Cervical metastases from small bowel carcinoid tumors

Small bowel carcinoid tumors usually metastasize to regional lymph nodes and the liver but metastases to the neck are extremely rare. Over a ten-year period 48 cases of small bowel carcinoid were diagnosed at our institution and of these, three cases (6%) were associated with neck metastases--one to the thyroid gland and two to cervical lymph nodes. The former patient and one of the latter patients had symptoms of the carcinoid syndrome. The other patient was asymptomatic and presented with a solitary neck mass. Urine levels of 5-hydroxyindolacetic acid (5-HIAA) were elevated in the two symptomatic patients but were undetectable in the asymptomatic patient. Extirpation of the involved cervical nodes and the primary small bowel lesion was performed in two patients. In addition, both patients have received chemotherapy with 5-fluorouracil. One patient remains asymptomatic four years after diagnosis but the other patient continues to have five to six bowel movements per day nine months after operation. Small bowel resection was performed in the patient with a metastasis to the thyroid. This patient died of sepsis after a second operation for an intraabdominal abscess. The histological patterns of the primary tumor and the metastatic lesions were similar and the cells of the metastases contained argentaffin-positive granules. We conclude that 1) an intraabdominal carcinoid tumor should be considered as the location of the primary tumor in patients who present with a neck mass containing metastatic carcinoid and 2) the prognosis for patients with extraabdominal metastases is similar to that for patients with intraabdominal disease only.     

23例恶性黑色素瘤小肠转移临床病例分析

目的：总结恶性黑色素瘤小肠转移的临床病例特点。方法：我院诊治1例,通过中国知网、万方医学网以及 MEDLINE（或 PUBMED）检索到国内外报道的黑色素瘤小肠转移病例共23例,并进行统计分析。收集一般情况、黑色素瘤原发部位、原发肿瘤至小肠转移间隔时间以及临床症状等。结果：23例（男14例,女9例）,平均年龄54.7岁,初次诊断至发现转移平均时间间隔为6.33年（0-20年）。主要临床表现为腹痛16例（69.6%）,黑便/便血7例（30.4%）,肠梗阻或肠套叠14例（60.9%）。肿瘤最大直径平均为5.82cm（2-15cm）。47.8%为小肠多发转移。结论：恶性黑色素瘤小肠转移主要临床表现为腹痛、黑便,易于发生肠梗阻或肠套叠;肿瘤常多发转移,且发现小肠转移距初次诊断时间间隔较长。     

Unknown primary melanoma

Of 230 melanoma patients treated during the past 8 years, 12 (5.2%) were found to have unknown primary lesions. Nine of these "unknown primary melanoma' patients presented with metastases in regional lymph nodes, one inside the parotid gland, and two presented with disseminated melanoma and no detectable primary tumor. The patients with melanoma confined to a regional lymph node underwent block dissection followed by adjuvant chemotherapy and immunotherapy. Four patients with metastasis in only one lymph node are disease free 4-6 years after diagnosis. One patient with multiple metastases in the groin is alive 8 years after lymphadenectomy. The other five patients with metastases in multiple regional lymph node died 16 months to 3 years after surgery. Both patients with disseminated melanoma succumbed to their disease within a month of diagnosis. The prognosis of unknown primary melanoma seems to be no worse than the typical melanoma at the same stage. This justifies the aggressive surgical approach to this unusual entity of melanoma.     

Long-term survival of metastatic melanoma to the ileum with evidence of primary cutaneous disease after 15 years of follow-up: a case report

The small bowel is the most common site of gastrointestinal metastasis from cutaneous melanoma. Malignant melanoma has a poor prognosis, especially if distant metastases appear. Although rare primary melanoma of the small bowel has been described, more frequently these lesions originate from unknown cutaneous melanoma. Here we report the case of a 58-year-old man with a diagnosis of melanoma of the ileum without evidence of primary cutaneous disease. After 15 years, during the clinical and radiological follow-up, a cutaneous melanoma in the left parietal side of the scalp, probably corresponding to the primary lesion with abdominal node metastasis, was diagnosed. After 6 months of chemotherapy with fotemustine, the patient showed a complete response. At present, he is still alive 18 years after the diagnosis of intestinal metastasis.     

Late recurrence of stage I malignant melanoma

Although the introduction of well-established risk factors has made the clinical course and prognosis of malignant melanoma disease much more predictable, in a considerable number of patients the disease's course is still not as expected. One group to which this applies are stage I melanoma patients who develop metastatic disease after 10 years or more of a disease-free interval. In our series of 94 such patients, 6 developed late relapse of their disease. The subsequent survival of these patients did not relate to any of the primary tumors' characteristics, but to the pattern of the late recurrence. Four patients with visceral metastases were dead within 1 to 5 years following relapse, one patient with lymph node involvement is alive with metastases, and another patient with skin metastases has no signs of disease following surgery and immunotherapy. Our conclusion is that malignant melanoma patients should be placed under close follow-up for the rest of their lives.     

Symptomatic gastrointestinal metastases from malignant melanoma

Twenty-two patients with symptomatic metastases to the gastrointestinal tract from malignant melanoma who presented to the Roswell Park Memorial Institute during the past 12 years were reviewed. Sixteen of 22 patients underwent abdominal surgery and most received satisfactory palliation. Of the six patients who were considered unsuitable for surgery, two died from perforation of the small bowel. The group had a median survival of 2.2 months. Thirteen patients with symptomatic intestinal metastases had a median survival of 4.5 months following resection of the involved portion of the intestine. One of these patients remains well, and free of disease 15 months later, and two lived more than 33 months after the surgical procedures.     

Hyperthermic isolated regional perfusion of the limb with carboplatin

AIMS: To investigate the feasibility of hyperthermic isolated regional perfusion (HIRP) with carboplatin in the management of locally recurrent and/or intransit metastases of melanoma or locally advanced soft tissue sarcoma. METHODS: Three patients, two with locally advanced melanoma and one with a low-grade liposarcoma of the lower extremity, were treated with HIRP under mild hyperthermia (39-40 degrees C) with 125 mg carboplatin/l perfused limb volume. RESULTS: No systemic toxicity was observed. Local toxicity consisted of post-perfusion oedema present in all three patients which resolved within 2 weeks. Clinically, a persistent local neuropathy was observed in all three patients, two of which were confirmed by electromyogram and nerve conduction study. Severe motor-sensory neuropathy was located mainly in the peroneal and sural nerves of the perfused limbs. Pharmacokinetic parameters of the carboplatin showed a higher concentration of carboplatin in the skin compared to the muscle. The two melanoma patients showed a complete response but developed local recurrences within 1.5 years after perfusion. The third patient underwent a delayed excision of the sarcoma 8 weeks after perfusion which revealed 50% viable tumour. One of the melanoma patients and the sarcoma patient died from lung metastases 56 and 31 months post-perfusion treatment, respectively. The other melanoma patient is alive 95+ months post-perfusion treatment. CONCLUSIONS: The local neurotoxicity observed did not warrant further research of carboplatin in HIRP.     

T cells in the human metastatic melanoma microenvironment express site‐specific homing receptors and retention integrins

T‐cell infiltration into the metastatic melanoma microenvironment (MME) correlates with improved patient survival. However, diffuse infiltration into tumor occurs in only 8% of melanoma metastases. Little is known about mechanisms governing T‐cell infiltration into human melanoma metastases or about how those mechanisms may be altered therapeutically. We hypothesized that T cells in the MME would be enriched for chemokine receptors CCR4, CCR5, CXCR3 and homing receptors relevant to the tissue site. Viably cryopreserved single cell suspensions from nineteen melanoma metastases representing three metastatic sites (tumor‐infiltrated lymph node, skin and small bowel) were evaluated by multiparameter flow cytometry and compared to benign lymph nodes and peripheral blood mononuclear cells from patients with Stage IIB–IV melanoma. T cells in the melanoma metastases contained large effector memory populations, high proportions of activated, moderately differentiated cells and few regulatory T cells. Site‐specific homing was suggested in bowel, with high expression of CCR9. We neither encounter the anticipated enrichment of integrin α4β7 in bowel, cutaneous leukocyte antigen (CLA) in skin, nor integrin α4β1 or receptor CXCR3 in metastatic sites. Retention integrins αEβ7, α1β1 and α2β1 were significantly elevated in metastases. These data suggest limited tissue site‐specific homing to human melanoma metastases, but a significant role for retention integrins in maintaining intratumoral T cells. Our findings also raise the possibility that T‐cell homing, infiltration, and retention in melanoma metastases may be increased by increasing expression of ligands for CLA, α4β1 and CXCR3 on intratumoral endothelium.     

Surgical treatment of melanoma metastases to the small bowel: A single cancer referral center real-life experience

IntroductionTreatment of metastatic melanoma has rapidly changed during the last years, and patients often require a multidisciplinary approach to achieve effective results. We aimed to assess the survival benefit achieved through surgical approach to patients with small bowel (SB) metastases from cutaneous melanoma, to emphasize the potential role of surgery in association with novel therapies.MethodsNinety consecutive patients with cutaneous melanoma diagnosed as having resectable SB metastases from 1995 to 2015 were retrospectively investigated.ResultsMedian age at surgery of melanoma metastases was 53.4 years. Among 30 patients who had a curative-intent resection, the 5- and 10-year survival rates were 61% and 54%, respectively, while among 60 patients treated with a palliative surgery the corresponding rates were both 4%. Among 29 patients, for whom the interval time between the occurrence of SB metastases and the previous surgical event on GI tract was ≥36 months, the 5-year overall survival rate was 42%; for 56 patients who had an interval time <36 months the corresponding survival rate was 14%. Within the whole series, an absence of any residual disease after surgery (R0) was a factor affecting better survival, regardless of the evidence of metastases in other organs.ConclusionOur observational data showed that surgical treatment for patients with SB metastases from melanoma might increase survival, but further studies are needed to confirm this finding. In the age of novel available therapies, the increase in survival time given by surgery may offer important chances for patients to benefit from systemic therapies.     

Alveolar soft part sarcoma metastatic to small bowel mucosa causing polyposis and intussuseption

A report of alveolar soft part sarcoma metastatic to the small bowel is presented. Hematogenous metastases to the small bowel from primary tumors outside the abdominal cavity are uncommon, and most remain asymptomatic and are not discovered until autopsy. However, small bowel metastases can lead to intestinal obstruction, intussuseption or even perforation. While metastases to the small bowel have been described for other tumor types, including melanoma and lung cancer, this is extremely uncommon for sarcoma, especially alveolar soft part sarcoma. We describe a 42-year-old male with a long history of alveolar soft part sarcoma, metastatic to the lung and brain, who developed an intussuseption from metastases to the small bowel.     

Evaluation of human lymphoblastoid interferon in advanced malignant melanoma

Seventeen patients with metastatic disease from malignant melanoma received treatment with injections of Human lymphoblastoid interferon. Fifteen of these had the drug by intramuscular injections. One started treatment by the intramuscular route but later proceeded with slow intravenous infusions. The remaining patient had interferon injected into the tumor only. With one exception, all patients had been pretreated with other methods for advanced regional or blood-borne metastases. A partial response (UICC criteria) lasting six months was seen in one patient who was treated with intramuscular injections for intransit cutaneous metastases in one leg. Human lymphoblastoid interferon appears to have minimal activity relating only to skin metastases in advanced and previously treated malignant melanoma. This activity is not superior to existing treatments.     

Surgery for melanoma metastases of the gastrointestinal tract: Indications and results

Aim

To assess survival, morbidity and mortality following therapeutic or palliative resection of gastrointestinal (GI) tract melanoma metastases.

Methods

A retrospective case series of 117 patients who underwent surgical resection of GI melanoma metastases between 1981 and 2005 was reviewed.

Results

The 117 patients underwent 142 operations for acute and/or sub-acute symptoms or for imminently symptomatic GI metastases detected radiologically. The intent of the surgery was palliative in 53 (37.3%) and therapeutic in 89 (62.7%) operations. The most common symptoms were due to anaemia (40.8%) or bowel obstruction (32.4%). The most frequently performed operation was small bowel resection (76.8%). Preoperative imaging and/or endoscopy were used in 83 cases, with computerised tomography (CT) being most frequent (85.5%). CT had a sensitivity of 68.8% when used alone to detect the presence of GI metastases in the study population. The mortality rate following GI resection was 1.4%, and 2.5% of patients had post-operative complications. Overall 5-year survival was 27%. On multivariate analysis, the presence of residual intraabdominal disease and the presence of non-GI metastases at the time of surgery or after surgery were the most significant prognostic indicators of survival.

Conclusions

Resection of GI melanoma metastases is safe, relieves symptoms and can achieve prolonged remission. In patients with limited disease, an aggressive surgical approach to symptomatic or imminently symptomatic GI melanoma metastases is warranted.     

Conservative surgical management of superficially invasive cutaneous melanoma

Between 1976 and 1980, 136 patients were evaluated for primary treatment of cutaneous melanoma. Forty-nine lesions were invasive to Clark's Level II (38 patients) or III (11 patients) with a thickness of 0.3 to 1.2 mm. Conservative re-excision was advised as definitive therapy for these patients. The margin of resection was defined as the maximum excision that would allow primary closure of the wound. Pathology reports of the re-excised specimens revealed the narrowest margins to be 0.7 to 4 cm. Unexpected residual tumor was present in 2 specimens and melanocytic hyperplasia in 12 specimens. After a follow-up period of 2.5 to 7.0 years, there have been no local recurrences. One patient developed regional lymph node metastases 16 months and, then central nervous system (CNS) metastases 25 months after primary treatment. A second patient died with pulmonary metastases 4.5 years after initial therapy. Melanomas that are not deeply invasive do not require wide excision and skin grafting for local control. Occasionally these thin lesions do produce systemic metastases, emphasizing the need for long-term follow-up of even "low-risk" patients.     

Treatment of locoregional metastases of malignant melanomas with radiotherapy and intralesional beta-interferon injection

Intralesional injection of beta-interferon can lead to remission of metastatic melanomas. Simultaneous radiotherapy may augment the effect of these injections. The effect of intralesional beta-interferon injections combined with radiotherapy was examined in patients with metastatic malignant melanoma. A total of 20 patients with inoperable, incapacitating and disfiguring malignant melanoma metastases were treated with simultaneous external beam radiotherapy (electrons and/or photons) and intralesional injection of beta-interferon. The total radiation dosage ranged from 40-50 Gy, fractionated as 1.8 Gy five times per week. beta-Interferon (Fiblaferon) 3-5 million units per injection was administered three times weekly until symptoms disappeared or until termination of therapy. One patient was treated with beta-interferon alone; the area harbouring the tumour had been previously irradiated. Five patients treated in this way showed partial remission after combined therapy and 12 showed complete remission, with permanent regression of metastases. The latter group included five patients with lengthy survival times, including one patient who has been free of symptoms for 7 years following treatment. Injected metastases showed complete regression in the patient who was treated exclusively with beta-interferon post-irradiation. In conclusion, combined treatment with radiotherapy and intratumoral injection of beta-interferon controlled local tumour growth in inoperable metastatic malignant melanomas.     

Artesunate in the treatment of metastatic uveal melanoma--first experiences

Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future.     

Regression of advanced melanoma upon withdrawal of immunosuppression: case series and literature review

We report two cases of stage IV malignant melanoma arising in patients treated with azathioprine for myasthenia gravis. In both cases, the melanoma metastases regressed upon withdrawal of immunosuppression. One patient remains melanoma free at 10 years, and the second patient experienced an 18-month disease free period. There is one prior case report in the medical literature to support full immune reconstitution for treatment in advanced immunosuppression-related melanoma, and one case series suggesting that transplant patients developing melanoma may benefit from a switch to sirolimus. Virtually, no data exist for the medical management of early stage melanoma in the immunosuppressed patients. We review the limited preclinical data in support of immune reconstitution and the data on immunosuppression as a risk factor for melanoma. We conclude that reduction or withdrawal of immunosuppression may be beneficial in patients with advanced stage melanoma and warrants further consideration in patients with early stage melanoma.     

Surgical approach to malignant melanoma in the gastrointestinal tract

The gastrointestinal (GI) tract is a common site for malignant melanoma. Diagnosis of lesions in the GI tract is usually delayed until complications occur, such as obstruction, bleeding, or perforation of the GI tract. Of 348 patients with malignant melanoma treated during a 10-year period, 11 had GI involvement either in a metastatic form or as a primary melanoma. Three of these patients were treated surgically for metastatic lesions in the small bowel causing intussusception, two for peritonitis secondary to perforation of the small bowel, and one for massive bleeding from metastatic melanoma in the stomach. Another patient had a primary melanoma in the esophagus and underwent esophagectomy. Three patients had primary melanomas of the anal canal and one of the rectum. Three of them underwent abdominoperineal resections, and two had bilateral groin dissection in addition. Six of the patients are alive 6 months to 4 years following diagnosis. The remaining five died of metastatic melanoma from 6 months to 4 years post-surgery.     

Preoperative nuclear scans in patients with melanoma

One hundred forty-one liver scans, 137 brain scans, and 112 bone scans were performed in 192 patients with clinical Stage 1 melanoma. One liver scan was interpreted as abnormal; liver biopsy of that patient showed no metastasis. There were 11 suggestive liver scans; three of the patients with suggestive liver scans had negative liver biopsies. The remaining eight patients were followed from 4 to 6 years and none of those patients developed clinical evidence of hepatic metastases. All of the brain scans were normal. Five patients had suggestive bone scans and none of those patients had manifested symptoms of osseous metastases with a follow-up of 2 to 4.5 years. This study demonstrates that the use of preoperative liver, brain and bone scan in the evaluation of patients with clinical Stage 1 melanoma is virtually unproductive.     

Central Nervous System Metastases of Cutaneous Malignant Melanoma: A Population-based Study

The objectives of this population-based study were to assess putative prognostic factors for central nervous system (CNS) metastases among patients with cutaneous malignant melanoma, to assess the cumulative risk of CNS metastases in different subsets of patients with recurrent disease, and to describe patient outcome. At a median follow-up of 11 years, 201/2516 patients with melanoma had developed CNS metastases, corresponding to a cumulative risk at 5 years of 7%. In 41 of these 201 patients the CNS metastases were recorded as the first site of recurrence. In a Cox's multivariate model, primary tumor thickness and ulceration in stage I patients were independent risk factors. The cumulative rates of incidence of CNS metastases 5 years after local or regional recurrence as first event were 5 and 42%, respectively. These results may help to form an individually based risk assessment, which might be of value for melanoma patients in certain occupations.     

Prognostic factors for survival in melanoma patients with brain metastases

BACKGROUND:

One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS).

METHODS:

An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS.

RESULTS:

Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded.

CONCLUSIONS:

The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials. Cancer 2011. © 2010 American Cancer Society.