Clin Exp Med DOI 10.1007/s10238-015-0353-6
REVIEW ARTICLE
Metastatic melanoma of the gallbladder: report of two cases and a review of the literature I. Giannini1 • D. A. Cutrignelli2 • L. Resta3 • A. Gentile3 • L. Vincenti4
Received: 25 March 2015 / Accepted: 20 April 2015 Ó Springer-Verlag Italia 2015
Abstract Melanoma is one of the most aggressive and highly metastatic cancers. The most common sites of distant metastases are soft tissues, lung, liver, skin and brain, whereas only few patients develop gastrointestinal metastases. Metastatic involvement of the gallbladder is rare and more often part of a widespread disease than a solitary lesion. The ‘‘gold-standard’’ treatment of metastatic melanoma of the gallbladder remains unclear. We report two cases of patients with past history of cutaneous melanoma who developed visceral metastases. The first patient was asymptomatic and had a widespread disease with metastatic involvement of both the spleen and the gallbladder. The second patient had an isolated metastasis of the gallbladder and complained of upper abdominal pain. The chosen treatment was open cholecystectomy (and splenectomy) in the first case and laparoscopic cholecystectomy in the second. A review of the literature is provided.
& I. Giannini [email protected] 1
General Surgery and Liver Transplantation Unit, Department of Emergency and Organ Transplantation, University ‘‘A. Moro’’ of Bari, Policlinico. Piazza G. Cesare, 11, 70124 Bari, Italy
2
Complex Operating Unit of Plastic Aesthetic and Reconstructive Surgery, Department of Emergency and Organ Transplantation, University ‘‘A. Moro’’ of Bari, Bari, Italy
3
Department of Emergence and Organ Transplantation, Institute of Pathological Anatomy, University ‘‘A. Moro’’ of Bari, Bari, Italy
4
General Surgery Unit, Policlinico of Bari, Bari, Italy
Keywords Melanoma Gallbladder metastasis Cholecystectomy Laparoscopic cholecystectomy
Introduction Melanoma is one of the most aggressive and highly metastatic types of cancer that arises from the melanocyte, a dendritic cell located above all in the basal layer of the skin, but also in the eye, the mucosa of the upper respiratory tract, the gastrointestinal tract and in normal lymph nodes [1]. Although it accounts for\5 % of all skin cancers, melanoma is responsible for the majority of the skin-related deaths, due to its high tendency to metastasize. The most common sites of distant metastases are soft tissues (50–75 %), lung (70–87 %), liver (54–77 %), skin (50–75 %) and brain [2– 5]. A small percentage of patients (from 2 to 4 %) affected by cutaneous melanoma are diagnosed with gastrointestinal metastases and the most common sites are small bowel, colon and stomach, with a low overall survival rate [6]. Metastatic involvement of the gallbladder is rare and, when present, is often part of a widespread complex of metastases with a very poor prognosis [6, 7]. In this paper, two cases of metastatic melanoma of the gallbladder are reported and a review of the literature is provided. Case 1 A 50-year-old male was admitted to our Unit with evidence at CT scan of two hyperdense lesions: one in the gallbladder and one in the spleen. Despite the radiological evidence, the patient was asymptomatic and the neoplastic markers were negative. A PET-CT scan was therefore performed that revealed increased metabolic activity in the gallbladder, but not in the spleen. In 2006, the patient underwent the surgical excision of a nodular, ulcerated melanoma of the back in a ‘‘vertical’’ growth
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phase; Breslow thickness 7 mm and Clark’s level IV. No evidence of metastases in the sentinel lymph node nor distant sites was revealed. Both laparotomic splenectomy and cholecystectomy were performed. Nodes of the hepatic pedicle appeared increased in volume and were thus removed, while the exploration of other abdominal organs did not highlight any other secondary localizations of malignancy. Macroscopically, the gallbladder showed no anomalies of the peritoneal surface and pathological examination revealed the presence of two brownish polypoid lesions in the lumen, arising from the mucosa of the fundus (2 9 1.5 cm) and of the body (1.5 9 1 cm), both referable to malignant metastatic melanoma (immunohistochemistry positive for Melan-A and HMB45) (Fig. 1). The spleen had a 6-cm subcapsular, soft, dark lesion that microscopically appeared as a poorly differentiated tumor referable to metastatic melanoma; hepatic pedicle’s nodes were free from neoplastic cells. The postoperative course was uneventful and patient was discharged on the sixth postoperative day. Unfortunately, the first oncological follow-up, 1 month after the surgical procedure, detected the presence of further metastases in the brain and pancreas. At present, 6 months after the operation, the patient is receiving radiotherapy and combined therapy with BRAF V600E (dabrafenib) and MEK inhibitors (trametinib) and is still alive 6 months after he was operated on. Case 2 In 2012, a 40-year-old female underwent a local excision of nodular melanoma in the right hemithorax (Breslow thickness 2.5 mm; Clark’s level III with no evidence of metastases in the sentinel lymph node nor distant sites).
Two years later, due to the onset of upper abdominal pain and in accordance with the oncological follow-up, an abdominal ultrasound was performed that revealed the presence of a pedunculated mass inside the gallbladder and a thickening of the wall. Neoplastic markers were within the normal range but, given the past history of malignant melanoma, the possibility of metastatic involvement of gallbladder was considered, which led to a PET/CT scan. Because an increased uptake of fluorodeoxyglucose in the gallbladder (SUV 7.5) was observed, the patient underwent a laparoscopic cholecystectomy. During the surgical procedure, the gallbladder was distended, but no abnormalities of the peritoneal surface were detected; the exploration of other abdominal organs was unremarkable. The gallbladder was removed and pulled out into an ‘‘endobag’’ to prevent the dissemination of neoplastic cells. A dissection of the hepatic pedicle nodes was also performed as they appeared macroscopically abnormal. A five-centimeter brown, pedunculated, polypoid lesion originating from the fundus was noticed once the gallbladder was opened (Figs. 2, 3). The histopathological findings were consistent with gallbladder metastasis of melanoma (immunohistochemistry positive for Melan-A and HMB45) (Fig. 4). No regional metastases were detected in the hepatic pedicle nodes. The postoperative course was uneventful, and the patient was discharged on the second postoperative day. The patient is following a strict oncological follow-up and is currently free of recurrence 6 months after the operation. The patient is receiving immunotherapy with Interferon 3000000 U. I. three times weekly.
Discussion Cutaneous melanoma represents the skin cancer with the highest mortality, although its biology is extremely unpredictable and variable, depending on the different stages.
Fig. 1 Gallbladder mucosa with thin normal papillae (bottom) merged by columnar epithelium and with foam macrophages in the stroma. Presence of large papillae (top) with preserved epithelium and invasion of the stroma by neoplastic undifferentiated cells. Dark pigment is focally present in the sub-epithelial space (H&E original magnification 9100)
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Fig. 2 Peritoneal surface of the gallbladder
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Fig. 3 Intraluminal metastasis
Fig. 4 Microscopic view of metastatic melanoma in the gallbladder wall. Undifferentiated neoplastic cells occupy the mucosal stroma and destroy the muscular layer. Dark pigment is evident among the neoplastic cells (H&E original magnification 9100)
Melanoma may arise from any mucosa containing melanocytes that migrate from the neural crest to endodermic tissue during embryogenesis [8, 9]. The frequency of this tumor is increasing worldwide: in the last 15 years, the number of cases of melanoma has virtually doubled. Each year there are approximately 100,000 new cases; in Italy 14 cases occur on average a year per 100,000 inhabitants (data AIRTUM 2009). The most important feature of the tumor is the Breslow thickness because it is directly proportional to the risk of the melanoma spreading [10–12]. Clark’s level is another staging system which describes the level of anatomical invasion of the melanoma in the skin. However, since 2002, it has been shown that Clark’s level has a lower predictive value, is less reproducible and more subjective than the Breslow thickness [13].
Melanoma can spread through the lymph system that drains into lymph nodes in the area around the primary skin melanoma and/or through the blood stream to distant sites. Distant metastatic sites include skin and soft tissues, lung, liver, brain and gastrointestinal tract [2–5, 14]. Among the gastrointestinal metastases, the most common sites are small bowel (35–67 %), colon (9–15 %) and stomach (5–7 %) [6]. The stage of the tumor is intricately related to long-term survival rate: 85–90 % of melanomas are clinically localized (stages 0–2) at the time of diagnosis, with a 5-year survival rate of more than 90 %. Conversely, the long-term survival rate of metastatic disease (stage 4) is very low with a median overall survival rate of 33 % after 1 year and 15 % after 5 years [15]. For patients with stage 4 disease, the median survival rate reported after surgery is 6–10 months and a long-term disease-free survival rate may be achieved only in a small percentage of patients [2, 6]. Isolated metastases of the gallbladder are rare and more commonly present in a widespread metastatic disease. However, among the metastatic gallbladder tumors, melanoma is the most common origin of malignancy: in fact, up to 60 % of all metastatic lesions of the gallbladder originate from a cutaneous melanoma [3, 6]. Dissemination of neoplastic cells occurs probably via the blood stream, but the gallbladder may also be involved through the implanting of these cells, carried by the bile, into the mucosa [16]. At autopsy, the gallbladder metastases occur in up to 20 % of patients who died of malignant melanoma, but are rarely reported during the patients’ lifetime because they are mostly symptom free [2, 3, 6]. When symptoms are present, the most common is upper abdominal pain resembling cholecystolithiasis; cases of hemobilia and biliary fistula have also been described [2, 8, 9, 17]. The conventional diagnostic work-up is based on abdomen ultrasonography, preferably with color–power Doppler, and CT scans that may detect the presence of an intraluminal mass; the fluorodeoxyglucose (FDG) PET/CT is a second-step investigation that could confirm the diagnosis by showing an increased uptake [6, 8, 9]. Due to the rarity of the disease, no therapeutic guidelines have yet been drawn up. A long series of patients who developed gastrointestinal metastases of cutaneous melanoma is reported by the group of the National Cancer Institute of Naples. Of these patients, 30 out of 1684 (1.7 %) developed metastases along the gastrointestinal tract, but only one of them developed an isolated gallbladder metastasis [6]. The first case of secondary melanoma of the gallbladder was reported by Henriques in 1955 [18]; since then only case reports and small case series have been described. Table 1 summarizes, to the best of our knowledge, the main English papers reporting two or more cases of
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I = isolated gallbladder metastasis; W = widespread disease; O = open cholecystectomy; L = laparoscopic cholecystectomy; CHT = chemotherapy; IT = immunotherapy; PID = patients with isolated disease; PCR = patients undergoing complete surgical resection; PNCR = patients undergoing not complete surgical resection or medical therapy; PUS = patients undergoing surgery; PNUS = patients not undergoing surgery
6 mos each 1 L; 1 O Cholecystectomy Hemitorax; back 1 upper abdominal pain; 1 asymptomatic 1 I: I W 40; 50 2015 Present paper
2
36 mos; 24 mos L Cholecystectomy Shoulder/back; unknown 1 biliary colic; 1 asymptomatic 1 I; I W 52; 60 2008 Samplaski et al. [8]
2
6 O; 3 L 9 cholecystectomy; 7 CHT; 7 IT 2007 Katz et al. [21]
13
Range 28–66
5 I; 8 W
6 asymptomatic; 7 various (not described)
7 trunk; 3 head/neck; 1 extremities, 1 vulva; 1 unknown
PUS: median l6 mos; PNUS: median 6 mos
2 PID: 110.9 mos and 165.5 mos; 6 PCR: 22.34 mos median; 11 PNCR: 6.08 mos median Not described 12 cholecystectomy; 2 cholecystostomy tube; 3 CHT (primary); 3 CHT (adjuvant): 1 IT only; 2 IT adjuvant 14 cholecystitis; 5 various (weight loss, nausea, vomiting) 1999 Dong et al. [20]
19
Mean 46.2 (range 24–68)
2 I; 17 W
12 trunk; 3 head/neck; 2 extremities; 2 unknown
10 mos; 11 mos O Cholecystectomy Face; neck 1 biliary colic; 1 symptoms of biliary obstruction 1 I; 1 W 21; 50 1979 McFadden et al. [19]
2
Symptoms I/W Patients’ age Pts Year Authors
Table 1 Main features of clinical cases reported in the English literature
Site of primary
Treatment
Open/ laparoscopy surgery
Overall survival after surgery
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cutaneous melanoma metastasized in the gallbladder which underwent surgical resection. The role of surgery in the treatment of gallbladder metastatic melanoma still remains questionable, since the majority of patients with distant metastases have widespread micro-metastatic disease even when clinical and imaging investigations suggest a limited spread [14]. However, metastasectomy continues to be the standard care for patients affected with solitary resectable melanoma metastasis to prolong their survival, and even in the presence of disseminated disease, resection of metastatic gallbladder could be a worthwhile palliative procedure to avoid clinical manifestations of the disease and to prevent further dissemination. In fact, the metastases to the gastrointestinal tract are likely to occur as a consequence of the spreading of tumor cells shed into the bile [8, 9, 22]. Dong et al. [20] reported a 100 % survival at 1 year in six patients with isolated and resectable gallbladder metastasis compared to 0 % in patients with a widespread disease. Martel et al. [23] reported a case of open cholecystectomy with an 18-month survival. Katz et al. [21] reported the experience of the Memorial Sloan-Kettering Cancer Center: 13 patients undergoing cholecystectomy for metastatic melanoma of the gallbladder with a median survival of 16 months after surgery; furthermore, authors emphasized factors associated with an improved survival rate: symptoms, isolated metastases and surgical operation. Seelig et al. [24] and Tuveri et al. [25] both reported a 20- and 60-month survival, respectively, in patients treated with laparoscopic cholecystectomy. This finding is supported by Kohler et al. [8] and by Samplaski et al. [26] who supported the suitability of laparoscopic cholecystectomy in patients with metastatic melanoma of the gallbladder. Therefore, laparoscopic cholecystectomy (LC) seems to be an adequate treatment for patients with isolated and resectable disease as the vast majority of metastatic melanoma is intraluminal and regional node dissection is not recommended for stage 4 melanoma [2, 25–27]. A very recent paper, on the contrary, encourages an open surgical approach rather than laparoscopic in order to avoid trocar recurrence and to detect other gastrointestinal metastases undetected preoperatively [28]. However, the main risks related to LC (perforation of the gallbladder and intra-abdominal bile leak and/or port sites) could be prevented with gentle dissection and use of the endobag [20, 25]. Besides surgical resection, therapies such as chemotherapy, immunotherapy and targeted therapy are current approaches, although the role of adjuvant therapies is still debated because of the scarce and disappointing data available in patients with metastatic disease [2–29]. High-dose bolus of interleukin-2 (IL-2) has proven to induce tumor remission in about 15 % of patients with
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metastatic melanoma who experienced progression after chemotherapy. However, due to its toxicity and difficulty with administration, IL-2 therapy could only be used in a small percentage of selected patients [30]. In recent years, the interest in BRAF inhibitors and immunotherapy is increasing due to the evidence of efficacy on the overall survival rate in patients with metastatic melanoma. The goal of these therapies is to stimulate the immune response against cancer [29, 31–34]. The efficacy of BRAF inhibitors has already been stated as monotherapies in patients with metastatic melanoma with BRAF V600E or V600 K mutations; however, combined therapy with MEK inhibitors (dabrafenib/trametinib and vemurafenib/cobimetinib) have shown improvement in the overall survival rate and progression-free survival without a significant increase in overall toxicity and the delay in the onset of resistance observed with BRAF inhibitors alone [35–38]. Very recently the utility of nivolumab in patients with previously untreated metastatic melanoma and without BRAF mutation has been studied: a significant improvement in the overall survival (72.9 %) and progression-free survival (5.1 months) has been described when compared to dacarbazine [39]. Another debated issue is the differential diagnosis between primary and metastatic melanoma of the gallbladder, given that there are no distinctive features that allow a clear distinction. Of course, a clinical history of cutaneous melanoma is more suggestive of secondary lesions and the immunohistochemical marker HMB45 could rule out the presence of junctional activity, which is typical of the primitive tumor. However, cutaneous melanoma could have a spontaneous regression and junctional activity could be present in advanced metastatic disease as well, or it could be missing in the primitive lesion characterized by a rapid growth which makes diagnosis challenging [8, 25]. The cases reported here are suggestive of two different situations that may occur in patients with stage 4 melanoma involving the gallbladder: the former presented a widespread tumor with no symptoms, while the latter revealed an isolated metastasis associated with upper abdominal pain. The patient affected by metastases of both the gallbladder and spleen (case 1) underwent surgery despite being symptom free and the disease being widespread, in order to prevent the possible complications (rupture of the spleen and hemoperitoneum, abdominal pain). We felt that in this case, laparotomy was mandatory due to the subcapsular localization of the splenic lesion, the patient’s obesity and the dual localization of metastases, all of which would have required a change of decubitus and trocar position to allow a laparoscopic approach for both the splenic and hepatic areas. The patient with single metastasis of the gallbladder (case 2) underwent LC because we felt that the laparoscopic
approach was the best choice to avoid possible complications related to the presence of the tumor inside the gallbladder (dissemination into the gastrointestinal tract), to treat the abdominal pain and to remove the metastasis, resulting in an improvement in both quality of life and survival. Although the laparoscopic dissection of the hepatic pedicle is a demanding procedure and some authors discourage the regional node dissection for stage 4 melanoma [2, 25–27], we feel that an expert laparoscopic surgeon can safely perform this procedure in cases when metastatic involvement of the nodes is supposed, as in case 2. In conclusion, for patients with a past history of cutaneous melanoma, any lesion of the gallbladder should be accurately investigated and suspected of being metastasis. The screening for secondary lesions plays a key role in early detection and treatment of metastases, improving patients’ prognosis, survival and quality of life. Although LC may not be considered the procedure of choice for metastatic gallbladder melanoma, we believe it is a feasible therapeutic option for resectable metastasis both in patients with widespread disease, to avoid clinical manifestations and to prevent the dissemination within the gastrointestinal tract, and in those with isolated metastases, with curative intent and to improve survival. Conflict of interest
None.
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26. Kohler U, Jacobi T, Sebastian G, Nagel M. Laparoscopic cholecystectomy in isolated metastasis of malignant melanoma to the gallbladder. Chirurg. 2000;71:1517–20. 27. Varsamidakis N, Panagiotou P, Yettimis E. Isolated gallbladder metastatic melanoma. HPB (Oxford). 2006;8:73. 28. Christou D, Katodritis N, Decatris MP, et al. Melanoma of the gallbladder: appropriate surgical management and review of the literature. Clin Case Rep. 2014;2:313–8. 29. Batus M, Waheed S, Ruby C, Petersen L, Bines SD, Kaufman HL. Optimal management of metastatic melanoma: current strategies and future directions. Am J Clin Dermatol. 2013;14:179–94. 30. Tarhini AA, Kirkwood LM, Gooding WE, Cai C, Agarwala SS. Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol. 2007;25:3802–7. 31. Robert L, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26. 32. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. 33. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16. 34. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119–27. 35. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9. 36. Larkin J, Ascierto PA, Dre´no B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76. 37. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88. 38. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. 39. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.
REVIEW ARTICLE
Metastatic melanoma of the gallbladder: report of two cases and a review of the literature I. Giannini1 • D. A. Cutrignelli2 • L. Resta3 • A. Gentile3 • L. Vincenti4
Received: 25 March 2015 / Accepted: 20 April 2015 Ó Springer-Verlag Italia 2015
Abstract Melanoma is one of the most aggressive and highly metastatic cancers. The most common sites of distant metastases are soft tissues, lung, liver, skin and brain, whereas only few patients develop gastrointestinal metastases. Metastatic involvement of the gallbladder is rare and more often part of a widespread disease than a solitary lesion. The ‘‘gold-standard’’ treatment of metastatic melanoma of the gallbladder remains unclear. We report two cases of patients with past history of cutaneous melanoma who developed visceral metastases. The first patient was asymptomatic and had a widespread disease with metastatic involvement of both the spleen and the gallbladder. The second patient had an isolated metastasis of the gallbladder and complained of upper abdominal pain. The chosen treatment was open cholecystectomy (and splenectomy) in the first case and laparoscopic cholecystectomy in the second. A review of the literature is provided.
& I. Giannini [email protected] 1
General Surgery and Liver Transplantation Unit, Department of Emergency and Organ Transplantation, University ‘‘A. Moro’’ of Bari, Policlinico. Piazza G. Cesare, 11, 70124 Bari, Italy
2
Complex Operating Unit of Plastic Aesthetic and Reconstructive Surgery, Department of Emergency and Organ Transplantation, University ‘‘A. Moro’’ of Bari, Bari, Italy
3
Department of Emergence and Organ Transplantation, Institute of Pathological Anatomy, University ‘‘A. Moro’’ of Bari, Bari, Italy
4
General Surgery Unit, Policlinico of Bari, Bari, Italy
Keywords Melanoma Gallbladder metastasis Cholecystectomy Laparoscopic cholecystectomy
Introduction Melanoma is one of the most aggressive and highly metastatic types of cancer that arises from the melanocyte, a dendritic cell located above all in the basal layer of the skin, but also in the eye, the mucosa of the upper respiratory tract, the gastrointestinal tract and in normal lymph nodes [1]. Although it accounts for\5 % of all skin cancers, melanoma is responsible for the majority of the skin-related deaths, due to its high tendency to metastasize. The most common sites of distant metastases are soft tissues (50–75 %), lung (70–87 %), liver (54–77 %), skin (50–75 %) and brain [2– 5]. A small percentage of patients (from 2 to 4 %) affected by cutaneous melanoma are diagnosed with gastrointestinal metastases and the most common sites are small bowel, colon and stomach, with a low overall survival rate [6]. Metastatic involvement of the gallbladder is rare and, when present, is often part of a widespread complex of metastases with a very poor prognosis [6, 7]. In this paper, two cases of metastatic melanoma of the gallbladder are reported and a review of the literature is provided. Case 1 A 50-year-old male was admitted to our Unit with evidence at CT scan of two hyperdense lesions: one in the gallbladder and one in the spleen. Despite the radiological evidence, the patient was asymptomatic and the neoplastic markers were negative. A PET-CT scan was therefore performed that revealed increased metabolic activity in the gallbladder, but not in the spleen. In 2006, the patient underwent the surgical excision of a nodular, ulcerated melanoma of the back in a ‘‘vertical’’ growth
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phase; Breslow thickness 7 mm and Clark’s level IV. No evidence of metastases in the sentinel lymph node nor distant sites was revealed. Both laparotomic splenectomy and cholecystectomy were performed. Nodes of the hepatic pedicle appeared increased in volume and were thus removed, while the exploration of other abdominal organs did not highlight any other secondary localizations of malignancy. Macroscopically, the gallbladder showed no anomalies of the peritoneal surface and pathological examination revealed the presence of two brownish polypoid lesions in the lumen, arising from the mucosa of the fundus (2 9 1.5 cm) and of the body (1.5 9 1 cm), both referable to malignant metastatic melanoma (immunohistochemistry positive for Melan-A and HMB45) (Fig. 1). The spleen had a 6-cm subcapsular, soft, dark lesion that microscopically appeared as a poorly differentiated tumor referable to metastatic melanoma; hepatic pedicle’s nodes were free from neoplastic cells. The postoperative course was uneventful and patient was discharged on the sixth postoperative day. Unfortunately, the first oncological follow-up, 1 month after the surgical procedure, detected the presence of further metastases in the brain and pancreas. At present, 6 months after the operation, the patient is receiving radiotherapy and combined therapy with BRAF V600E (dabrafenib) and MEK inhibitors (trametinib) and is still alive 6 months after he was operated on. Case 2 In 2012, a 40-year-old female underwent a local excision of nodular melanoma in the right hemithorax (Breslow thickness 2.5 mm; Clark’s level III with no evidence of metastases in the sentinel lymph node nor distant sites).
Two years later, due to the onset of upper abdominal pain and in accordance with the oncological follow-up, an abdominal ultrasound was performed that revealed the presence of a pedunculated mass inside the gallbladder and a thickening of the wall. Neoplastic markers were within the normal range but, given the past history of malignant melanoma, the possibility of metastatic involvement of gallbladder was considered, which led to a PET/CT scan. Because an increased uptake of fluorodeoxyglucose in the gallbladder (SUV 7.5) was observed, the patient underwent a laparoscopic cholecystectomy. During the surgical procedure, the gallbladder was distended, but no abnormalities of the peritoneal surface were detected; the exploration of other abdominal organs was unremarkable. The gallbladder was removed and pulled out into an ‘‘endobag’’ to prevent the dissemination of neoplastic cells. A dissection of the hepatic pedicle nodes was also performed as they appeared macroscopically abnormal. A five-centimeter brown, pedunculated, polypoid lesion originating from the fundus was noticed once the gallbladder was opened (Figs. 2, 3). The histopathological findings were consistent with gallbladder metastasis of melanoma (immunohistochemistry positive for Melan-A and HMB45) (Fig. 4). No regional metastases were detected in the hepatic pedicle nodes. The postoperative course was uneventful, and the patient was discharged on the second postoperative day. The patient is following a strict oncological follow-up and is currently free of recurrence 6 months after the operation. The patient is receiving immunotherapy with Interferon 3000000 U. I. three times weekly.
Discussion Cutaneous melanoma represents the skin cancer with the highest mortality, although its biology is extremely unpredictable and variable, depending on the different stages.
Fig. 1 Gallbladder mucosa with thin normal papillae (bottom) merged by columnar epithelium and with foam macrophages in the stroma. Presence of large papillae (top) with preserved epithelium and invasion of the stroma by neoplastic undifferentiated cells. Dark pigment is focally present in the sub-epithelial space (H&E original magnification 9100)
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Fig. 2 Peritoneal surface of the gallbladder
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Fig. 3 Intraluminal metastasis
Fig. 4 Microscopic view of metastatic melanoma in the gallbladder wall. Undifferentiated neoplastic cells occupy the mucosal stroma and destroy the muscular layer. Dark pigment is evident among the neoplastic cells (H&E original magnification 9100)
Melanoma may arise from any mucosa containing melanocytes that migrate from the neural crest to endodermic tissue during embryogenesis [8, 9]. The frequency of this tumor is increasing worldwide: in the last 15 years, the number of cases of melanoma has virtually doubled. Each year there are approximately 100,000 new cases; in Italy 14 cases occur on average a year per 100,000 inhabitants (data AIRTUM 2009). The most important feature of the tumor is the Breslow thickness because it is directly proportional to the risk of the melanoma spreading [10–12]. Clark’s level is another staging system which describes the level of anatomical invasion of the melanoma in the skin. However, since 2002, it has been shown that Clark’s level has a lower predictive value, is less reproducible and more subjective than the Breslow thickness [13].
Melanoma can spread through the lymph system that drains into lymph nodes in the area around the primary skin melanoma and/or through the blood stream to distant sites. Distant metastatic sites include skin and soft tissues, lung, liver, brain and gastrointestinal tract [2–5, 14]. Among the gastrointestinal metastases, the most common sites are small bowel (35–67 %), colon (9–15 %) and stomach (5–7 %) [6]. The stage of the tumor is intricately related to long-term survival rate: 85–90 % of melanomas are clinically localized (stages 0–2) at the time of diagnosis, with a 5-year survival rate of more than 90 %. Conversely, the long-term survival rate of metastatic disease (stage 4) is very low with a median overall survival rate of 33 % after 1 year and 15 % after 5 years [15]. For patients with stage 4 disease, the median survival rate reported after surgery is 6–10 months and a long-term disease-free survival rate may be achieved only in a small percentage of patients [2, 6]. Isolated metastases of the gallbladder are rare and more commonly present in a widespread metastatic disease. However, among the metastatic gallbladder tumors, melanoma is the most common origin of malignancy: in fact, up to 60 % of all metastatic lesions of the gallbladder originate from a cutaneous melanoma [3, 6]. Dissemination of neoplastic cells occurs probably via the blood stream, but the gallbladder may also be involved through the implanting of these cells, carried by the bile, into the mucosa [16]. At autopsy, the gallbladder metastases occur in up to 20 % of patients who died of malignant melanoma, but are rarely reported during the patients’ lifetime because they are mostly symptom free [2, 3, 6]. When symptoms are present, the most common is upper abdominal pain resembling cholecystolithiasis; cases of hemobilia and biliary fistula have also been described [2, 8, 9, 17]. The conventional diagnostic work-up is based on abdomen ultrasonography, preferably with color–power Doppler, and CT scans that may detect the presence of an intraluminal mass; the fluorodeoxyglucose (FDG) PET/CT is a second-step investigation that could confirm the diagnosis by showing an increased uptake [6, 8, 9]. Due to the rarity of the disease, no therapeutic guidelines have yet been drawn up. A long series of patients who developed gastrointestinal metastases of cutaneous melanoma is reported by the group of the National Cancer Institute of Naples. Of these patients, 30 out of 1684 (1.7 %) developed metastases along the gastrointestinal tract, but only one of them developed an isolated gallbladder metastasis [6]. The first case of secondary melanoma of the gallbladder was reported by Henriques in 1955 [18]; since then only case reports and small case series have been described. Table 1 summarizes, to the best of our knowledge, the main English papers reporting two or more cases of
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I = isolated gallbladder metastasis; W = widespread disease; O = open cholecystectomy; L = laparoscopic cholecystectomy; CHT = chemotherapy; IT = immunotherapy; PID = patients with isolated disease; PCR = patients undergoing complete surgical resection; PNCR = patients undergoing not complete surgical resection or medical therapy; PUS = patients undergoing surgery; PNUS = patients not undergoing surgery
6 mos each 1 L; 1 O Cholecystectomy Hemitorax; back 1 upper abdominal pain; 1 asymptomatic 1 I: I W 40; 50 2015 Present paper
2
36 mos; 24 mos L Cholecystectomy Shoulder/back; unknown 1 biliary colic; 1 asymptomatic 1 I; I W 52; 60 2008 Samplaski et al. [8]
2
6 O; 3 L 9 cholecystectomy; 7 CHT; 7 IT 2007 Katz et al. [21]
13
Range 28–66
5 I; 8 W
6 asymptomatic; 7 various (not described)
7 trunk; 3 head/neck; 1 extremities, 1 vulva; 1 unknown
PUS: median l6 mos; PNUS: median 6 mos
2 PID: 110.9 mos and 165.5 mos; 6 PCR: 22.34 mos median; 11 PNCR: 6.08 mos median Not described 12 cholecystectomy; 2 cholecystostomy tube; 3 CHT (primary); 3 CHT (adjuvant): 1 IT only; 2 IT adjuvant 14 cholecystitis; 5 various (weight loss, nausea, vomiting) 1999 Dong et al. [20]
19
Mean 46.2 (range 24–68)
2 I; 17 W
12 trunk; 3 head/neck; 2 extremities; 2 unknown
10 mos; 11 mos O Cholecystectomy Face; neck 1 biliary colic; 1 symptoms of biliary obstruction 1 I; 1 W 21; 50 1979 McFadden et al. [19]
2
Symptoms I/W Patients’ age Pts Year Authors
Table 1 Main features of clinical cases reported in the English literature
Site of primary
Treatment
Open/ laparoscopy surgery
Overall survival after surgery
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cutaneous melanoma metastasized in the gallbladder which underwent surgical resection. The role of surgery in the treatment of gallbladder metastatic melanoma still remains questionable, since the majority of patients with distant metastases have widespread micro-metastatic disease even when clinical and imaging investigations suggest a limited spread [14]. However, metastasectomy continues to be the standard care for patients affected with solitary resectable melanoma metastasis to prolong their survival, and even in the presence of disseminated disease, resection of metastatic gallbladder could be a worthwhile palliative procedure to avoid clinical manifestations of the disease and to prevent further dissemination. In fact, the metastases to the gastrointestinal tract are likely to occur as a consequence of the spreading of tumor cells shed into the bile [8, 9, 22]. Dong et al. [20] reported a 100 % survival at 1 year in six patients with isolated and resectable gallbladder metastasis compared to 0 % in patients with a widespread disease. Martel et al. [23] reported a case of open cholecystectomy with an 18-month survival. Katz et al. [21] reported the experience of the Memorial Sloan-Kettering Cancer Center: 13 patients undergoing cholecystectomy for metastatic melanoma of the gallbladder with a median survival of 16 months after surgery; furthermore, authors emphasized factors associated with an improved survival rate: symptoms, isolated metastases and surgical operation. Seelig et al. [24] and Tuveri et al. [25] both reported a 20- and 60-month survival, respectively, in patients treated with laparoscopic cholecystectomy. This finding is supported by Kohler et al. [8] and by Samplaski et al. [26] who supported the suitability of laparoscopic cholecystectomy in patients with metastatic melanoma of the gallbladder. Therefore, laparoscopic cholecystectomy (LC) seems to be an adequate treatment for patients with isolated and resectable disease as the vast majority of metastatic melanoma is intraluminal and regional node dissection is not recommended for stage 4 melanoma [2, 25–27]. A very recent paper, on the contrary, encourages an open surgical approach rather than laparoscopic in order to avoid trocar recurrence and to detect other gastrointestinal metastases undetected preoperatively [28]. However, the main risks related to LC (perforation of the gallbladder and intra-abdominal bile leak and/or port sites) could be prevented with gentle dissection and use of the endobag [20, 25]. Besides surgical resection, therapies such as chemotherapy, immunotherapy and targeted therapy are current approaches, although the role of adjuvant therapies is still debated because of the scarce and disappointing data available in patients with metastatic disease [2–29]. High-dose bolus of interleukin-2 (IL-2) has proven to induce tumor remission in about 15 % of patients with
Clin Exp Med
metastatic melanoma who experienced progression after chemotherapy. However, due to its toxicity and difficulty with administration, IL-2 therapy could only be used in a small percentage of selected patients [30]. In recent years, the interest in BRAF inhibitors and immunotherapy is increasing due to the evidence of efficacy on the overall survival rate in patients with metastatic melanoma. The goal of these therapies is to stimulate the immune response against cancer [29, 31–34]. The efficacy of BRAF inhibitors has already been stated as monotherapies in patients with metastatic melanoma with BRAF V600E or V600 K mutations; however, combined therapy with MEK inhibitors (dabrafenib/trametinib and vemurafenib/cobimetinib) have shown improvement in the overall survival rate and progression-free survival without a significant increase in overall toxicity and the delay in the onset of resistance observed with BRAF inhibitors alone [35–38]. Very recently the utility of nivolumab in patients with previously untreated metastatic melanoma and without BRAF mutation has been studied: a significant improvement in the overall survival (72.9 %) and progression-free survival (5.1 months) has been described when compared to dacarbazine [39]. Another debated issue is the differential diagnosis between primary and metastatic melanoma of the gallbladder, given that there are no distinctive features that allow a clear distinction. Of course, a clinical history of cutaneous melanoma is more suggestive of secondary lesions and the immunohistochemical marker HMB45 could rule out the presence of junctional activity, which is typical of the primitive tumor. However, cutaneous melanoma could have a spontaneous regression and junctional activity could be present in advanced metastatic disease as well, or it could be missing in the primitive lesion characterized by a rapid growth which makes diagnosis challenging [8, 25]. The cases reported here are suggestive of two different situations that may occur in patients with stage 4 melanoma involving the gallbladder: the former presented a widespread tumor with no symptoms, while the latter revealed an isolated metastasis associated with upper abdominal pain. The patient affected by metastases of both the gallbladder and spleen (case 1) underwent surgery despite being symptom free and the disease being widespread, in order to prevent the possible complications (rupture of the spleen and hemoperitoneum, abdominal pain). We felt that in this case, laparotomy was mandatory due to the subcapsular localization of the splenic lesion, the patient’s obesity and the dual localization of metastases, all of which would have required a change of decubitus and trocar position to allow a laparoscopic approach for both the splenic and hepatic areas. The patient with single metastasis of the gallbladder (case 2) underwent LC because we felt that the laparoscopic
approach was the best choice to avoid possible complications related to the presence of the tumor inside the gallbladder (dissemination into the gastrointestinal tract), to treat the abdominal pain and to remove the metastasis, resulting in an improvement in both quality of life and survival. Although the laparoscopic dissection of the hepatic pedicle is a demanding procedure and some authors discourage the regional node dissection for stage 4 melanoma [2, 25–27], we feel that an expert laparoscopic surgeon can safely perform this procedure in cases when metastatic involvement of the nodes is supposed, as in case 2. In conclusion, for patients with a past history of cutaneous melanoma, any lesion of the gallbladder should be accurately investigated and suspected of being metastasis. The screening for secondary lesions plays a key role in early detection and treatment of metastases, improving patients’ prognosis, survival and quality of life. Although LC may not be considered the procedure of choice for metastatic gallbladder melanoma, we believe it is a feasible therapeutic option for resectable metastasis both in patients with widespread disease, to avoid clinical manifestations and to prevent the dissemination within the gastrointestinal tract, and in those with isolated metastases, with curative intent and to improve survival. Conflict of interest
None.
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