “mammary-like gland,” from which the majority of vulvar adenocarcinomas as well as EMP arise, according to the author [10]. It is not clear from the literature whether different types of vulvar adenocarcinoma differ with respect to prognosis or optimal treatment. Radical vulvectomy and bilateral inguinal– femoral lymphadenectomy has been suggested for all histologic types of Bartholin gland carcinoma [3]. However, another series of patients with Bartholin gland carcinoma found that wide excision, ipsilateral inguinal lymphadenectomy, and adjunctive irradiation to the vulva and regional lymph nodes produced excellent results [2]. Radical surgery with or without adjuvant radiotherapy is also advocated for patients with EMP with associated vulvar adenocarcinoma [4, 17]. Chemotherapy has been used in the setting of locally advanced primary or recurrent squamous cell carcinoma of the vulva; however, results have been disappointing. A regimen of bleomycin, methotrexate, and CCNU resulted in a median
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progression-free interval of 4.8 months and median survival of 7.8 months [18]. Among patients treated with piperazinedione or cisplatin in Phase II GOG trials, no objective regressions were observed [19]. A multimodality approach combining radiation with chemotherapeutic agents, such as cisplatin, 5-fluorouracil, and mitomycin-C, appears to benefit patients with locally advanced squamous cell carcinoma of the vulva [20 –22]. For metastatic vulvar adenocarcinoma, no standard therapy has been established, and a paucity of data exists. There have been several case reports on the use of systemic chemotherapy and/or radiotherapy in this setting. In 1988, Balducci reported on combination chemotherapy with mitomycin-C and 5-fluorouracil for scrotal Paget’s disease with metastatic disease to the pelvic and retroperitoneal lymph nodes. The CT normalized after one course of treatment, but after 6 months of treatment, the patient developed liver and lung metastases and died shortly thereafter [23]. In another report, Yamamoto described primary radiotherapy with concurrent cisplatin and 5-fluorouracil for Stage IVb vulvar adenocarcinoma associated with extramammary Paget’s disease. While the primary tumor mass regressed, presumably in response to radiotherapy, progression of osseous and hepatic metastases indicated lack of efficacy of the systemic chemotherapy regimen [24]. Massad described the successful treatment of two patients with locally advanced Bartholin gland carcinoma using radiotherapy with concurrent cisplatin and 5-fluorouracil [25]. In the present case, the patient presented with vulvar adenocarcinoma, associated EMP, and extensive nodal involvement. Pathology demonstrated extensive mucinous adenocarcinoma involving the vulva and regional lymph nodes, with relatively minor intraepidermal involvement with EMP, and no evidence of an internal malignancy. On immunophenotyping the tumor cells showed reactivity with antibodies to cytokeratin 7 (CK7) and failed to react with antibodies to cytokeratin 20 (CK20) and to gross cystic disease fluid protein 15 (GCDFP15), an apocrine differentiation marker. The relatively short duration of cutaneous symptoms prior to invasion, the immunophenotype, the relatively minor intraepidermal component, and the mucinous histology of the invasive portion argued for a primary adenocarcinoma of the vulva with secondary EMP, rather than primary EMP with invasion [26]. Subsequent to treatment with combination chemotherapy and radiotherapy to the vulva and groin, the patient developed widely metastatic lesions, including extensive nodal, pulmonary, osseous, intracranial, and subcutaneous metastases. The patient was then treated with single-agent Doxil with a remarkable response. The selection of the chemotherapy agent Doxil was based upon its dosing schedule, favorable toxicity profile, and results of the drug-resistance assay performed by Oncotech. While a complete remission has not been achieved, the patient has benefited from dramatic regression of her lesions, allowing her to resume independent living and enjoy a satisfactory quality of life.
The complete resolution of the patient’s brain metastases, as demonstrated by CT, is particularly notable. A recent report by Koukourakis documents the ability of liposomal doxorubicin to cross the blood– brain barrier [27]. In Koukourakis’ study, 10 patients with metastatic brain tumors were treated with radiolabeled liposomal doxorubicin concurrent with radiotherapy. Accumulation of radiolabeled liposomal doxorubicin was 7 to 13 times higher in the metastatic lesions, compared to the normal brain, suggesting that liposomal doxorubicin selectively overcomes the blood– brain barrier in tumoral areas. The clinical response seen in those patients suggested a possible synergistic effect of radiotherapy and chemotherapy. The patients in Koukourakis’ study received radiotherapy concurrent with liposomal doxorubicin, while the patient described in this report had completed radiotherapy prior to the initiation of Doxil therapy. While the initial regression of the intracranial tumor seen in August 2000 may reflect primarily the response to radiation therapy, the continued regression of the tumor leading to complete resolution by March 2001 likely reflects contributory effect of the Doxil treatment administered during that interval. The patient discussed here has had a durable response to Doxil for treatment of widely metastatic vulvar adenocarcinoma that was previously refractory to chemotherapy and radiotherapy. We observed that single-agent Doxil is a welltolerated and effective therapy for treating patients with metastatic vulvar adenocarcinoma, and warrants further investigation. In addition, the administration of Doxil following irradiation for treatment of brain metastases appeared to be particularly efficacious, suggesting possible synergism between these two modalities. REFERENCES 1. Berek JS, Hacker NF. Practical gynecologic oncology. Philadelphia: Lippincott Williams & Wilkins, 2000;xix, 937. 2. Copeland LJ, Sneige N, Gershenson DM, McGuffee VB, Abdul-Karim F, Rutledge FN. Bartholin gland carcinoma. Obstet Gynecol 1986;67:794 – 801. 3. Leuchter RS, Hacker NF, Voet RL, Berek JS, Townsend DE, Lagasse LD. Primary carcinoma of the Bartholin gland: a report of 14 cases and review of the literature. Obstet Gynecol 1982;60:361– 8. 4. Curtin JP, Rubin SC, Jones WB, Hoskins WJ, Lewis JL, Jr. Paget’s disease of the vulva. Gynecol Oncol 1990;39:374 –7. 5. Feuer GA, Shevchuk M, Calanog A. Vulvar Paget’s disease: the need to exclude an invasive lesion. Gynecol Oncol 1990;38:81–9. 6. Hart WR, Millman JB. Progression of intraepithelial Paget’s disease of the vulva to invasive carcinoma. Cancer 1977;40:2333–7. 7. Parker LP, Parker JR, Bodurka-Bevers D, Deavers M, Bevers MW, Shen-Gunther J, Gershenson DM. Paget’s disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol 2000;77:183–9 (doi:10.1006/gyno.2000.5741). 8. Boehm F, Morris JM. Paget’s disease and apocrine gland carcinoma of the vulva. Obstet Gynecol 1971;38:185–92. 9. Crawford D, Nimmo M, Clement PB, Thomson T, Benedet JL, Miller D,
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Gilks CB. Prognostic factors in Paget’s disease of the vulva: a study of 21 cases. Int J Gynecol Pathol 1999;18:351–9. van der Putte SC, van Gorp LH. Adenocarcinoma of the mammary-like glands of the vulva: a concept unifying sweat gland carcinoma of the vulva, carcinoma of supernumerary mammary glands and extramammary Paget’s disease. J Cutan Pathol 1994;21:157– 63. Escalonilla P, Grilli R, Canamero M, Soriano ML, Farina MC, Manzarbeitia F, Sainz R, Matsukura T, Requena L. Sebaceous carcinoma of the vulva. Am J Dermatopathol 1999; 21:468 –72. Rich PM, Okagaki T, Clark B, Prem KA. Adenocarcinoma of the sweat gland of the vulva: light and electron microscopic study. Cancer 1981;47: 1352–7. Rose PG, Roman LD, Reale FR, Tak WK, Hunter RE. Primary adenocarcinoma of the breast arising in the vulva. Obstet Gynecol 1990;76: 537–9. Bolis GB, Maccio T. Clear cell adenocarcinoma of the vulva arising in endometriosis. A case report. Eur J Gynaecol Oncol 2000;21:416 –7. Goldblum JR, Hart WR. Vulvar Paget’s disease: a clinicopathologic and immunohistochemical study of 19 cases. Am J Surg Pathol 1997;21: 1178 – 87. Lloyd J, Flanagan AM. Mammary and extramammary Paget’s disease. J Clin Pathol 2000;53:742–9. Creasman WT, Gallager HS, Rutledge F. Paget’s disease of the vulva. Gynecol Oncol 1975;3:133– 48. Wagenaar HC, Colombo N, Vergote I, Hoctin-Boes G, Zanetta G, Pecorelli S, Lacave AJ, van Hoesel Q, Cervantes A, Bolis G, Namer M, Lhomme C, Guastalla JP, Nooij MA, Poveda A, Scotto di Palumbo V, Vermorken JB. Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. European Organization for Research and Treatment of Cancer. Gynecol Oncol 2001; 81:348 –54 (doi:10.1006/gyno.2001.6180).
19. Thigpen JT, Blessing JA, Homesley HD, Lewis GC, Jr. Phase II trials of cisplatin and piperazinedione in advanced or recurrent squamous cell carcinoma of the vulva: a Gynecologic Oncology Group Study. Gynecol Oncol 1986;23:358 – 63. 20. Han SC, Kim DH, Higgins SA, Carcangiu ML, Kacinski BM. Chemoradiation as primary or adjuvant treatment for locally advanced carcinoma of the vulva. Int J Radiat Oncol Biol Phys 2000;47:1235– 44. 21. Akl A, Akl M, Boike G, Hebert J, Graham J. Preliminary results of chemoradiation as a primary treatment for vulvar carcinoma. Int J Radiat Oncol Biol Phys 2000;48:415–20. 22. Montana GS, Thomas GM, Moore DH, Saxer A, Mangan CE, Lentz SS, Averette HE. Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2000;48:1007–13. 23. Balducci L, Athar M, Smith GF, Khansur T, McKenzie D, Crawford ED. Metastatic extramammary Paget’s disease: dramatic response to combined modality treatment. J Surg Oncol 1988;38:38 – 44. 24. Yamamoto R, Sakuragi N, Shirato H, Shimizu M, Fujimoto S. Radiotherapy with concurrent chemotherapy for vulvar adenocarcinoma associated with extramammary Paget’s disease. Gynecol Oncol 2001;80:267–71 (doi: 10.1006/gyno.2000.6054). 25. Massad LS, De Geest K. Multimodality therapy for carcinoma of the Bartholin gland. Gynecol Oncol 1999;75:305–7 (doi:10.1006/gyno.1999.5542). 26. Kohler S, Smoller BR. Gross cystic disease fluid protein-15 reactivity in extramammary Paget’s disease with and without associated internal malignancy. Am J Dermatopathol 1996;18:118 –23. 27. Koukourakis MI, Koukouraki S, Fezoulidis I, Kelekis N, Kyrias G, Archimandritis S, Karkavitsas N. High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer 2000;83:1281– 6 (doi:10.1054/ bjoc.2000.1459).
CASE REPORT Liposomal Doxorubicin for Treatment of Metastatic Chemorefractory Vulvar Adenocarcinoma Gloria S. Huang, M.D.,* Margrit Juretzka, M.D.,* Giuseppe Ciaravino, M.D.,* Sabine Kohler, M.D.,† and Nelson N. H. Teng, M.D., Ph.D.* ,1 *Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94303; and †Department of Pathology, Stanford University School of Medicine, Stanford, CA 94303 Received March 12, 2002
Background. Primary adenocarcinoma of the vulva is a rare entity, and for widely metastatic vulvar adenocarcinoma, no effective treatment has been established. Case. A 65-year-old woman was diagnosed with regionally advanced vulvar adenocarcinoma, with bulky involvement of bilateral groin lymph nodes, and associated extramammary Paget’s disease. Initial therapy consisted of multiagent chemotherapy and vulvar and groin irradiation, followed by radical vulvectomy with groin and pelvic lymph node dissection. She subsequently developed widely metastatic disease including brain, pulmonary, hepatic, osseus, and subcutaneous lesions. Treatment with liposomal doxorubicin (Doxil) resulted in dramatic regression of metastatic lesions and marked improvement in quality-of-life. She remains clinically well, greater than 1 year since initiating Doxil treatment for widely metastatic vulvar adenocarcinoma, and has surpassed 5 years of survival since her initial diagnosis. Conclusions. We report the first case of Doxil used for the treatment of metastatic chemorefractory vulvar adenocarcinoma. We observed that Doxil was a well-tolerated and effective agent for this gynecologic malignancy, and warrants further investigation. © 2002 Elsevier Science (USA) Key Words: vulvar neoplasm; adenocarcinoma; extramammary Paget’s disease; doxorubicin; liposome.
INTRODUCTION Primary adenocarcinoma of the vulva is a rare entity, representing less than 10% of vulvar cancers [1]. Most commonly, vulvar adenocarcinomas arise from the Bartholin gland or from invasion of extramammary Paget’s cells [2–9]. Some vulvar adenocarcinomas appear to originate from vulvar sweat glands or anogenital “mammary-like glands,” or rarely, from sebaceous glands, aberrant breast tissue, cloacal remnants, paraure1 To whom correspondence and reprint requests should be addressed at: Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5317. Fax: 650.723.7448. E-mail: [email protected].
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thral glands, minor vestibular glands, or endometriosis [1, 10 –14]. The usual treatment for vulvar adenocarcinoma is patterned after the treatment for vulvar squamous carcinoma, which is primarily a surgical approach. However, for widely metastatic disease, no standard treatment has been established, and long-term survival is extremely rare. Here we report the first case of liposomal doxorubicin (Doxil, Alza Pharmaceuticals) for the treatment of metastatic vulvar adenocarcinoma with associated extramammary Paget’s disease. CASE REPORT The patient is a 65-year-old postmenopausal woman who presented with a 4-year history of vulvar irritation and erythema. A vulvar biopsy performed in May 1996 showed invasive vulvar adenocarcinoma, with extramammary Paget’s disease (EMP) of the overlying epidermis. Computerized tomography (CT) of the chest, abdomen, and pelvis confirmed inguinal lymphadenopathy, but no evidence of an internal malignancy. Mammography, bone scintigraphy, and cervical cytology were also negative. Due to her regionally advanced disease, she was initially treated with systemic multiagent chemotherapy, beginning in August 1996, consisting of three cycles of CAF (cyclophosphamide, adriamycin, and fluorouracil), three cycles of carboplatin/fluorouracil, followed by one additional cycle of CAF, without significant response clinically or by CT. She then received external beam radiotherapy consisting of 6040 cGy to the bilateral inguinal–femoral regions in 33 fractions, and a total of 7870 cGy to the vulva in 40 fractions over 65 days, completed in June 1997, with clinical improvement in her pagetoid skin changes. A follow-up CT December 1997 showed persistent inguinal lymphadenopathy. In April 1998, CT demonstrated enlarging right inguinal lymphadenopathy measuring 4 ⫻ 6 cm and development of new right iliac lymphadenopathy. The patient presented to our institution, where vulvar biopsy 0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
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FIG. 1. (A) Adenocarcinoma of the vulva deeply invading the dermis as large tumor nodules. The overlying epidermis is broadly ulcerated. (B) Adjacent intact epidermis shows tumor cells with prominent full thickness pagetoid spread. Focally tumor cells along the dermal– epidermal junction form glands. (C) Extensive angiolymphatic invasion in the papillary dermis. (D) Areas of mucinous differentiation with islands of tumor cells set in a background of mucin.
confirmed persistent invasive adenocarcinoma. She then underwent radical vulvectomy with advancing abdominal skin flap, bilateral groin lymph node dissection, and right pelvic lymph node dissection in August 1998. The vulvar specimen demonstrated invasive mucinous adenocarcinoma, with associated Paget’s disease of the overlying epidermis (Fig. 1). Bilateral groin lymph nodes as well as the right external iliac lymph nodes were extensively replaced by metastatic adenocarcinoma. Postoperatively, the patient received right pelvic irradiation consisting of 3600 cGy in 20 fractions. The patient’s subsequent chest radiograph demonstrated enlarging pulmonary nodules; a CT-guided fine needle aspiration of the lung in May 1999 was consistent with metastatic adenocarcinoma from her vulvar primary. She was treated with 4980 cGy external beam radiotherapy to her lung metastases (3980 cGy in 20 fractions to the right hilum and lower lobe mass and 1000 cGy to right hilum off cord), completed July 1999. Shortly thereafter, she developed subcutaneous nodules of the scalp and back, as well as supraclavicular adenopathy.
She pursued palliative therapy with a variety of agents including brief courses of tamoxifen, thalidomide, and Japanese mushrooms. In May 2000, she was hospitalized for nausea, vomiting, and generalized pain. Her left back and lower extremity pain was palliated with radiotherapy consisting of 4600 cGy to her left iliac metastases. During treatment, she developed a left lower extremity deep venous thrombosis requiring anticoagulation. In June 2000, evaluation of severe neck pain led to the discovery of extensive osseous metastases involving the cervical spine, skull, scapula, thoracic–lumbar vertebrae, left sacroiliac joint, and right femur. A head CT was notable for a 4-cm enhancing right frontal mass with surrounding edema and mass effect with midline shift of 7 mm, as well as erosion through the bone into the subcutaneous tissues (Fig. 2A). Abdominal/ pelvic CT demonstrated multiple pulmonary nodules in the lung bases, multiple hepatic nodules up to 4-cm diameter, and multiple subcutaneous nodules (Fig. 3, top). Due to the findings on head CT, treatment with dexamethasone and radiother-
CASE REPORT
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FIG. 2. (A) Head CT: 4-cm enhancing right frontal mass with surrounding edema and mass effect. (B) Head CT: Decrease in size of the right frontal mass following radiation therapy and one course of Doxil therapy. (C) Head CT: Resolution of right frontal mass at the time of cycle eight of Doxil therapy.
apy was initiated. She received 3084 cGy in 11 fractions to the whole brain on a German helmet field, completed in June 2000. Due to her advanced symptomatic disease, the patient was unable to ambulate and was residing in a skilled nursing facility, requiring morphine sulfate PCA for pain control. An abdominal/pelvic CT scan in July 2000 confirmed disease progression, with interval increase in size and number of numerous hepatic and subcutaneous nodules. The patient wished to pursue chemotherapeutic options and was offered treatment with Doxil. Selection of this agent was based on its dosing schedule and toxicity profile, as well as results of the tumor resistance assay performed on her radical vulvectomy specimen, which showed low drug-resistance to Doxil. In July 2000, she began Doxil therapy at a dosage of 30 mg/m 2 every 4 weeks. Within 1 month of initiating Doxil therapy, abdominal/pelvic CT demonstrated a decrease in tumor volume. Also, a head CT (Fig. 2B) in August 2000 showed a decrease in the
tumor volume of the intracranial mass, which could reflect a response to either radiation therapy or Doxil therapy or both. After five cycles of Doxil, she was able to live at home again and perform her activities of daily living. She was able to ambulate with a walker, and she noted improved energy and appetite. Examination demonstrated resolution of her supraclavicular lymphadenopathy and regression of her numerous subcutaneous nodules, with a single 2-cm subcutaneous nodule representing the only remaining palpable disease. Head CT in March 2001 was remarkable for resolution of her intracranial soft tissue mass (Fig. 2C). In addition, abdominal/pelvic CT in March 2001 showed marked decrease in size and number of her multiple pulmonary, hepatic, subcutaneous metastases, and slight decrease in size of bony and adrenal lesions, as well as resolution of pleural effusions and subcutaneous edema. For instance, the largest pulmonary mass, previously 2.8 cm in diameter, measured 9 mm, and the largest hepatic mass, pre-
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wall motion abnormality. The patient has remained clinically well, with residual disease (pulmonary, hepatic, bony, subcutaneous, and adrenal), now greater than 1 year since the finding of widely metastatic disease and 5 years since her original diagnosis of vulvar adenocarcinoma. DISCUSSION
FIG. 3. (Top) Abdominal CT: Multiple hepatic; pulmonary, and subcutaneous nodules. (Bottom) Abdominal CT: Regression of metastatic lesions following Doxil therapy.
viously 4 cm in diameter, decreased in size to 1.6 cm (Fig. 3, bottom). The patient completed her ninth cycle of Doxil therapy in April 2001, with a total dosage administered equal to 492 mg (270 mg/m 2). Possible chemotherapy-related toxicities encountered during her Doxil treatment included one hospitalization for nausea and vomiting following her first cycle of Doxil, as well as a treatment delay prior to her fourth cycle, due to port site erythema and desquamation necessitating removal of the Mediport for suspicion of infection. No cardiotoxicity was encountered; the patient’s follow-up MUGA scan (resting equilibrium gated nuclear angiocardiography) demonstrated normal left ventricular ejection fraction of 54% and no focal
Vulvar adenocarcinoma and extramammary Paget’s disease of the vulva are rare, but often associated conditions, whose origins have long been debated in the literature. Due to the lack of consensus in their etiologies and relationship to each other, the nomenclature and classification of these diseases have varied over the years. Extramammary Paget’s disease is characterized by epidermal infiltration by neoplastic cells showing apocrine and glandular differentiation and, as such, is traditionally considered an “apocrine adenocarcinoma in situ” [9, 15, 16]. At times, however, the Paget’s cells will invade the dermis producing either superficial dermal invasion or a fully invasive adenocarcinoma with metastatic capability. Conversely, extramammary Paget’s disease can arise secondarily from an underlying carcinoma, such as a primary vulvar adenocarcinoma, or be associated with an internal malignancy [4 – 8]. As for the etiology of vulvar adenocarcinoma, Bartholin gland carcinoma is one of the relatively more common types of vulvar adenocarcinoma, with more than 200 cases reported in the literature, including all histologic types [3]. Progression of EMP also accounts for some cases of vulvar adenocarcinoma; these cases are often referred to as “invasive Paget’s disease” or “metastatic Paget’s disease” [6 – 8] Additional types of vulvar adenocarcinoma include sweat gland carcinomas and other skin adnexal carcinoma, as well as those arising from ectopic breast tissue, cloacal remnants, paraurethral glands, minor vestibular glands, or endometriosis [1, 11–14]. It has also been proposed that there exists a special type of vulvar gland, called the anogenital “mammary-like gland,” from which the majority of vulvar adenocarcinomas as well as EMP arise, according to the author [10]. It is not clear from the literature whether different types of vulvar adenocarcinoma differ with respect to prognosis or optimal treatment. Radical vulvectomy and bilateral inguinal– femoral lymphadenectomy has been suggested for all histologic types of Bartholin gland carcinoma [3]. However, another series of patients with Bartholin gland carcinoma found that wide excision, ipsilateral inguinal lymphadenectomy, and adjunctive irradiation to the vulva and regional lymph nodes produced excellent results [2]. Radical surgery with or without adjuvant radiotherapy is also advocated for patients with EMP with associated vulvar adenocarcinoma [4, 17]. Chemotherapy has been used in the setting of locally advanced primary or recurrent squamous cell carcinoma of the vulva; however, results have been disappointing. A regimen of bleomycin, methotrexate, and CCNU resulted in a median
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CASE REPORT
progression-free interval of 4.8 months and median survival of 7.8 months [18]. Among patients treated with piperazinedione or cisplatin in Phase II GOG trials, no objective regressions were observed [19]. A multimodality approach combining radiation with chemotherapeutic agents, such as cisplatin, 5-fluorouracil, and mitomycin-C, appears to benefit patients with locally advanced squamous cell carcinoma of the vulva [20 –22]. For metastatic vulvar adenocarcinoma, no standard therapy has been established, and a paucity of data exists. There have been several case reports on the use of systemic chemotherapy and/or radiotherapy in this setting. In 1988, Balducci reported on combination chemotherapy with mitomycin-C and 5-fluorouracil for scrotal Paget’s disease with metastatic disease to the pelvic and retroperitoneal lymph nodes. The CT normalized after one course of treatment, but after 6 months of treatment, the patient developed liver and lung metastases and died shortly thereafter [23]. In another report, Yamamoto described primary radiotherapy with concurrent cisplatin and 5-fluorouracil for Stage IVb vulvar adenocarcinoma associated with extramammary Paget’s disease. While the primary tumor mass regressed, presumably in response to radiotherapy, progression of osseous and hepatic metastases indicated lack of efficacy of the systemic chemotherapy regimen [24]. Massad described the successful treatment of two patients with locally advanced Bartholin gland carcinoma using radiotherapy with concurrent cisplatin and 5-fluorouracil [25]. In the present case, the patient presented with vulvar adenocarcinoma, associated EMP, and extensive nodal involvement. Pathology demonstrated extensive mucinous adenocarcinoma involving the vulva and regional lymph nodes, with relatively minor intraepidermal involvement with EMP, and no evidence of an internal malignancy. On immunophenotyping the tumor cells showed reactivity with antibodies to cytokeratin 7 (CK7) and failed to react with antibodies to cytokeratin 20 (CK20) and to gross cystic disease fluid protein 15 (GCDFP15), an apocrine differentiation marker. The relatively short duration of cutaneous symptoms prior to invasion, the immunophenotype, the relatively minor intraepidermal component, and the mucinous histology of the invasive portion argued for a primary adenocarcinoma of the vulva with secondary EMP, rather than primary EMP with invasion [26]. Subsequent to treatment with combination chemotherapy and radiotherapy to the vulva and groin, the patient developed widely metastatic lesions, including extensive nodal, pulmonary, osseous, intracranial, and subcutaneous metastases. The patient was then treated with single-agent Doxil with a remarkable response. The selection of the chemotherapy agent Doxil was based upon its dosing schedule, favorable toxicity profile, and results of the drug-resistance assay performed by Oncotech. While a complete remission has not been achieved, the patient has benefited from dramatic regression of her lesions, allowing her to resume independent living and enjoy a satisfactory quality of life.
The complete resolution of the patient’s brain metastases, as demonstrated by CT, is particularly notable. A recent report by Koukourakis documents the ability of liposomal doxorubicin to cross the blood– brain barrier [27]. In Koukourakis’ study, 10 patients with metastatic brain tumors were treated with radiolabeled liposomal doxorubicin concurrent with radiotherapy. Accumulation of radiolabeled liposomal doxorubicin was 7 to 13 times higher in the metastatic lesions, compared to the normal brain, suggesting that liposomal doxorubicin selectively overcomes the blood– brain barrier in tumoral areas. The clinical response seen in those patients suggested a possible synergistic effect of radiotherapy and chemotherapy. The patients in Koukourakis’ study received radiotherapy concurrent with liposomal doxorubicin, while the patient described in this report had completed radiotherapy prior to the initiation of Doxil therapy. While the initial regression of the intracranial tumor seen in August 2000 may reflect primarily the response to radiation therapy, the continued regression of the tumor leading to complete resolution by March 2001 likely reflects contributory effect of the Doxil treatment administered during that interval. The patient discussed here has had a durable response to Doxil for treatment of widely metastatic vulvar adenocarcinoma that was previously refractory to chemotherapy and radiotherapy. We observed that single-agent Doxil is a welltolerated and effective therapy for treating patients with metastatic vulvar adenocarcinoma, and warrants further investigation. In addition, the administration of Doxil following irradiation for treatment of brain metastases appeared to be particularly efficacious, suggesting possible synergism between these two modalities. REFERENCES 1. Berek JS, Hacker NF. Practical gynecologic oncology. Philadelphia: Lippincott Williams & Wilkins, 2000;xix, 937. 2. Copeland LJ, Sneige N, Gershenson DM, McGuffee VB, Abdul-Karim F, Rutledge FN. Bartholin gland carcinoma. Obstet Gynecol 1986;67:794 – 801. 3. Leuchter RS, Hacker NF, Voet RL, Berek JS, Townsend DE, Lagasse LD. Primary carcinoma of the Bartholin gland: a report of 14 cases and review of the literature. Obstet Gynecol 1982;60:361– 8. 4. Curtin JP, Rubin SC, Jones WB, Hoskins WJ, Lewis JL, Jr. Paget’s disease of the vulva. Gynecol Oncol 1990;39:374 –7. 5. Feuer GA, Shevchuk M, Calanog A. Vulvar Paget’s disease: the need to exclude an invasive lesion. Gynecol Oncol 1990;38:81–9. 6. Hart WR, Millman JB. Progression of intraepithelial Paget’s disease of the vulva to invasive carcinoma. Cancer 1977;40:2333–7. 7. Parker LP, Parker JR, Bodurka-Bevers D, Deavers M, Bevers MW, Shen-Gunther J, Gershenson DM. Paget’s disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol 2000;77:183–9 (doi:10.1006/gyno.2000.5741). 8. Boehm F, Morris JM. Paget’s disease and apocrine gland carcinoma of the vulva. Obstet Gynecol 1971;38:185–92. 9. Crawford D, Nimmo M, Clement PB, Thomson T, Benedet JL, Miller D,
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