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The orderly progression of melanoma nodal metastases

ObjectiveThe aim of this study was to determine the order of melanoma nodal metastases. Summary Background DataMost solid tumors are thought to demonstrate a random nodal metastatic pattern. The incidence of skip nodal metastases precluded the use of sampling procedures of first station nodal basins to achieve adequate pathological staging. Malignant melanoma may be different from other malignancies in that the cutaneous lymphatic flow is better defined and can be mapped accurately. The concept of an orderly progression of nodal metastases is radically different than what is thought to occur in the natural history of metastases from most other solid malignancies. MethodsThe investigators performed preoperative and intraoperative mapping of the cutaneous lymphatics from the primary melanoma in an attempt to identify the “sentinel” lymph node in the regional basin. All patients had primary melanomas with tumor thicknesses > 0.76 mm and were considered candidates for elective lymph node dissection. The sentinel lymph node was defined as the first node in the basin from which the primary site drained. The sentinel lymph node was harvested and submitted separately to pathology, followed by a complete node dissection. The null hypothesis tested was whether nodal metastases from malignant melanoma occurred in equal proportions among sentinel and nonsentinel nodes. ResultsForty-two patients met the criteria of the protocol based on prognostic factors of their primary melanoma. Thirty-four patients had histologically negative sentinel nodes, with the rest of the nodes in the basin also being negative. Thus, there were no skip metastases documented. Eight patients had positive sentinel nodes, with seven of the eight having the sentinel node as the only site of disease. In these seven patients, the frequency of sentinel nodal metastases was 92%, whereas none of the higher nodes had documented metastatic disease. Nodal involvement was compared between the sentinel and nonsentinel nodal groups, based on the binomial distribution. Under the null hypothesis of equality in distribution of nodal metastases, the probability that all seven unpaired observations would demonstrate that involvement of the sentinel node is 0.008.

Detection of Submicroscopic Lymph Node Metastases with Polymerase Chain Reaction in Patients with Malignant Melanoma

BackgroundThe presence or absence of lymph node metastases in patients with malignant melanoma is the most powerful prognostic factor for predicting survival. If regional nodal metastases are found, the 5-year survival for the patient decreases approximately 50%. If the presence or absence of regional nodal metastases will determine which patients receive formal dissections or which patients enter adjuvant trials, then a technique is needed to accurately screen lymph node samples for occult disease. Routine histopathologic examination routinely underestimates the number of patients with metastases. This study was initiated to develop a highly sensitive clinically applicable method to detect micrometastases by examining lymph nodes for the presence of tyrosinase messenger RNA (mRNA). The hypothesis was that if mRNA for tyrosinase is found in the lymph node preparation, that finding is good evidence that metastatic melanoma cells are present. MethodsThe assay is accomplished using the combination of reverse transcription and double-round polymerase chain reaction (RT-PCR). The amplified samples are examined on a 2% agarose gel and tyrosinase cDNA is seen as a 207 base pair fragment. Lymph node preparations from 29 patients who were clinically stage I and II and undergoing elective node dissections were analyzed both by standard pathologic staining and RT-PCR. ResultsEleven of 29 lymph node (38%) samples from 29 patients with intermediate thickness melanoma were pathologically positive. Nineteen of the 29 lymph node preparations (66%) were RT-PCR-positive, and these included all of the pathologically positive samples, so that the false-negative rate was 0. In a spiking experiment, one SK-Mel-28 melanoma cell in a background of one million normal lymphocytes could be detected, thus indicating the sensitivity of this method. In addition, analysis by restriction enzyme mapping showed that the amplified 207-bp PCR product produced is part of the tyrosinase gene sequence.

Pathologic examination of the sentinel lymph node in malignant melanoma.

Sentinel lymphadenectomy is gaining increasing popularity in the staging and treatment of patients with melanoma at risk for metastases. As a result, pathologists are encountering these specimens more frequently in their daily practice. The pathologic status of the sentinel lymph node is pivotal to the patients care because it provides staging information that dictates the need for further therapy, and therefore detailed pathologic assessment is warranted. A standard pathology protocol to handle these nodes has been developed at our institution and involves complete submission of all tissue with routine use of immunohistochemical staining for S-100 protein. By using this protocol, 838 sentinel lymph nodes from 357 patients have been examined, and metastases were found in 16% of patients. Although the metastasis was clearly seen on sections stained with hematoxylin and eosin in 55% of the positive patients, the immunostain showed metastatic disease not appreciable on initial hematoxylin and eosin screening in an additional 28 lymph nodes (45% of node-positive patients). Intraoperative touch preparation cytology may be used as an adjunct technique in sentinel lymph nodes grossly suspicious for metastatic disease. This technique has been performed on 23 sentinel lymph nodes, with no false positives and an overall sensitivity of 62%. The thorough pathologic evaluation of sentinel lymph nodes in patients with malignant melanoma requires complete submission of all tissue, routine use of immunohistochemistry, and touch preparation cytology in selected cases.

Lymphoscintigraphy in malignant melanoma

The development and rationale for the use of lymphoscintigraphy in the preoperative evaluation of patients with malignant melanoma being considered for elective lymph node dissection is reviewed. This overview is updated by an analysis of 135 patients with early stage malignant melanoma involving the head, neck, shoulders, and trunk at Moffitt Cancer Center and Research Institute at the University of South Florida (Tampa, FL). High discordancy rates (overall, 41%) were seen between drainage patterns predicted from historical anatomical guidelines and those revealed by the lymphoscintigraphic examination. The high discordancy rate was most pronounced in the head (64%) and the neck (73%). Surgical management was changed in 33% of the patients, overall. A preoperative lymphoscintigram is recommended for all patients with melanoma with head, neck, and truncal lesions evaluated for elective lymph node dissection as the lymphatic drainage patterns are often unpredictable and variable.

The use of lymphoscintigraphy in melanoma of the head and neck

Lymphoscintigraphy has been shown to be of assistance in defining the lymphatic drainage pattern of melanoma. In this study, lymphoscintigraphy was performed on 25 patients with primary melanoma (stages I and II at diagnosis) of the head and neck to determine whether the lymphatic drainage seen on lymphoscintigram was the same as the surgeons expected lymphatic drainage. The lymphoscintigrams were discordant in 21 of the patients (84 percent) with drainage to a lymphatic basin not predicted clinically. Based on the discordant lymphoscintigram, a change in surgical therapy occurred in 13 of 21 patients (62 percent). Of the 25 patients, 18 underwent prophylactic node dissections and 7 did not. Of the nodal basins removed, 27 of 38 nodal bases (71 percent) were seen on lymphoscintigraphy. Melanoma metastatic to lymph nodes was removed from nodal basins identified by the lymphoscintigram, but not predicted clinically, in two patients (8 percent). Historical anatomical patterns of lymph drainage and the clinical impression of experienced surgeons cannot reliably predict the pattern of lymphatic drainage in patients with melanoma of the head and neck.

Accurate Nodal Staging of Malignant Melanoma.

The incidence of malignant melanoma is increasing at a faster pace than that of any other cancer in the United States. It is estimated that people born in the year 2000 will have a 1:75 risk of developing melanoma sometime during his or her lifetime. Stimulated by novel lymphatic mapping techniques, the surgical care of the melanoma patient is evolving toward more conservative resections that can provide the same staging information but without the added morbidity of more radical surgeries. This approach promises to yield positive results in the age of health care reform, outcome measurements, and cost:benefit considerations.

Metastatic melanoma with an unknown primary.

An infrequent initial presentation for malignant melanoma is the diagnosis of metastatic disease without a history of an obvious primary lesion. Confusion exists in the literature concerning the workup, treatment, and prognosis of the unknown primary melanoma. A retrospective, computer-aided chart review of 580 consecutively registered patients with melanoma at the University Treatment Center (Tampa, FL), identified 18 patients with an unknown primary presentation. There were 10 males and 8 females with a mean age of 38.4 years. Ninety-four percent of the patients were diagnosed with metastatic disease in a nodal basin, whereas 1 patient had a resected isolated lung mass as the initial presentation. In the patients who presented after having a biopsy of a single positive node for diagnosis, more disease was recovered in the nodal basin with a formal node dissection in 59% of the patients. Actuarial survival curves were constructed for the group with unknown primary melanoma. As a control population, survival curves were constructed of the subpopulation of patients with melanoma who had a known primary and had stage III (regional nodal disease) at diagnosis. There was no difference in survival between those with known and unknown primary melanoma (p = 0.96).

Parotid selective lymphadenectomy in malignant melanoma.

Malignant melanoma of the head and neck can metastasize to lymph nodes within the parotid gland. Selective lymphadenectomy is the modern method of staging regional lymph node basins in clinically localized melanoma. This procedure involves intraoperative lymphatic mapping and directed, selective removal of the first draining nodes or sentinel lymph nodes (SLNs). Historically, the assessment of parotid lymph nodes would involve a superficial parotidectomy with facial nerve dissection. Since 1993, 28 patients with localized melanoma of the head and neck have demonstrated lymphatic drainage to parotid lymph nodes on preoperative lymphoscintigraphy. The overall success rate of parotid selective lymphadenectomy is 86% (24 of 28 patients). Of the 28 patients, there were 6 early patients in whom blue dye alone was utilized intraoperatively, and the success rate is 50% (3 of 6 patients). When blue dye and radiocolloid mapping techniques are combined, the parotid selective lymphadenectomy is successful in 95% of patients (21 of 22 patients). Four of the 24 patients (17%) had metastases to the SLNs and underwent therapeutic superficial parotidectomy and/or modified radical neck dissection. After completion of the therapeutic superficial parotidectomy, 1 of the 4 patients was found to have an additional parotid (nonsentinel) node with melanoma metastases. None of the patients incurred injury to the facial nerve by parotid selective lymphadenectomy. To date, 2 of 28 patients (7%) have had regional recurrence to the parotid gland. Failure of the SLN technique may occur when blue dye alone is used, when human serum albumin (not sulfur colloid) is the radiocolloid, when prior wide excision and skin graft is present before lymphatic mapping, and when all SLNs are not retrieved. We conclude that parotid selective lymphadenectomy is a safe and reliable alternative to superficial parotidectomy for staging clinically localized melanoma of the head and neck.

Chronic pressure ulcer carcinomas

Carcinomas arising from chronic pressure ulcers, Marjolins ulcers, are an uncommon occurrence. They are virulent cancers that require aggressive surgical treatment. We present 3 such cancers including the first report of a squamous cell carcinoma arising in a distal extremity pressure ulcer. Carcinomas arising in chronic pressure ulcers behave more aggressively than other types of Marjolins ulcers and, therefore, they need to be treated more aggressively. Extensive surgical excisions with wide surgical margins are necessary and elective lymph node dissections should be considered for optimal therapy.

The Evaluation of Putative Tumor Markers for Malignant Melanoma

Biomarkers have long held out the promise that malignancies might be diagnosed early and that patients could be monitored more confidently during their clinical course to more reliably predict recurrence and the effect of therapy. Reliable tumor markers have been described for colon carcinoma, hepatomas, and other tumors, but no reliable marker has been identified to monitor the course of malignant melanoma. Recently, the plasma level of lipid-bound sialic acid (LASA-P) has been described as reflecting an alteration in the surface membrane of cancer cells. An attempt was made to correlate the LASA-P level, along with the serum level of neuron-specific enolase, a glycolytic enzyme specific to cells of neuroectoderm origin including melanocytes, with clinical disease activity with a follow-up to at least 2 years. Two hundred seventy patients had blood samples drawn at various times during their clinical course for assay of LASA-P and neuron-specific enolase. Eighty of the patients (30%) sampled developed a recurrence sometime during their clinical course, whereas another 10 patients had active disease noted at diagnosis with evaluative tumor markers. The sensitivity and specificity of neuron-specific enolase was 27% and 77%, respectively, and cannot be recommended as a marker for melanoma. LASA-P showed a sensitivity of 65%, with 55 patients recurring and having active disease with abnormally high markers and 35 patients recurring or having active disease with normal markers. Specificity of the LASA-P test was 76%. When recurrence was associated with elevated LASA-P levels, the elevated level preceded recurrence by a median of 9.3 months. LASA-P may be a useful marker to follow patients with malignant melanoma.