Desmoplastic Melanoma Case Study

Natalia Jaimes, MD
Fundación Cáncer de Piel Colombia
Dermatology Service
Aurora Skin Cancer Center
Medellín, Colombia

Ashfaq A. Marghoob, MD
Clinical Associate Professor
Dermatology Service
Memorial Sloan-Kettering Cancer Center
New York, NY

Diagnosis of desmoplastic melanoma (DM) has long been a challenge for clinicians and pathologists alike. However, new clues and strategies are emerging to aid in early detection and diagnosis and to better determine prognosis. DM is an uncommon variant of spindle cell melanoma, believed by some to represent a sarcomatoid variant of melanoma. It accounts for less than 4 percent of primary cutaneous melanomas, and the overall incidence rate has been reported to be 2.0 per million US persons, with an annual 4.6 percent increase.1,2 The definition and classification of DM has evolved through the years. It was first used in 1971 by Conley, et al3 to refer to the association of invasive tumor cells with abundant stromal collagen. Eight years later, Reed and Leonard4 introduced the term neurotropic melanoma to describe a variant of DM with prominent neural involvement (neurotropism). Subsequently, in 2004, Busam, et al5 further classified DMs into pure DM (pDM) and mixed DM (mDM), based on the degree of desmoplasia (growth of dense connective tissue or stroma) present in the tumor; pDMs have more and mDMs less than 90 percent desmoplasia. The distinction between pDM and mDM appears to have clinical, therapeutic, and prognostic significance; pDM is associated with better overall survival (OS) and less frequent metastasis to regional lymph nodes than mDM. In contrast, mDM appears to display similar biologic behavior to other, non-desmoplastic melanoma subtypes, such as superficial spreading melanoma.

Risk Factors

DM has been associated with risk factors such as male gender, older age, chronic ultraviolet radiation exposure, and sun-damaged skin2 (Table 1). In general, men have about twice the risk of developing DM as women, and this disparity grows even higher in the older population.

Diagnosis

Diagnosis of DM can be difficult, not only clinically but histologically. Clinically, early diagnosis of DM is challenging, since it often presents with a non-specific or non-descript morphology. While it may manifest a morphology commonly associated with malignant tumors (e.g., basal cell carcinoma, squamous cell carcinoma, and amelanotic melanoma), it is often mistaken for a benign lesion (e.g., scar, dermatofibroma, neurofibroma, cyst, sclerosing melanocytic nevus).6 In a recent study at eight dermatology clinics for highrisk patients,7 at least 27 percent of DM cases were initially diagnosed as benign lesions and treated with cryotherapy, lasers, or intralesional steroids before the definitive diagnosis of DM was confirmed by biopsy.7

Efforts to enhance clinical recognition of suspected DM are ongoing. Improved knowledge of its risk factors as well as its clinical and dermoscopic characteristics may provide clues, leading to earlier biopsy.

1. Clinical and Dermoscopic Characteristics

DM often manifests features commonly associated with banal lesions, and frequently presents as amelanotic, firm, palpable, or indurated lesions with ill-defined borders. Since it most often appears on sun-damaged skin, especially on the head and neck,2,7 it is not uncommon for patients to present with a history of a non-specific or scarlike lesion located on chronically sundamaged skin that developed without any antecedent trauma.

The primary clinical morphology of DM alone provides insufficient criteria for recognition. However, two case series have shown that dermoscopy may provide additional information indiscernible to the unaided eye; it thus can prompt clinical concern and further testing.8,7 Dermoscopically, DMs may appear as featureless lesions or may reveal one or more lanoma-specific structures, in particular atypical vascular structures, granularity, blue-white veils, atypical globules, and crystalline structures or atypical networks. In addition, dermoscopic features of lentigo maligna melanoma (LMM), such as annular granular pattern and polygonal lines, can be seen in up to one third of DM cases7 (Table 2).

Jaimes, Chen, Dusza, et al7 recently described the clinical and dermoscopic features of DM as a function of the histopathological subtypes. Their research demonstrated that pDM and mDM cannot be clinically distinguished from one another; however, with dermoscopy some differences were noted: pDMs more often reveal a monomorphous vessel pattern, with dotted vessels being the most common. In contrast, mDMs tend to present with a polymorphous vascular pattern and a vascular blush.

Since DMs have a prominent dermal stromal component, palpation remains an important part of the clinical examination. Accordingly, DM should be considered in the differential diagnosis of any firm lesion encountered on chronically sun-damaged skin, even if under dermoscopy it appears to be featureless. In addition, since DMs can be associated with LMM, all clinically suspect LMMs should also be palpated to ensure there are no subcutaneous firm nodules within. For any such firm areas discovered, if a benign diagnosis cannot be assured, a biopsy should be performed. Furthermore, if a firm lesion also reveals any of the dermoscopic structures described in Table 2, a biopsy should be strongly contemplated.

2. Histopathology of DM

On routine hematoxylin and eosinstained sections, DMs are characterized by the presence of an invasive melanoma with abundant collagenous matrix. Usually, pDMs are pauci-cellular with a prominent component of desmoplasia throughout the majority of the tumor (>90 percent). In contrast, mDMs have a higher cell density, which may be observed throughout the tumor, or may manifest as nodules of solid spindle and/or epithelioid melanocytes against a background of classic pauci-cellular DM.5

In approximately one third of DMs, there is no identifiable in situ elanoma, and histopathologic recognition of the malignant dermal spindle cells may be challenging. DMs associated with an in situ melanoma in the epidermis and/or follicular epithelium are easier to recognize histopathologically. LM is the most common type of melanoma associated with DM, followed by superficialspreading melanoma (SSM).5,7,9 It has been suggested that mDMs may be easier to recognize clinically, based on the presence of a superficial component consisting of either an LM or an SSM. In contrast, early pDMs may be relatively inconspicuous, since these tumors usually appear as dermal nodules or plaques and generally lack epidermal clues such as pigmentation.

Immunohistochemical studies are often needed for optimal assessment of tumor thickness and to distinguish DMs from non-melanocytic mimickers. S-100 is one of the most valuable diagnostic markers for the disease. However, caution is warranted when evaluating scars for possible residual DM. Scars can contain S-100-positive cells, which may be confused with DM; however, these S-100 positive cells tend to be scattered and isolated in scars, whereas they are strongly positive in DMs.6 Tumors of Schwann cells, such as Schwannoma, neurofibroma, or malignant peripheral nerve sheath tumors, cannot be distinguished from DM by S-100. Other immunohistochemical studies that can be useful in select cases include antibodies, nerve growth factor receptor, and Sox 10.10,11 Other melanocyte differentiation antigens, such as gp100, Melan-A/ Mart-1, tyrosinase, and microphthalmia transcription factor are usually negative in DM.12

DMs, especially deeply infiltrating tumors located in the head and neck region,2,13,14 can infiltrate and extend along nerves (neurotropism). Neurotropic DMs (NDM) have been associated with deeper tumors, greater mitotic activity, local infiltration, multiple recurrences, and more metastases than DMs without neurotropism.1,4 When NDM involves the head and neck region, it may give rise to trigeminal and facial nerve neuropathies, and may result in higher rates of CNS metastases due to direct tumor extension.15,16 As a result, some have advocated adjuvant radiation therapy to improve local control.17

3. Molecular findings

There is a paucity of information regarding the molecular profile of DM. Some studies have demonstrated a decrease in the expression of genes involved in melanin synthesis and increased expression of the glycoprotein clusterin, which is involved in physiological processes such as cell adhesion and tissue and fibrous remodeling.18 Unfortunately, fluorescence in situ hybridization has had limited diagnostic value in differentiating DM from benign melanocytic lesions.19 However, arraycomparative genomic hybridization may prove helpful in select cases – for example, in distinguishing DM from sclerosing Spitz nevus through detection of a copy number gain of chromosome 11p in the absence of any other chromosomal changes. Such a finding would support the diagnosis of a benign nevus and, for all practical purposes, exclude the diagnosis of DM.

Prognosis

Five-year and 10-year DM-specific survival have been reported to be 84.8 and 79.2 percent respectively, with five-year OS between 67 percent and 89 percent.2,20 Factors associated with an increased risk for DM-specific death include male gender, advancing age, and location on the head or neck.2

Whether the prognosis of DM is more or less favorable than for non-DMs remains unclear. Some studies have reported no significant difference in patient survival rates.1 Other studies have shown a poorer prognosis for DM,28,29 while still others have demonstrated a more favorable prognosis for DM compared to non-DMs of similar thickness.15 Some studies have even suggested that desmoplasia may confer better survival for patients with tumors greater than 4mm.21,22

The classification of DMs into the two histologic subtypes (pDM and mDM) has demonstrated prognostic differences in disease-free survival.5 Patients with mDM have shown a 3.5-fold greater risk for metastasis or death, and a shorter time to recurrence,14 while pDMs have a lower frequency of regional lymph in NDM.1,22 node involvement (1 percent) as compared with mDM (10 percent) or other melanoma subtypes (6 percent; P<0.05, pDM vs. other types).23

The impact of neurotropism onsurvival continues to be studied. Someresearchers have shown that NDM is associated with a 30 percent decrease in 8-year survival,15 while others have reported no association of neurotropism with a worse OS, despite the observation of a higher local recurrence rate in patients with NDM.1,22

Sentinel Lymph Node Biopsy (SLNB)

The impact of regional lymph node status on the survival of patients with DM remains uncertain and somewhat controversial. Regional lymph node involvement is reported in 0 to 18.8 percent of cases, which is less frequent than observed for other cutaneous melanomas.15,31-33 Unlike non-DMs, the nodal status of patients with DMs does not appear to predict prognosis, with the 5-year OS being virtually the same for node-positive and node-negative patients (65 percent for node-negative, 64 percent for node-positive, p=0.86).20,24 Nevertheless, some studies show that the risk of death is higher for patients with DM-positive lymph nodes (95 percent CI: 1.94-4.65).2 These inconsistencies may be due to differences in definitions used for selecting DM cases for inclusion in studies, or to the use of data acquired prior to our understanding of the differences between pDM and mDM.

Overall, the consensus of experts in the field is that the risk of developing nodal involvement in DM is in fact lower than for patients with non-DM melanoma. Given this lower risk and the questionable prognostic value of knowing the patient’s SLNB status, the utility of SLNB in management of DM patients has been brought into question, with some authors now recommending against routine SLNB.20,25,26 This is particularly true for patients with pDMs, since significant differences in lymph node positivity have been observed between patients with pDM and those with mDM (1.4 percent in pDM patients staged by SLNB compared to 18.5 percent in mDM patients.)26 In fact, Mohebati, et al27 recently reported that staging pDMs of the head and neck by SLNB may not be necessary, given the preponderance of negative LNBs and the low incidence of both lymphovascular invasion and recurrence.

Weighing all the facts, many have suggested that rather than eliminating SLNB altogether, selective SLNB should still be considered and encouraged in patients with mDM, as well as in pDM patients with additional high-risk factors,such as younger age, presence of neurotropism, high mitotic rate, and tumor ulceration.22

Distant Metastases

Systemic metastasis occurs in 7-44 percent of DM cases, with lung, liver,and bone the most commonly involved areas.13 Risk for distant metastasis can vary depending on histopathological type, the risk higher for patients with mDM than for those with pDM.28

Management

Wide Local Excision (WLE) remains the main line of treatment for DM. The extent of surgical resection, independent of tumor thickness, has been shown to be a predictor for survival.20 Patients undergoing WLE with margins greater than 1cm have a better OS than those undergoing excisions of less than 1cm (67 percent vs. 60 percent; p=0.029).20 In addition, wide margins can reduce the rate of local recurrence resulting from persistent disease present focally near the excision margin and/or along nerves (neurotropism). The recurrence rate is as high as 20 percent in neurotropic DM cases vs. only 6.8 percent in non-neurotropic DM cases.1 It has also been shown that DMs excised with margins <1 cm have a higher rate of local recurrence than those excised with margins >2 cm.1,17

Maurichi, et al28 compared outcomes with different surgical margins based on histologic type, in both thin (<2 mm) and thick (>2 mm) pDMs and mDMs. Thin pDMs excised with 1 cm margins had a higher rate of recurrence and worse 5-year OS (60 percent versus 85.2 percent, P=0.014) than those treated with 2 cm margins. Patients whose thick pDMs were excised with 2 cm margins had similar survival to patients whose thin pDMs were excised with 2cm margins (86.6 percent versus 85.2 percent). Finally, the mortality risk in patients with mDM increased according to their stage but was independent of width of excision margins, suggesting that the behavior of mDM is similar to that of non-desmoplastic melanomas. Hence, to minimize the risk of local recurrence and metastasis, WLE with clear margins is recommended for both subtypes of DM, and whenever feasible, a 2 cm margin appears to offer the highest cure rates.

However, there are cases where wide margins and deep excisions are not feasible, for example with DMs that are deeply infiltrating or located in cosmetically, structurally, or functionally sensitive areas such as the periorbital or periocular regions of the face.25,28 In these circumstances, adjuvant radiation therapy may improve local control of the disease.29 There is some evidence that adjuvant radiotherapy may provide added value for DMs at high risk for local recurrence, including tumors excised with narrow margins, those removed with positive excision margins, or those with neurotropism.30,31 However, given the limited data aboutadjuvant radiation therapy’s role in DM, the available evidence remains somewhat controversial, and the most appropriate dose, fractionation, and target volume of radiation remain to be elucidated.2,17,20,32 Ongoing prospective studies on adjuvant radiation therapy for DM will likely clarify its role in management of the disease.

Finally, since there are scarce followup data pertaining to the management of patients with distant metastatic DM, the role for systemic therapies with medications such as ipilimumab remains to be determined.33,34

    Conclusion

    Although DM can be a diagnostic challenge for clinicians and pathologists, certain clues may improve detection and aid in diagnosis of these tumors. For instance, diagnosis of DM should be considered when evaluating nonspecific, scar-like lesions displaying irregular vessels under dermoscopy, or when a dermal firm nodule is noted during palpation of a suspected LMM. Once a DM is diagnosed, the pathologic distinction between pDM and mDM should be documented, since this information enhances management decisions and provides prognostic information. While routine SLNB may not be necessary for pDMs, it should be discussed with patients and considered for those with additional high-risk features. To reduce local recurrence, WLE with clear margins is recommended, and whenever feasible, 2 cm margins are ideal. Adjuvant radiotherapy should be considered for tumors at high risk for local recurrence. We remain optimistic that future studies will improve our current knowledge and understanding of the biology of DMs. This in turn will likely lead to more accurate diagnosis and help to target therapies for this malignancy.

    References

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    16. Smithers BM, McLeod GR, Little JH. Desmoplastic melanoma: patterns of recurrence. World J Surg 1992; 16:186-90.
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    19. Gerami P, Beilfuss B, Haghighat Z, Fang Y, Jhanwar S, Busam KJ. Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic melanomas from sclerosing melanocytic nevi. J Cutan Pathol 2011; 38:329-34.
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    INTRODUCTION

    Section:

    Desmoplastic melanoma (DM) is a histological subtype of melanoma that has been reported to account for approximately 1% of all cases of melanoma1 and accounts for 2.8% of all cases in our database of patients with cutaneous melanoma seen at the Massachusetts General Hospital (MGH). DM was described first by Conley et al2 in 1971 as being characterized by a dermal spindle cell population of malignant melanocytes in a background of abundant collagen. DM may occur as a separate histological subtype or as a feature of a pre-existing pigmented lesion, most commonly lentigo maligna melanoma.

    The largest series of patients with DM published thus far came from the Sydney Melanoma Unit.1 Published in 1998, this study of 280 patients found that DM was more common in males, occurred at a relatively late age, and was usually in the head and neck area. The median tumor thickness at presentation was 2.5 mm, which was much higher than the median thickness of 1.0 mm in the general Sydney Melanoma Unit population of patients with melanoma.

    In general, series published by numerous other institutions support these findings.3-9 It has also been reported that the occurrence of lymph node involvement in patients with DM, both at presentation and as regional lymph node recurrence, is lower than that generally seen in the melanoma population as a whole.1,4,10,11 For this reason, some authors have suggested that sentinel lymph node biopsy may not be indicated for this group of patients.11 Although patients with DM usually present with thicker tumors, survival is thought to be better than for other forms of melanoma with the same thickness.6,12

    However, a case-matched control study has never been performed. Thus, comparison with other forms of melanoma with respect to lymph node involvement and outcome has been influenced heavily by a significant difference in tumor thickness. In an effort to draw conclusions solely on the basis of the difference in histology, we compared the population of patients with DM seen at our institution with a group of controls matched for thickness, age, and sex. Because views on melanoma management have changed over the study period,13,14 we also matched for year of diagnosis to compare patients treated with similar standards of care.

    PATIENTS AND METHODS

    Section:

    We identified 89 patients with DM from our database that contains information on 3,202 patients who presented to the MGH with melanoma between 1970 and 2002. Patients were classified as having DM if the pathology report, signed by a staff dermatopathologist, indicated there was at least a partial desmoplastic component. Because slides were often not available in our archives, the lesions were not rereviewed systematically. However, primary lesions of patients with DM with positive lymph nodes were rereviewed by one of our staff dermatopathologists (T.J.F.).

    Subsequently, the two closest matches in the database were identified for each DM patient with respect to sex, tumor thickness, year of diagnosis, and age. If more than two matches for a DM patient were found in the initial query, two controls were selected by using computerized randomization. If the initial query did not yield two or more matches, the age range was broadened to a maximum of 5 years' difference. If this did not yield enough matches, the range for year of diagnosis was broadened to a maximum of 2 years' difference. For tumor thickness, although an exact match was not always possible, all matches were within the same American Joint Committee on Cancer (AJCC) staging thickness subgroup. All cases were sex-matched. Thus, a study population was formed and consisted of 89 patients with DM and 178 controls.

    Information on patient characteristics, pathology, recurrences, and cause of death was subsequently collected from medical records, the social security death index, and the Massachusetts Department of Public Health Registry of Vital Records and Statistics. In case of conflicting sources, medical-record review was determined to be the most accurate. Patients were staged according to the criteria of the latest AJCC staging system for melanoma.15

    The date of first recurrence or of last follow-up was used as the end point for determination of disease-free survival.

    Statistical methods used included Student's t test for comparing age, the Mann-Whitney test for comparing tumor thickness, and Pearson's χ2 test for comparing categoric variables such as sex, stage, and mitotic rate between patients with DM and controls. Survival curves were produced on the basis of the Kaplan-Meier method, and patients with DM were compared with controls by using a Cox proportional-hazards model. If cause of death was unknown, patients were censored in cause-specific survival analysis. The effects of clinical and pathologic characteristics on cause-specific survival were assessed with a Cox multivariate stepwise-regression model. P < .05 was considered statistically significant. SAS statistical software (SAS Institute, Cary, NC) was used for statistical analyses.

    Surgical management of primary melanoma in general changed during the study period, as did surgical management of the lymph nodes. The extent of surgical margins was generally reduced during the study period to the current goal of resection of at least a 1-cm margin of normal skin on the face and at least a 2-cm margin in other anatomic locations, restricted only by functional or cosmetic limitations. The anticipated need for a skin graft or flap for adequate closure generally did not reduce the planned surgical margin. Elective lymph node dissection was used to stage lymph nodes before 1994, after which time sentinel node mapping was used to stage lymph nodes.

    This retrospective study was carried out under a waiver of patient consent granted by the institutional review board of MGH.

    RESULTS

    Section:

    Finding Case-Matched Controls

    To identify criteria for matching a control group, the DM group was first compared to the general database of 3,202 melanoma patients seen at MGH between 1970 and 2002. Sex and age were examined in addition to aspects of the primary lesion that, according to the current staging system, affect outcome, such as Breslow thickness and ulceration.

    The median Breslow thickness was 2.60 mm in the DM group and 0.96 mm in the overall database (P < .001). Thus, tumor thickness was selected as a matching criterion. The male-to-female ratio was 1.7:1 in the DM group and 1.1:1 in the overall database (P = .067). Because the difference approached statistical significance and it has been shown that males with melanoma have a poorer prognosis than females, 16 sex was used to select case-matched controls. The mean age was 62.3 years in the DM group and 52.7 years in the overall database (P < .001). Therefore, age was also chosen as one of the matching criteria. There was no significant difference in ulceration between the DM group and the overall database. The size of the general database would only allow us to match for one additional criterion, and we therefore preferred to match for year of diagnosis to ensure that control patients had the same diagnostic and therapeutic opportunities as patients with DM. This was necessary because the views on melanoma management evolved over the study period.13,14

    Subsequently, 178 controls were identified for 89 patients with DM. A 2:1 matching ratio was chosen to obtain greater statistical power. After the matching procedure, there were no significant differences between the two groups with respect to sex, age, or tumor thickness (Table 1).

    General Patient Characteristics

    General patient and histology characteristics for the DM and case-matched control groups are listed in Table 1.

    The most common site of the primary melanoma in the DM group was head and neck, whereas the trunk was the most common site in the control group. There was no difference in the incidence of nonpigmented melanomas between the groups.

    Although data on neurotropism were incomplete, this histological feature was observed much more commonly in patients with DM. Clark's level of invasion was significantly higher and mitotic rate was significantly lower in the DM group.

    Patients with DM presented with an earlier stage of disease than did control patients, although it should be noted that patients were matched for tumor thickness, which thus was not factored into this stage comparison. Five percent of the patients with DM versus 21% of control patients presented with stage III or IV disease (P < .001).

    Sixteen patients (17.9%) with DM had more than one primary melanoma, whereas only 12 controls (6.7%) had more than one primary melanoma (P = .004). This was an unexpected finding, and we therefore examined patients with DM with multiple primary melanomas more closely. Second primaries were only scored as such if they were invasive; thus, none of the second primaries were in situ melanomas. Thirteen of these 16 patients had another primary melanoma before diagnosis of DM. None had more than one primary DM; six patients had lentigo maligna melanoma as a second primary, and five had superficial spreading melanoma. Family history was positive in five of 16 patients with DM with multiple primary melanomas and negative in nine of 16 patients with DM.

    Patients with DM also had significantly more nonmelanoma skin cancers, which additional analysis showed to be caused by a higher prevalence of basal cell carcinoma. No difference was observed in the prevalence of squamous cell carcinoma between the two groups. Two patients with DM had a leiomyosarcoma, one in the stomach before diagnosis of the melanoma and one in the spinal cord after the diagnosis of melanoma. There was no significant difference in prevalence of other cancers, dysplastic nevi, immune suppression, or a positive family history.

    Treatment of Primary Lesion

    Standard treatment of the primary lesion was wide local excision, usually after an initial biopsy. We found that patients with DM required significantly more re-excisions than control patients to obtain clear margins. More than 20% of the patients with DM had microscopically positive margins after wide local excision, which required at least one re-excision, compared to only 6.4% of the controls (Table 2).

    Lymph Node Evaluation

    There was no difference between the two groups with respect to the number of sentinel lymph node biopsies or elective lymph node dissections. Table 3 shows the number of sentinel lymph node biopsies and lymph node dissections without lymphatic mapping for both groups, as well as the number of positive results. Although the proportions of DM and control patients who underwent sentinel node biopsy were similar, patients with DM had a significantly lower rate of positive sentinel lymph nodes compared with control patients (8.0% v 33.8%, respectively; P = .013). After having a positive sentinel lymph node, one of two patients with DM and four of 20 control patients had at least one additional positive node at completion of lymph node dissection (P = NS).

    No positive lymph nodes were identified in patients who underwent elective lymph node dissection, either in the DM group or the control group. Therapeutic lymph node dissection was performed more often in the control group, but the difference did not reach statistical significance (P = .054). The maximum number of positive nodes in an individual patient was two in the DM group and six in the control group. Overall, 5% of the patients with DM had positive lymph nodes at the time of presentation, compared with 20% of the control patients (P = .005).

    After closer analyses of the four patients with DM who had positive nodes, we found that the thicknesses of their primary lesions were 2.9, 3.0, 3.8, and 7.0 mm, respectively. All four primary lesions had evidence of neurotropism, and three of the four were ulcerated. The primary lesions of two of these patients showed a mitotic rate between one and four mitoses per 10 high-power fields; the other two had more than four mitoses per 10 high-power fields.

    Busam et al17 recently described a distinction between “combined DM” (in which a desmoplastic component is seen in a lesion that is primarily a nondesmoplastic “conventional” invasive melanoma) and pure DM (in which the lesion is completely desmoplastic). We re-examined the primary lesions of three of the four patients with positive lymph nodes according to their criteria. One of two patients who underwent therapeutic lymphadenectomy for positive nodes had a primary melanoma that could be classified as pure DM. Neither of the two lymphatic mapping patients with positive sentinel nodes had pure DM. The slides of the primary lesion were irretrievable in one patient who underwent therapeutic lymphadenectomy for positive nodes.

    Recurrences

    Of all patients with DM, 24.7% had at least one recurrence, in comparison with 29.8% of the controls, a difference that is not statistically significant (Table 4). There was no significant difference in the number of local, regional, or distant recurrences, either as first or as any recurrence, between patients with DM and controls. The lungs were the most common site of distant metastasis in both groups, and there was no significant difference in the occurrence of metastases to lungs, bone, liver, CNS, or gastrointestinal tract. The sites of distant metastases are listed in Table 5.

    Survival

    Compared with the entire melanoma database, overall survival was significantly worse in the DM group (P < .001). Having a case-matched control group, however, allowed for more accurate comparison of survival between DM and other forms of melanoma. No difference in overall, cause-specific, or disease-free survival was observed between DM and the control group (Figs 1, 2, and 3, respectively). Thirty-three patients with DM (16 related, two of unknown cause) and 56 controls (35 related, five of unknown cause) died during the study period. Mean follow-up time was 5.5 years in the DM group and 6.0 years in the control group (median, 4.3 and 4.8 years, respectively). Five-year overall survival was 72.6% in the DM group and 76.9% in the control group, and 5-year disease-free survival was 65.7% and 67.4%, respectively.

    In univariate analysis, Breslow thickness, ulceration, mitotic rate, and presentation with AJCC stage III (as opposed to stage I or II) were of significant negative influence on cause-specific survival of patients with DM. Sex, age, site of primary melanoma, Clark's level, neurotropism, and the necessity of multiple re-excisions had no statistically significant effect on cause-specific survival. In multivariate analysis, tumor thickness and presentation with AJCC stage III remained as independent significant predictors of poor outcome (Table 6).

    DISCUSSION

    Section:

    This is the first study on DM to include a case-matched control group for direct comparison with other forms of melanoma. A comparison of patients with DM with a control group matched for sex, age, tumor thickness, and year of diagnosis provides interesting insights into the clinical and biologic behavior of this rare form of melanoma.

    In general, the presented data are consistent with several previously described characteristics of the initial presentation of DM. Our study supports previous observations that DM is locally invasive. The average thickness of the primary lesions of patients with DM was greater than that of the other patients in our database of 3,288 patients with melanoma, which is in accordance with results from other studies on DM.1,18 In addition, Clark's level of invasion was higher in the DM group than in the case-matched control group. Obtaining clear surgical margins in patients with DM was significantly more difficult than in control patients. Looking more closely at the characteristics of patients with DM who required multiple re-excisions, we noted that 12 of these 19 patients had their primary lesion in the head and neck area, where anatomic and cosmetic considerations often limit surgical options. Furthermore, 10 of these 19 primary tumors showed neurotropism, which has been shown to be associated with local aggressiveness of DM.1,19 Regional or distant metastases at time of presentation, however, were much less frequent in the DM group compared to case-matched controls.

    To our knowledge, this is the first study on DM to look at other diseases occurring in these patients. It is noteworthy that patients with DM have significantly more other primary melanomas, as well as basal cell carcinomas, than do control patients. The prevalence of second primary melanomas in patients with DM is surprisingly high, and we could not find a clear explanation for this observation. None of these patients had multiple DMs, and they did not have a positive family history more often than other patients. A possible explanation could be increased sun exposure in these patients, but we could not verify this retrospectively.

    We also found that two patients with DM had leiomyosarcoma. Thus, the prevalence of leiomyosarcoma in our group of patients with DM is substantially greater than would be expected for the general population. The incidence of soft-tissue sarcomas is approximately two to four cases per 100,000, with leiomyosarcoma only constituting approximately 10% to 25% of them.20,21 Although this is an interesting observation, our study was not initially designed to address the relationship between leiomyosarcoma and DM. The fact remains that we observed only two cases of leiomyosarcoma.

    Our results also confirm the lower incidence of positive sentinel node biopsies among patients with DM reported in literature. The 8% rate of positive sentinel node biopsies in our series is in accordance with a recently published study by Su et al,10 who reported a rate of 12%. The mean tumor thickness in their study was higher than in our series, which may explain their slightly higher fraction of patients with positive sentinel nodes.

    Gyorki et al11 found no positive sentinel lymph nodes in their study of 24 patients with DM undergoing sentinel lymph node biopsy and concluded that sentinel lymph node biopsy might not be indicated in this subgroup of patients with melanoma. In our series, 8% of the patients who underwent mapping had positive nodes, and presentation with AJCC stage III was an independent predictor of cause-specific survival in multivariate analysis. It is our impression, therefore, that although the likelihood of a positive lymph node at time of diagnosis is lower in patients with DM, the prognostic value of such a finding is of no less significance. Considering the nature of the primary lesions of the four patients with DM in our series that had positive nodes, we suspect that sentinel node biopsy might be particularly useful in subgroups with advanced primary lesions (ie, tumors that are thicker than 2.0 mm, ulcerated, or have neurotropism).

    We should emphasize that desmoplastic primary lesions are located significantly more often on the head and neck, because sentinel node biopsy has been reported to be more difficult in this area than in other parts of the body. A recent large study on this topic reported a lower number of positive sentinel nodes and higher false-negative rates for sentinel lymph nodes biopsies in the head and neck area than in other body parts.22

    In contrast with suggestions from previous studies,1,23 we observed no significant difference in recurrence patterns between patients with DM and case-matched controls. Previous studies reported high local recurrence rates in patients with DM, although the most recent studies show somewhat lower local recurrence rates than earlier series. In this study we found a local recurrence rate of 7.9% as first recurrence and 11.2% as any recurrence. Although these rates are higher than for melanoma in general, they are not significantly higher than the local recurrence rates in the thickness-matched control group. However, initial local control, in terms of clear surgical margins, was significantly harder to obtain in the DM group; patients with DM required significantly more re-excisions.

    The difference in regional recurrence between the two groups also did not reach statistical significance, which is contrary to results from prior studies.1,11 However, although not statistically significant, the local recurrence rate is twice as high in the DM group compared with the control group, and the regional recurrence rate was approximately twice as low. Despite this large absolute difference and the fairly large study population of 267 patients, the frequency of these events was too low for this difference to be statistically significant. Because this is the first study to include a control group for statistical comparison, it was not possible to combine these data with those from previous publications to perform a meta-analysis.

    In a review of their experience with 92 patients with DM, Busam et al17 showed that a distinction can be made between combined DM (in which a desmoplastic component is seen in a lesion that is primarily a nondesmoplastic “conventional” invasive melanoma) and pure DM (in which the lesion is completely desmoplastic). In their series, in patients with pure DM, nodal status is negative more often and survival is better in pure DM compared with combined DM. Previously, Anstey et al24 did not find these differences after making a similar distinction, but their study population consisted of only 25 patients. In our series we did not distinguish between combined and pure DM. If combined versus pure DM histology proves to be an important prognostic variable, this factor may account for some differences in results between the studies. We did review the primary lesions of three of four patients with DM with positive nodes and found that one of these patients had pure DM. This patient had a primary lesion with a thickness of 7 mm that was diagnosed before the advent of sentinel lymph node biopsies, and multiple positive nodes were found after therapeutic lymph node dissection. Therefore, although we have no patients with pure DM with positive sentinel node biopsies, we believe that this procedure may be considered for patients with particularly thick pure-DM lesions.

    There was no difference in the number of patients with distant metastases between the groups. Numerous studies of general melanoma populations reported the lungs, liver, and bone as the most common sites of metastasis.25,26 The results of our study are in accordance with this result and show that DM does not differ significantly from other forms of melanoma with respect to preferential sites of distant metastasis.

    Previous studies provide conflicting conclusions concerning the prognosis of patients with DM versus non-DM, although the former usually present with locally more advanced disease.5,12,23

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