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Desmoplastic and neurotropic melanoma
Analysis of 33 patients with lymphatic mapping and sentinel lymph node biopsy
Article first published online: 15 DEC 2003
Copyright © 2003 American Cancer Society
Volume 100, Issue 3, pages 598–604, 1 February 2004
How to Cite
Su, L. D., Fullen, D. R., Lowe, L., Wang, T. S., Schwartz, J. L., Cimmino, V. M., Sondak, V. K. and Johnson, T. M. (2004), Desmoplastic and neurotropic melanoma. Cancer, 100: 598–604. doi: 10.1002/cncr.11947
Fax: (734) 936-2756
- Issue published online: 20 JAN 2004
- Article first published online: 15 DEC 2003
- Manuscript Accepted: 4 NOV 2003
- Manuscript Revised: 30 OCT 2003
- Manuscript Received: 5 JUN 2003
- sentinel lymph node biopsy;
Desmoplastic and neurotropic melanoma (DNMM) occasionally metastasizes to regional lymph nodes and extranodal sites. The value of sentinel lymph node biopsy (SLNB) has not been demonstrated clearly for patients with DNMM. The authors report on the utility of SLNB in the management of patients with DNMM.
The authors identified 33 patients with DNMM who were seen during a 5-year period in their institution who underwent lymphatic mapping and SLNB. Clinical and histopathologic data were reviewed.
Thirty-three patients with DNMM underwent SLNB (mean Breslow depth, 4.0 mm; median, 2.8 mm). There were 25 male patients and 8 female patients with a median age of 61 years (range, 31–86 years). Fifty-two percent of tumors presented in the head and neck region, and 24% were associated with lentigo maligna. Four of 33 patients (12%) without clinical evidence of metastatic disease who underwent SLNB had at least 1 positive sentinel lymph node. No additional positive lymph nodes were found in subsequent therapeutic regional lymphadenectomy in any of these four patients.
SLNB detected subclinical metastases of DNMM to regional lymph nodes. SLNB at the time of resection can provide useful information to guide early treatment and, coupled with lymphadenectomy in positive patients, may limit tumor spread and prevent recurrence at the draining lymph node basin. Cancer 2004. © 2003 American Cancer Society.
In 1971, Conley et al. described an uncommon and distinct variant of melanoma that often presented as a hard, subcutaneous tumor of fibrous appearance deep to a primary, superficial, melanotic lesion.1 These bulky tumors generally were located in the head and neck region, often beneath lentigo maligna. The tumors were highly malignant, stubbornly recurring, and often metastasizing neoplasms. In their seminal study, those authors observed regional lymph node metastases in 3 of 7 patients (42%), pulmonary metastases in 4 of 7 patients (57%), and death related to disseminated disease in 4 of 7 patients (57%). The authors proposed the term desmoplastic malignant melanoma for this unusual variant of spindle cell melanoma accompanied by dense fibrosis. Eight years later, Reed and Leonard observed that spindle cell melanomas with a dominant neuroid appearance and neurotropism often also manifested desmoplasia, and those authors suggested that neurotropic melanoma is best considered a variant of desmoplastic melanoma.2 In their study of desmoplastic and neurotropic malignant melanoma (DNMM), Reed and Leonard noted regional lymph node metastases in 2 of 16 patients (12.5%), pulmonary metastases in 1 of 16 patients (6%), and death related to disease in 9 of 16 patients (56%). Other investigators have observed similar behavior and metastatic rates for DNMM.3–10
In patients with DNMM without clinical evidence of regional lymph node involvement, there is general consensus that combined lymphatic mapping and sentinel lymph node biopsy (SLNB) is the most appropriate strategy for obtaining staging information.3, 4, 11–13 SLNB detects early metastases to regional lymph nodes in a variety of malignancies.14–23 Given the low rate of associated morbidity and complications,24 SLNB seems an ideal staging tool for these tumors. However, to our knowledge to date, the results reported in the literature have suggested that the use of SLNB may not be reliable for DNMM. Indeed, in 4 recent studies involving a total of 62 patients with DNMM who underwent SLNB, only 1 patient was diagnosed with a positive sentinel lymph node (SLN).4, 11–13 Given the infrequent involvement of SLNs by DNMM, could SLNB lack sensitivity in detecting lymph node metastasis for this tumor type? Or is SLNB a sensitive technique with a low yield because DNMM does not spread preferentially to lymph nodes? Should a staging SLNB be performed at all for patients with DNMM? To address these important questions, we reviewed our experience with DNMM and the results of SLNB for this tumor type.
MATERIALS AND METHODS
We searched the clinical data base of the University of Michigan Multidisciplinary Melanoma Clinic for all patients with DNMM who underwent SLNB from October, 1997 to October, 2002. Clinical data and histopathologic material were reviewed on all patients. At our institution, indications for SLNB are clinically localized melanoma ≥ 1.0 mm Breslow depth or clinically localized melanoma ≤ 1.0 mm with other potentially adverse features, such as ulceration and extensive vertical regression to at least 1.0 mm in depth. Young patients with tumors exhibiting a high mitotic rate (> 1 per mm) also are counseled regarding SLNB. Contraindications for SLNB include poor health/high surgical risk and the presence of suspected palpable lymph node and/or distant metastatic disease.
The procedures for lymphatic mapping and SLNB used in our institution are similar to those described previously.14–16, 23 Briefly, 1 mCi of unfiltered Tc99m-sulfur colloid is injected intradermally at 4 points around the primary tumor site 2–4 hours prior to surgery. Dynamic imaging is performed on the neck, axillary, and groin regions to localize the SLN(s). The patient is then brought to the operating room, where 1–2 cc of Lymphazurin blue dye (isosulfan blue) are injected intradermally around the primary tumor site. After induction of general anesthesia, the surgical sites are prepared, sterilized, and draped. In vivo tracer counts of the primary tumor site and lymph node basins are measured with a hand-held γ probe. An incision is made in the lymph node basin(s) showing increased radioactivity, within the confines of a putative radical lymphadenectomy incision. All blue-stained, hot lymph nodes (defined as in vivo tracer counts > 100 cpm above background or 10% of the cpm of the hottest detected lymph node, whichever was less) are identified and removed. After harvesting SLNs, the primary tumor site is excised with 1–2-cm margins. All tissues are submitted in 10% buffered formalin for histopathologic evaluation.
Primary tumor specimens were processed routinely in the histology laboratory. SLNs were sectioned serially into 2–3-mm-thick sections and embedded in paraffin. Two serial, 5-μm sections of each SLN tissue block were stained with hematoxylin and eosin (H&E) for routine histologic examination. To confirm metastatic disease identified on H&E-stained sections or detect occult metastases, a 5-μm section of each SLN block was immunostained for S-100 protein (1:500 dilution; Dako Corporation, Carpinteria, CA) and for melan-A (1:12.5 dilution; Dako Corporation).
Patients with at least one positive sentinel lymph node were offered regional lymphadenectomy. All lymph nodes retrieved from the lymphadenectomy specimen were sectioned serially into 2–3-mm-thick sections and were processed routinely in the histology laboratory. H&E sections of the lymph nodes were evaluated for metastatic tumor. Immunohistochemical stains (S-100 protein and melan-A) were not obtained routinely on lymph nodes from the complete lymph node dissection.
Clinicopathologic data from each patient were tabulated (Table 1). For statistical comparisons of continuous variables (Breslow depth with or without SLN metastasis or mitotic rate with or without SLN metastasis), we used a Student two-sample t test, assuming unequal variance, with all P values two-tailed. Data were analyzed with Microsoft Excel Software (Microsoft Corp., Bellevue, WA). To test for a nonrandom association between categoric variables (site on head and neck or ulceration or neurotropism) and SLN metastasis, we used a 2-sided Fisher exact test because of the small number in 50–75% of statistical cells. Data were analyzed with MedCalc Statistic Software (MedCalc, Mariakerke, Belgium). This study was conducted under an exemption granted by the University of Michigan Institutional Review Board for Human Subject Research.
|Patient||Gender||Age (yrs)||Site of primary tumor||Coexisting in situ melanoma||Breslow depth (mm)||Clark level||Dermal mitotic rate (per mm2)||Ulceration||Neutropism||SLNs||Follow-up and duration (mos after diagnosis)|
|1||Male||70||Scalp||LM||6.0||V||3||Present||Present||Left neck||2/6||0/27 LNs in LAD AWOD (4)|
|2||Male||66||Left neck||LM||3.7||IV||2||Present||None identified||Left neck||1/1||0/19 LNs in LAD AWOD (6)|
|3||Female||47||Midback||None identified||4.8||IV||1||None identified||Present||Left axilla||1/3||0/31 LNs in LAD AWOD (8)|
|4||Male||31||Right foot||AL||2.8||V||1||None identified||Present||Right groin||2/2||0/20 LNs in LAD AWOD (17)|
|5||Male||68||Left shoulder||None identified||2.6||IV||< 1||None identified||None identified||Back + neck||0/3||AWOD (66)|
|6||Female||37||Left chin||None identified||5.3||IV||1||None identified||Present||Left neck||0/1||AWOD (37)|
|7||Male||53||Right arm||None identified||0.8||IV||< 1||None identified||None identified||Right axilla||0/1||AWOD (22)|
|8||Male||65||Left neck||LM||2.4||IV||< 1||None identified||None identified||Left parotid||0/1||LTFU|
|9||Male||69||Scalp||LM||1.8||IV||6||None identified||None identified||Left neck||0/2||AWOD (4)|
|10||Female||68||Back||SSM||2.5||IV||1||None identified||None identified||Right axilla||0/2||AWOD (17)|
|11||Male||60||Left shoulder||SSM||7.8||IV||< 1||None identified||None identified||Left axilla||0/2||AWOD (12)|
|12||Male||81||Right arm||None identified||9.0||V||1||Present||Present||Right axilla||0/1||AWOD (25)|
|13||Male||80||Left lower lip||None identified||5.0||IV||< 1||None identified||Present||Left submental||0/4||LTFU|
|14||Female||50||Left arm||None identified||1.9||IV||< 1||None identified||None identified||Left axilla||0/4||AWOD (4)|
|15||Female||55||Left arm||None identified||1.5||IV||< 1||Present||None identified||Left axilla||0/2||Developed lung nodules; LTFU|
|16||Male||86||Left cheek||None identified||4.7||V||1||None identified||Present||Left neck||0/2||AWOD (7)|
|17||Male||56||Right temple||None identified||9.0||V||< 1||None identified||Present||Right neck||0/2||Mets to lung and to 1 right neck LN: DOD (20)|
|18||Female||42||Posterior neck||None identified||6.0||V||< 1||Present||Present||Bilateral neck||0/6||AWOD (53)|
|19||Male||74||Left ear||None identified||1.9||IV||< 1||None identified||None identified||Left cervical||0/2||AWOD (37)|
|20||Male||37||Scalp||None identified||8.2||V||< 1||None identified||Present||Right neck||0/2||AWOD (5)|
|21||Male||78||Right leg||SSM||1.1||V||1||None identified||None identified||Right groin||0/2||AWOD (3)|
|22||Male||58||Midback||None identified||3.4||IV||1||None identified||None identified||Right axilla||0/4||AWOD (14)|
|23||Male||49||Right arm||SSM||1.9||IV||< 1||None identified||None identified||Right axilla||0/1||AWOD (38)|
|24||Male||59||Left cheek||LM||1.9||IV||< 1||None identified||Present||Left cervical||0/1||AWOD (39)|
|25||Male||78||Scalp||None identified||8.5||V||1||None identified||None identified||Left neck||0/1||AWOD (2)|
|26||Male||73||Left shoulder||None identified||1.0||IV||1||None identified||None identified||Left supraclav||0/1||AWOD (9)|
|27||Male||79||Scalp||LM||2.6||V||1||None identified||Present||Left neck||0/3||AWOD (10)|
|28||Male||40||Scalp||LM||5.5||V||< 1||None identified||Present||Left neck||0/4||AWOD (39)|
|29||Male||64||Chest wall||SSM||7.8||IV||< 1||None identified||None identified||Bilateral axilla||0/5||AWOD (24)|
|30||Male||47||Right back||SSM||7.0||IV||4||Present||Present||Bilateral groin||0/2||AWOD (7)|
|31||Male||60||Scalp||None identified||1.7||IV||10||None identified||None identified||Bilateral neck||0/2||AWOD (13)|
|32||Female||63||Right arm||None identified||1.6||IV||< 1||None identified||None identified||Right axilla||0/1||AWOD (45)|
|33||Female||61||Right neck||LM||0.9||IV||< 1||None identified||None identified||Right cervical||0/1||AWOD (2)|
We identified 33 patients (4%) with DNMM from our data base of 836 patients with melanoma who underwent wide local excision and SLNB between October, 1997 and October, 2002 (Table 1). There were 25 male patients and 8 female patients with a median age of 61 years (range, 31–86 years). Tumors measured 4.0 mm in mean Breslow thickness (median, 2.8 mm; range, 0.8–9.0 mm). Tumors were located in the head and neck region (n = 17 patients), back and trunk (n = 7 patients), and limbs (n = 9 patients). A preexisting in situ melanoma was identified in 15 of 33 patients (45%), including lentigo maligna (n = 8 patients), superficial spreading (n = 6 patients), and acral lentiginous (n = 1 patient) types. Nearly all were deeply invasive into reticular dermis and subcutis (Clark level IV and V). In the primary tumors, neurotropism was observed in 14 tumors, 3 of which metastasized to SLNs. Six tumors were ulcerated, two of which metastasized to SLNs. None of the primary tumors demonstrated angiolymphatic spread or satellitosis in histologic sections. The dermal mitotic rate ranged from < 1 mm2 to 10/mm2.
Of 33 patients with DNMM who underwent SLNB, 30 patients underwent tumor resection and SLNB at our institution. Four of 33 patients (12%) had 1 or more positive SLNs. In one patient with DNMM arising in the scalp (Fig. 1), tumor metastasized to two of six SLNs in the left neck (Fig. 2). In another patient with DNMM from the neck (Fig. 3), tumor spread to an SLN in the neck (Fig. 4). In both patients, metastatic tumor retained a spindled appearance and elicited a fibrosing reaction that obliterated the subcapsular sinus and expanded the lymph node capsule (Figs. 2, 4). In two patients with DNMM from the midback region (Fig. 5) and right foot (Fig. 6), tumor metastasized to one of three left axillary SLNs and to two of two right groin SLNs, respectively. In both patients, a few clusters of tumor cells displayed an epithelioid morphology (Figs. 7, 8). No additional involved lymph nodes were identified in subsequent regional lymphadenectomy.
No statistically significant association was noted between several clinicopathologic factors and SLN metastasis. The mean Breslow depth of tumors that metastasized to SLNs was not significantly different from the mean Breslow depth of tumors that did not metastasize to SLNs (4.33 mm vs. 3.98 mm; P = 0.70). The mean mitotic rate of tumors that metastasized to SLNs (1.75/mm2) was not significantly different from the mean mitotic rate of tumors that did not metastasize to SLNs (1.00/mm2; P = 0.27). There was no significant association between SLN metastasis and site on the head and neck (P = 1.00), tumor ulceration (P = 0.14), or neurotropism (P = 0.29).
Clinical follow-up was available on 30 of 33 patients (91%) who underwent SLNB, ranging in duration from 2 months to 66 months (median, 13.5 months; mean, 20 months). All four patients with positive lymph node status were alive and well without clinically apparent disease at the time of this report. Of the remaining 29 patients with negative SLNs, the tumor recurred in a regional lymph node and metastasized to the lungs of one patient (Patient 17) 9 months and 13 months after SLNB, respectively. The patient died of disseminated disease 20 months after the initial diagnosis of DNMM. One patient (Patient 15) developed lung nodules that were suspicious for metastatic disease but was lost to follow-up. Two patients with negative SLNs were lost to follow-up. The remaining 25 patients with negative SLNs were alive and well without evidence of disease at the time of last follow-up.
An analysis of the experience with DNMM at the University of Michigan Cancer Center confirms many of the observations in the literature regarding the presentation and natural history of this uncommon melanoma. DNMM typically presents in the head and neck region of elderly males.3 The tumor most often occurs in lentigo maligna (42%) and, in the majority of patients, is deeply invasive at the time of diagnosis.3 In our study, DNMM presented predominantly in the head and neck region (52%) of males (76%) with a mean age of 61 years. Tumors were deeply invasive (mean Breslow depth, 4.0 mm; median Breslow depth, 2.8 mm), and many were associated with lentigo maligna (24%).
Findings from this study also offer new insights into the clinical significance of SLNB for this tumor. Specifically, we document the utility of SLNB in detecting early metastases of DNMM to regional lymph nodes. The incidence of lymph node metastasis has been estimated to range from 8% to 15% for DNMM,11 although a few studies have observed higher rates (Table 2). Of 33 patients with DNMM who underwent SLNB, positive SLNs were identified in 4 of 33 patients (12%), which is consistent with the incidence of lymph node metastasis reported in the literature.3–11
|Investigators||Average age (yr)||Average Breslow depth (mm)||No. of patients (%)||Follow-up (mos)|
|Regional lymph node metastases||Pulmonary metastases||Mortality rate|
|Devaraj et al.6||67||5.78||4/13 (31.0)||4/13 (31.0)||3/13 (23.0)||Mean, 40.0|
|Quinn et al.3||61||2.5||26/280 (9.0)||NR||27.8%||60.0|
|Smithers et al.7, 8||61||4.5||6/45 (13.0)||2/45 (4.0)||5/45 (11.0)||1–108|
|Beenken et al.9||63||5.75||2/13 (15.4)||5/13 (38.0)||4/13 (30.0)||Mean, 55.0|
|Payne et al.4||63||2.6||3/30 (10.0)||2/30 (6.0)||1/30 (3.0)||Mean, 18.0|
|Reed and Leonard2||59||NR||2/16 (12.5)||1/16 (6.0)||9/16 (56.0)||24–108|
|Egbert et al.10||61||NR||3/25 (12.0)||NR||3/25 (12.0)||Mean, 32.4|
|Carlson et al.5||59||4.1||4/28 (14.0)||3/28 (11.0)||3/26 (11.5)||Mean, 36.0|
|Conley et al.1||53||NR||3/7 (42.0)||4/7 (57.0)||4/7 (57.0)||NR|
Cumulative data in the literature suggest that, compared with non-DNMM melanomas of the same depth, DNMM metastasizes less commonly to regional lymph nodes.3, 11–13 The reported incidence of lymph node metastasis in non-DNMM melanomas with a Breslow thickness of 1.5–4.0 mm ranges from 19% to 28.7%.25, 26 In our institutional data base, 22% of non-DNMM melanomas with a mean Breslow thickness of 2.9 mm had positive SLNB results. In contrast, only 12% of DNMM with an mean Breslow thickness of 4.0 mm had positive SLNB results, supporting the observation that, although DNMM is often deeply invasive, the tumor metastasizes to lymph nodes less frequently than conventional melanoma.
Despite the lower incidence of lymph node involvement in DNMM compared with non-DNMM melanoma, an argument can be made for performing SLNB in DNMM. It has been proposed that SLNB should be considered when a primary melanoma measures thicker than 1 mm and should be applied selectively for tumors that measure ≤ 1.0 mm, if ulceration is present, and perhaps if the lesion is invasive to Clark level IV or higher.27 If SLNB should be considered for melanomas 1 mm thick, with an expected SLN positivity of about 8%,26 then the higher observed SLN positivity rate of 12% for DNMM offers a reason to perform the procedure.
It is important for the histopathologist to recognize several possible pitfalls in the interpretation of SLNs for DNMM. First, the microscopic features of metastatic DNMM can vary and may not resemble the primary tumor.1, 2 In lymph nodes, their histology can manifest as that of classic malignant melanoma, that of a desmoplastic spindle cell tumor, or both.1, 2 In two patients in the current study, melanoma cells in SLNs displayed an epithelioid morphology, even though the primary tumor consisted predominantly of spindle cells (Figs. 5–8). In two other patients, metastatic DNMM exhibited a spindle cell morphology with associated desmoplastic stroma resembling the primary tumor (Figs. 1–4). Second, interpretation may be complicated by the presence of only a few tumor cells in the SLNs. In two patients in the current study, only a few clusters of melanoma cells were identified in SLN sections (Figs. 7, 8). Immunohistochemical stains for melan-A were pivotal in identifying microscopic metastases in both patients. Third, although DNMM usually expresses S-100 protein, the tumor often does not mark for more specific melanocyte markers, such as HMB-45, and inconsistently expresses melan-A.28, 29 We encountered two such patients who were negative for melan-A (Figs. 1–4). However, a positive diagnosis was made on each case based on the combined histopathologic and immunophenotypical features (highly atypical, S-100 positive spindle cells obliterating the lymph node sinuses and abnormally expanding the capsule).
The use of SLNB for DNMM has been reported in 4 studies involving a total of 62 patients with only 1 SLNB (1.6%) that produced positive results.4, 11–13 In contrast, in the current study, we present a group of 33 patients in which SLNB detected occult lymph node disease in 4 patients (12%). SLNB allowed early detection of occult, metastatic DNMM, which, coupled with lymphadenectomy, may have limited tumor spread and prevented tumor recurrence at the draining lymph node basin in these four patients. Whether early detection and treatment of lymph node metastasis improves overall survival is not clear at this time, and long-term follow-up of these patients will be required to make this determination.
- 24Morbidity of lymphadenectomy for melanoma. Surg Oncol Clin North Am. 1992; 1: 195–204., .