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An unusual indication for central pancreatectomy - late pancreatic metastasis of ocular malignant melanoma
T. Dumitrascu, Simona Dima, Carmen Popescu, D.I. Gheonea, T. Ciurea, A. Saftoiu, I. Popescu (Chirurgia, 103 (4): 479-485)

Introduction
Pancreatic metastases are considered to be rare, but can occur from a variety of primary neoplasia. A recent review examined the literature reports concluding that metastases represent about 2% of all pancreatic tumors (1), the most frequent originating sites being kidney followed by lung, breast, colon, rectum and skin (melanoma)(2, 3). A striking characteristic is the long interval between the initial diagnosis and the development of pancreatic metastasis, sometimes even after 10-15 years of evolution (4, 5).
Malignant melanoma in particular has an increasing incidence, although the mortality has leveled off (6). Most frequent metastases of malignant melanoma include the lung, liver, gastrointestinal tract, central nervous system, adrenals and extremely rare the pancreas. Malignant melanoma has a high propensity to spread to distant organs, even years after successful "curative" resection of the primary lesion. The appearance of distant metastases consequently determines a poor prognosis with a median survival of 4 to 8 months, with less than 5% of patients being alive after 5 years (7). Although experience with pancreatic resection for metastatic melanoma is limited and controversial (8), radical resection of pancreatic melanoma metastases can result in prolonged long-term survival for selected patients (6, 7, 9).
Central pancreatectomy is an alternative technique to pancreatoduodenectomy or left pancreatectomy for some neoplasms of the pancreatic body, having the main advantage to spare normal pancreatic parenchyma. Mainly, central pancreatectomy is suitable for benign pancreatic lesions, but it was also used for pancreatic metastases (10-13).
We present the case of a patient with resected ocular malignant melanoma diagnosed later with a unique pancrea-tic metastasis and two lung metastases. Initially a central pancreatectomy was performed for pancreatic metastasis and 3 weeks later an inferior right pulmonary lobectomy. At 12 months after operation the patient is asymptomatic and without clinical or imagistic signs of recurrence.

Case Report
A 43-years-old woman, with medical history of malignant ocular melanoma treated by right eye enucleation (4 years ago) followed by adjuvant chemotherapy (Cisplatin and Vinblastin) was investigated in February 2007 in the Department of Gastroenterology for fatigue, anorexia, weight loss, epigastric pain. Clinical exam was unremarkable, while the blood tests indicated normal values. Ocular examination showed no evidence of recurrent melanoma.
TUS showed a hypoechoic tumor, of approximately 20 mm, located in the neck of the pancreas, with a peripheral halo and faint vascular signals in the peripheral part. Abdominal CT scans showed the same isodense tumor with intense peripheral up-taking of the contrast and necrotic areas inside the lesion. The EUS also depicted the hypoechoic tumor, with necrotic areas inside and peripheral halo (fig. 1). However, color Doppler and power Doppler clearly showed intra-tumoral signals (fig. 2), consistent with the iodophilic nature of the tumor shown by contrast-enhanced CT. EUS-guided FNA was subsequently performed with two passes without immediate complications, and tissue material was further sent for pathology exams.

Figure 1
Figure 2
Figure 3
Figure 4

Several smears were prepared for usual cytology examinations (May-Grünwald-Giemsa and Papanicolau stains), while a cell-block was further prepared for immunohistochemical stains. Consequently, immunocytochemistry showed an intense cytoplasmatic and nuclear immunostaining for S100 inside the atypical cells (fig. 3), an intense cytoplasmatic immunostaining for HMB45 inside the atypical cells (fig. 4), as well as nuclear immunostaining for Ki67 in approximately 20% of the atypical cells (fig. 5). The diagnosis of pancreatic metastasis of malignant melanoma was thus confirmed based on the positive reaction of atypical cells for S100 and HMB45.
The diagnosis of lung metastases was done by chest radiography and thoracic contrast-enhanced CT.

Figure 5
Figure 6

The patient was further referred to Center of General Surgery and Liver Transplantation where initially a pancreatic resection was performed for pancreatic metastasis.
After an upper midline abdominal laparotomy, the lesser sac was opened by division of the gastro-colic ligament and the anterior surface of the pancreas was exposed showing a pigmented tumoral mass located in the body of the pancreas, around 1.8 / 2 cm diameters, having macroscopic characteristics of metastatic malignant melanoma (fig.6). Intraoperative exploration and ultrasound were performed in order to confirm the absence of other intraabdominal metastatic lesions. A central pancreatectomy was performed after a technique described elsewhere (12). Transection of the pancreas was done within oncological edges of at least 1 cm. The proximal pancreatic stump was closed and the distal pancreatic stump, was implanted in a Roux-en-Y limb of jejunum. One drain was placed close to the proximal pancreatic stump and one drain close to the pancreatico-jejunal anastomosis. Final pathological examination of the operative specimen confirmed the metastatic melanoma (fig. 7a, b).
The postoperative course was complicated in the first postoperative day by upper gastrointestinal hemorrhage from the distal pancreatic stump which imposed a re-laparotomy for the bleeding control. After that the patient developed a grade A pancreatic fistula (according to the International Study Group on Pancreatic Fistula definition) (14). The pancreatic fistula healed spontaneously after 2 weeks, no specific treatment being necessary.
Three weeks after central pancreatectomy, a right inferior pulmonary lobectomy was performed for the two lung metastases.
The postoperative course was uneventful, the patient being discharged on the 14th postoperative day.
The patient oncological follow-up included clinical examination, TUS, chest radiography every 3 months, CT scans at 6 and 12 months, EUS at 12 months. Endocrine function of the pancreas was also evaluated by serum glucose level, glycosylated hemoglobin, insulin and C-peptide levels (all within normal ranges).
At 12 months after operation the patient is asymptomatic with no imagistic signs of local recurrence or metastasis (fig. 8). No clinical signs of exocrine pancreatic insufficiency were recorded.

Figure 7A
Figure 7B
Figure 8

Discussion
Isolated metastases to the pancreas are rare, in most cases pancreatic involvement being associated with widespread metastatic disease (8). In patients with a pancreatic mass, a metastatic disease should be considered, especially in patients with medical history of a malignant disease (2). The diagnosis is initially suspected based on imaging studies, with TUS and CT being the most frequently used methods. Tissue confirmation of these lesions has become increasingly important for the precise diagnosis and individualized management of these patients. In most of the cases, surgical resection leads to improved long-term survival, hence precise diagnosis is imperative for the proper management of such patient (6, 7, 9, 15). However, confirmation of the metastatic origin of a pancreatic mass is not an easy task, even for experienced pathologists (16).
TUS is considered the first choice investigation in patients with clinical suspicion of pancreatic metastasis.
CT scan appearance of the pancreatic mass, with well-defined margins, higher enhancement of the lesion in the peripheral part and a central area of low attenuation is highly suggestive for the diagnosis of pancreatic metastasis from a distant cancer (17, 18). CT differentiation may be extremely difficult in patients with neuroendocrine tumors (NET) of the pancreas and patients with primary clear-cell carcinoma of the pancreas (19). Consequently, percutaneous CT-guided FNA was deemed necessary for the correct pre-operative diagnosis, although it was largely replaced by EUS-guided FNA. The main reason was the transgastric route needed for CT-guided FNA in most of the cases, associated with an increased risk of needle tract seeding or peritoneal contamination. Indeed, the only study that compared CT-guided with EUS-guided FNA showed an increased rate of peritoneal carcinomatosis in the patients with percutaneous CT-guided interventions (20). Moreover EUS-FNA has a better accuracy as compared with CT-guided FNA in order to obtain a tissue diagnosis of pancreatic masses (21).
EUS and EUS-guided FNA are particularly helpful in the preoperative management of small pancreatic masses, especially for small neuroendocrine tumors and metastatic lesions that are masquerading as primary pancreatic adenocarcinoma (19). Several case series and multicentric studies highlighted the value of EUS for the diagnosis of pancreatic metastasis (22-25). Thus, EUS features are very different as compared with pancreatic adenocarcinoma, with hypo-echopic appearance, well-defined, regular margins, usually hypervascular on color or power Doppler examinations (26). EUS-FNA is considered useful to establish a final diagnosis, through comparison of cytology from a pancreatic metastasis to previous cytology or histology from the primary or other metastatic site (22). In the same large multicentric study this was considered sufficient for a complete cytological diagnosis of a pancreatic metastasis even in the absence of confirmatory immunocytochemistry. In our case, EUS-guided FNA confirmed the origin of the pancreatic tumor as a metastasis from an ocular malignant melanoma, consequently referring the patient for surgery. Immunohistochemical examinations may be helpful in establishing the diagnosis if clinical and histomorphological features indicate the possibility of a metastasis to the pancreas (2). The most frequently used melanocytic markers in clinical practice are S-100 protein and HMB45. S-100 positive/ HMB-45 positive immuno-profile in metastatic melanoma has a sensitivity of 80% and a specificity of 100% (27).
The role of surgery in metastatic malignant melanoma is controversial. The prognostic factors that determine survival for patients with metastases to the pancreas are indeterminate, the only factor that appears to be associated with improved survival is a long disease-free interval after the treatment of primary malignancy, reflecting favorable tumor biology with a slow growth pattern (28-30). Thus, the American Joint Committee on Cancer (AJCC) considers usually surgical resection of little value for the management of stage IV malignant melanoma patients with multiple distant metastases (7). The results of chemotherapy are generally disappointing (8, 31). The survival outcome of patients with visceral metastases from melanoma is considered dismal, with a median survival of 6-12 months (7). However, nowadays surgical resection seems to be the only potentially curative treatment option, several reports of long-term survival after resection of distant melanoma metastases clearly showing the importance of surgery in carefully selected patients (3;28;29). After complete resection of the isolated metastatic melanoma to the pancreas the 5-years survival seems to be much better than in cases treated by non-operative procedures (50% vs. 9%) (7). The 5-years survival is considerably reduced in cases of multiple melanoma metastases completely resected (25%) and in cases with incomplete resection the prognosis is similar with those of untreated patients (7). Thus, incomplete surgical resection has no survival benefit, complete tumor resection being considered more important than the number of detectable metastases (7).
The type of pancreatic resection for pancreas metastasis is in accordance with number and localization. Most of the pancreatic metastases reported in the literature were surgically treated by standard pancreatectomies (pancreato-duodenectomy, distal pancreatectomy or even total pancreatectomy) (3, 7, 28-30).
Central pancreatectomy (CP) is a surgical procedure that removes the middle segment of the pancreas and preserves the distal pancreas and spleen. The indications for central pancreatectomy include mainly benign tumours located in the body of the pancreas. This limited resection has the advantage of conserving normal, uninvolved pancreatic parenchyma, thus reducing the possibility of postoperative exocrine and endocrine dysfunction. The review of the literature showed that central pancreatectomy could play o role in the treatment of metastatic lesions to the pancreas. Thus, several reports on pancreatic metastases, mainly from renal cell carcinoma, showed that central pancreatectomy can be safely performed with low morbidity and mortality rates and good oncological results (10-13, 32, 33).
The role of central pancreatectomy in the treatment of melanoma metastasis to the pancreas was not yet established, till now only one case being reported with good oncological result, the patient being alive with no signs of recurrence at 30 months after operation (10). It seems that central pancrea-tectomy does not influence the oncological outcome comparing with standard pancreatic resections (if the resection of the metastasis is complete) having the major advantage of preserving both endocrine and exocrine pancreatic functions. The main disadvantage of CP is the higher risk of postoperative pancreatic fistula comparing with standard pancreatic resections, almost 30% and over (10, 12, 33), but there are surgical centers with great experience in pancreatic surgery that reports only 7.5% rate of pancreatic fistula (13).
In conclusion, surgical resection remains the single hope for cure for these patients. Central pancreatectomy could be an optimal choice for metastatic malignant melanoma to the body of the pancreas only if a complete resection of the tumor can be achieved and can be accomplished by other surgical procedures for other sites of metastatic melanoma. The single hope for long term survival in metastatic melanoma is achievement of a complete resection of all the metastatic lesions.

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