From the Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif (Dr Swetter); and the Departments of Dermatology (Drs Swetter and Harvell and Mr Ecker), Surgery (Dr Johnson), and Pathology (Dr Harvell), Stanford University Medical Center, Stanford, Calif. Dr Harvell is currently with North Georgia Dermatopathology, Marietta, Ga. The authors have no relevant financial interest in this article.
The term primary dermal melanoma has been used to describe a subtype of melanoma confined to the dermis and/or subcutaneous fat that histologically simulates metastasis but is associated with an unexpectedly prolonged survival. We report 7 cases of primary dermal melanoma diagnosed from 1998 to 2002 with no identifiable junctional or epidermal component or nevoid precursor. Histopathologic and immunohistochemical features were compared with known cases of cutaneous metastasis and nodular melanoma in an attempt to differentiate this entity from clinical and pathologic mimics.
Seven patients had a single dermal and/or subcutaneous focus of melanoma. Metastatic staging workup findings were negative, including results fromsentinel node and imaging studies. Mean Breslow depth was 7.0 mm, and mean maximum tumor diameter was 6.2 mm. The study cohort showed 100% survival at mean follow-up of 41 months (range, 10-64 months). Immunohistochemical analysis with S100, HMB-45, Ki-67, CD34, and p75 antibodies showed no significant staining patterns compared with metastatic and nodular melanomas.
Primary dermal melanoma appears to be a distinct subtype of melanoma based on the excellent prognosis associated with this case series and others. Additional research focusing on cause, appropriate staging, and outcome of previously identified solitary dermal metastasis is warranted to further delineate this entity.
THERE HAVE BEEN SEVERAL observations in the literature of so-called solitary metastasizing melanoma of unknown primary origin with unexpectedly prolonged survival. In particular, a report from the University of Michigan1 documented a cohort of 11 patients with melanomas confined to the dermis and/or subcutaneous fat that histologically simulated metastasis. The unusually high survival of that cohort prompted the authors to assert that these lesions likely did not represent metastases of unknown primary origin but were instead primary melanomas, called primary dermal melanomas, that arose within the dermis or subcutaneous fat.
We identified a nearly identical cohort of 7 patients within the Stanford Multidisciplinary Melanoma Clinic, the Veterans Affairs Palo Alto Health Care System (VAPAHCS) Mole/Melanoma Clinic, and the Stanford Dermatopathology database with clinical features most suggestive of a dermal and/or subcutaneous cystic process and histologic features most consistent with cutaneous melanoma metastasis. In all cases, metastatic staging workup findings were negative, including sentinel lymph node dissection, full body imaging studies with positron emission tomography or computed tomography, and brain magnetic resonance imaging.
According to the 2002 American Joint Committee on Cancer melanoma staging guidelines,2 these cases would be identified as stage IV M1a disease (distant skin/subcutaneous metastasis with normal lactate dehydrogenase findings; TNM classification, any T, any N, M1a) and carry an estimated 5-year survival of 19%. Our cohort exhibited 100% survival at up to 5 years of follow-up (mean, 41 months), markedly better than what would be expected for primary cutaneous melanoma with similar Breslow thickness or metastatic melanoma of unknown primary origin. We describe this unique cohort in detail and compare histologic and immunohistochemical properties with known cases of nodular and metastatic melanoma.
Following approval by the panel on human subjects in medical research (institutional review board) at Stanford University and the VAPAHCS research and development committee, we conducted a retrospective review of patients presenting to the Stanford Multidisciplinary Melanoma Clinic and the VAPAHSC Mole/Melanoma Clinic with a histologic diagnosis suggestive of metastatic melanoma. We searched the Veterans Affairs Tumor Registry melanoma database from 1990 through 2002 for similar cases, and the Stanford dermatopathology database from 1995 through 2002. The total number of melanoma cases from the Stanford and VAPAHCS melanoma databases was 1800.
The initial biopsy specimen from each case demonstrated a solitary circumscribed dermal melanoma without an associated nevoid precursor, follicular epithelium connection, or a dermal-epidermal junctional component despite examination of multiple sections. Histopathologic inclusion criteria were (1) a dermal-based melanocytic neoplasm, typically with nodular or multinodular architecture; (2) well-accepted features of malignancy, including cytologic atypia, numerous mitoses, and areas of necrosis; (3) no evidence of an intraepidermal (in situ) component even with multiple sections; (4) absence of ulceration (which may have precluded identification of an intraepidermal component); (5) positive findings for S100; (6) absence of continuity with large peripheral nerves (to distinguish the lesions from malignant neural tumors, which are also S100 positive); (7) absence of a preexisting melanocytic nevus; and (8) absence of regression. No primary lesion or visceral metastasis was identified in the study cohort, and the resultant diagnosis was primary dermal melanoma.
To discern whether primary dermal melanoma could be distinguished from cutaneous metastasis of melanoma, we compared histopathologic and immunohistochemical features of our cases with cutaneous metastasis seen in 7 patients with known stage IV melanoma. We also compared the immunohistochemical features of dermal melanomas with 4 primary nodular melanomas. The additional cases of cutaneous metastasis and nodular melanoma were culled from the Stanford dermatopathology archives. The following antibodies were used for the immunohistochemical comparison: S100 (BioGenex, San Ramon, Calif), HMB-45 (Novocastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom), Ki-67 (Dako Corporation, Carpinteria, Calif), CD34 (Becton Dickinson, San Jose, Calif), and p75 (Dako Corporation).
To determine any possible relationship with unique subtypes of melanoma, we studied the dermal melanomas for p75 and CD34 expression. p75 was chosen because it is preferentially expressed in desmoplastic melanomas.3,4 CD34 was chosen for its documented expression in 2 rare dermal-based melanocytic proliferations of uncertain biological potential—CD34-positive cellular blue nevus5 and neurocristic hamartoma.6 The latter lesion is hypothesized to derive from primitive neurocristic cells capable of melanocytic differentiation, and it not infrequently undergoes malignant transformation.
Seven cases of primary dermal melanoma were identified, including 2 women and 5 men (median age at diagnosis, 75 years; age range, 22-85 years); all were white (Table 1). Clinical descriptions of lesions included "violaceous papule," "subcutaneous cyst," "gray cystic lesion," "ill-defined multilobulated subcutaneous mass," "bluish dermal nodule," and "amelanotic inflamed cyst." Clinical differential diagnoses included cyst/ruptured follicle, morphea, basal cell carcinoma, squamous cell carcinoma, dermatofibroma, hemangioma, and in 1 case melanoma (Figure 1). The histologic diagnosis of probable metastatic melanoma was made in all cases, and wide local excision of the dermal lesion was performed in each case.
Bluish dermal nodule on the left upper arm. This lesion represents the only case in the series in which "melanoma" was listed in the differential diagnosis.
All patients underwent metastatic staging workup including sentinel lymph node biopsy, and 6 of the 7 patients had negative findings on chest, abdomen, and pelvis computed tomography and/or whole-body positron emission tomography. The other patient had a negative chest radiograph. Five of the 7 patients also underwent brain magnetic resonance imaging, which showed no evidence of metastasis. Sentinel lymph nodes were negative for micrometastasis in 6 cases. A specimen from 1 patient was lost in histopathologic processing and so was unavailable for pathologic review. This same patient was the only one to experience a local recurrence 7 months after diagnosis consisting of a solitary satellite metastasis adjacent to the melanoma scar. This was subsequently excised, and repeat imaging studies were again negative for nodal or visceral metastasis. Two of the 7 patients received 1 year of adjuvant therapy with high-dose interferon according to the standard US Food and Drug Administration–approved regimen.7 Six of the 7 patients have been closely observed at Stanford University Medical Center and VAPAHCS following diagnosis, and all patients were disease free as of June 2003 after a mean follow-up of 41 months (range, 10-64 months).
Histopathologic assessment of the 7 cases revealed dermal-based melanocytic neoplasms with well-accepted superimposed features of malignancy including cytologic atypia, excessive mitotic activity, and in 3 of 7 cases, areas of zonal necrosis (Figure 2). Architecturally, the melanocytes were arranged as either single or multiple expansile nodules, usually with rounded and pushing margins. Despite examination of multiple sections, there was no evidence of an intraepidermal component, and in 6 of 7 cases there was a distinct Grenz zone that separated the dermal neoplasm from the overlying epidermis (Figure 2A). Individual melanocytes were epithelioid in shape in 4 cases, spindled in 1 case, and both epithelioid and spindled in 2 cases. Heavy cytoplasmic melanin characterized 2 cases, but the remaining 5 were either sparsely pigmented or without discernible melanin pigment. A lymphocytic host response was seen at the periphery of the neoplasm in 6 of 7 cases, but none showed features that would suggest a displaced lymph node. In all cases, there was no definite evidence of blood vessel or lymphatic invasion, and, as required for inclusion into the study, there was no evidence of ulceration or regression. Furthermore, the original reviewing pathologist had considered the possibility of metastatic melanoma in all cases.
A, Scanning magnification (×2) of a primary dermal melanoma (case 4); note the well-circumscribed dermal nodule separated from the overlying epidermis by a narrow Grenz zone. B, Single high-power field (original magnification ×40) of the same case with 4 mitotic figures (arrows) (hematoxylin-eosin used for both images).
Traditional Breslow depth, as measured from the top of the granular layer to the deepest aspect of the tumor, ranged from 2.5 to 11.7 mm with a mean depth of 7.0 mm. Because there was an obvious discrepancy between the measured Breslow depth and clinical outcome, we sought an alternative measurement of maximum tumor diameter in the vertical plane. This ranged from 2.4 to 8.9 mm (mean, 6.2 mm) (Table 2).
All 7 cases were S100 positive and 6 of 7 were HMB-45 positive (Table 2). Proliferation rate as estimated by Ki-67 ranged from 10% to 30%. None of the dermal melanomas was positive for CD34. Reactivity for p75 was present in only 2 of 6 tested cases and only in a small subset of the neoplastic cell population. As can be seen from Table 2, the antibodies selected for this study revealed no distinctive immunohistochemical differences between primary dermal melanomas, cutaneous metastases, and primary nodular melanomas.
Melanoma confined to the dermis or subcutaneous tissue in the absence of a known primary tumor is generally classified as stage IV disease, according to the 2002 American Joint Committee on Cancer melanoma staging guidelines.2 Stage IV M1a melanoma is associated with a poor prognosis: an estimated 37% 2-year and 19% 5-year survival rate.2 Over the past 5 years, we have identified 7 (0.39%) of 1800 total patients who presented with a solitary focus of melanoma confined to the dermis or subcutaneous tissue with no known primary tumor and negative metastatic findings. This low prevalence is similar to the 0.61% reported by Bowen et al,1 0.92% by Giuliano et al,8 and 0.51% by Schlagenhauff et al.9 Most importantly, these patients remain disease free after up to 5 years of follow-up and show unprecedented survival (100%) compared with typical stage IV M1a melanoma survival rates.
The estimated 5-year survival in patients with melanoma of unknown primary site has ranged from 15% in series of patients with distant (non–lymph node) disease to 100% in patients with solitary cutaneous metastasis alone.1,8- 15 Our high survival rate is similar to that reported in 4 other case series of presumptive primary dermal melanoma. Specifically, Schlagenhauff et al9 reported an 83% 5-year survival in 38 patients with "cutaneous or subcutaneous in-transit metastasis with unknown primary"; Giuliano et al8 reported an apparent 80% 5-year survival in 4 of 5 patients with "subcutaneous metastases without visceral disease"; and Anbari et al13 reported a 4-year survival of 100% in 3 patients with a "solitary subcutaneous melanoma nodule of unknown primary site." All patients were treated with surgical resection alone. In a review by Bowen et al of "solitary melanoma confined to the dermal and/or subcutaneous tissue,"1 the Kaplan-Meier 8-year survival estimate was 83%, and 1 of 11 patients succumbed to pulmonary metastasis 46 months after observation. All patients in that series underwent wide local excision, and 1 received adjuvant therapy with interferon alfa. None underwent sentinel lymph node dissection.
Primary dermal melanoma may be clinically unrecognizable as an atypical melanocytic process because its features resemble a subcutaneous cystic or vascular process or nonmelanoma skin cancer (squamous cell carcinoma or basal cell carcinoma). In fact, "melanoma" was among the initial clinical differential diagnoses in only 1 of our 7 cases. Primary dermal melanoma does not appear to localize to any specific region on the body: the head, neck, trunk, and extremity locations were all reported in our case series and others.1,13 Likewise, it does not affect one particular age group, although 6 of 7 of our patients were older than 65 years, which is similar to the mean age of 55.7 years described by Bowen et al.1
Given that these neoplasms arise primarily within the dermis, we believed that the traditional Breslow depth measurement from the top of the granular layer to the deepest portion of tumor might overestimate clinical aggressiveness. An alternative measure of maximum tumor diameter in the vertical plane was recorded to determine if it would more accurately reflect the uniformly favorable long-term outcome observed in our series. As seen in Table 2, the mean of this surrogate measure (6.2 mm) differed only minimally from the mean Breslow measure (7.0 mm), and it too would have predicted for a clinically aggressive melanoma in all cases.
The histopathologic differential diagnosis for primary dermal melanoma includes cellular blue nevus, nodular melanoma, clear cell sarcoma, malignant peripheral nerve sheath tumor, malignant blue nevus, and, of course, metastatic melanoma. Primary dermal melanoma may exhibit features that overlap with other dermal-based S100-positive entities. However, clinical and/or histologic features help distinguish this entity from malignant cellular blue nevus, clear cell sarcoma, and malignant peripheral nerve sheath tumor.1
The heavy cytoplasmic pigmentation and spindled morphology seen in 2 of the 7 cases made us strongly consider the possibility of malignant blue nevus. There is no doubt that on histologic grounds, 2 of our cases could be considered examples of malignant blue nevus by some experts.16 Malignant blue nevus is an exceedingly rare form of melanoma associated with a very poor prognosis. Barnhill17 and others18,19 reserve the diagnosis of malignant blue nevus for those examples that clearly arise from a preexisting benign blue nevus. In this respect, the 2 cases with blue nevus features would not be considered true examples of malignant blue nevus because they were uniformly atypical throughout and lacked a discernible benign or low-grade component. The remaining 5 cases would not likely be confused with malignant blue nevus because they lacked heavy cytoplasmic pigmentation and exhibited epithelioid rather than spindled or dendritic cellular morphologic features.
The distinction between primary dermal melanoma and nodular melanoma rests largely on identifying an intraepidermal component within the latter. In some cases of nodular melanoma, the in situ component occupies only a small portion of the epidermis, which underscores the importance of examination of multiple sections before concluding that an intraepidermal component is absent. It could be argued that the primary dermal melanomas of this series represent nothing more than nodular melanomas in which the intraepidermal component is inconspicuous or very minor. However, the absence of sentinel lymph node metastasis in 6 of 7 completed cases and the markedly high overall survival of our cohort (100% in up to 5 years of follow-up) compared with nonulcerated nodular melanomas with similar Breslow depth (stage IIB, T4a N0 M0, with 67% estimated 5-year survival)2 suggests a different biological progression. Other studies of presumed primary dermal melanoma have documented a similar favorable prognosis, again supporting the notion that this entity is distinct from the nodular melanoma subtype.1,2,8,9,12,13
Perhaps the most important distinction to be made is with metastatic melanoma, since the prognoses for stage IV melanoma and primary dermal melanoma are vastly different. Unfortunately, in comparing the 7 primary dermal melanomas with 7 known cutaneous metastases of melanoma, we could find no reliable histopathologic or immunohistochemical differences. Thus, the distinction is ultimately a clinical one that documents a lack of any primary cutaneous or visceral melanoma, lack of a prior melanocytic lesion that has either spontaneously regressed or been destroyed without pathologic examination, and lack of other nodal, visceral, or central nervous system metastasis at presentation.
The dramatic difference in survival of our melanoma cohort compared with cases of stage IV M1a melanoma strongly suggests that primary dermal melanoma represents a unique subtype of melanoma, which may even be biologically less aggressive than primary melanoma of similar Breslow thickness. Bowen et al1 postulate that primary dermal melanoma may arise from nonepidermal melanocytes, from melanocytes associated with deeper appendageal structures, or from embryologic-melanocyte migration remnants; its true origin remains unclear. Likewise, no specific immunohistochemical staining pattern can be used to differentiate primary dermal melanoma from nodular or metastatic melanoma. The diagnosis of primary dermal melanoma requires clinicopathologic correlation and should be considered in patients with a solitary melanoma confined to the dermis and/or subcutaneous tissue with no identifiable primary site and no evidence of disease elsewhere. Subsequent larger studies are warranted to evaluate appropriate metastatic staging and to confirm the high survival rate for this subtype of melanoma.
Corresponding author and reprints: Susan M. Swetter, MD, Department of Dermatology, Stanford University Medical Center, 900 Blake Wilbur Dr, W0069, Stanford, CA 94305 (e-mail: firstname.lastname@example.org).
Accepted for publication July 18, 2003.
We acknowledge Duke Khuu, MD, for his assistance with initial data collection as a Stanford medical student. We also greatly appreciate the helpful suggestions and manuscript review by Richard W. Sagebiel, MD.
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