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Background
Melanoma can be a simple cancer for the pathologist to diagnose under the microscope or it can be one of the most difficult. It is often a mimic of other cancers and the pathologist may rely upon specialized studies such as special stains or immunoperoxidase studies to confirm the diagnosis.
OUTLINE
HISTOLOGICAL TYPES CHARACTERIZATION BIOPSY SAMPLING
- Impact of thorough block sampling in the histologic evaluation of melanomas.
Dyson SW, Bass J, Pomeranz J, Jaworsky C, Sigel J, Somach S.
Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Arch Dermatol. 2005 Jun;141(6):734-6. Abstract quote
OBJECTIVE: To determine if changes in histologic parameters obtained from intermittent sampling of the entire block correlated with differences in prognosis and management.
DESIGN: Prospective analysis of skin biopsy specimens.
SETTING: Skin pathology laboratory.Patients One hundred consecutive patients with an unequivocal diagnosis of melanoma.Interventions Two initial slides were prepared from serial sections of 5-mum thickness. When evaluation of the initial slide revealed melanoma, 5 additional slides were obtained by sectioning at levels through the entire block. Breslow depth, Clark level, ulceration, tumor infiltrating lymphocytes, vascular invasion, regression, presence of a precursor lesion, and histologic type of melanoma for the first slide and the additional 6 slides were analyzed and compared.
RESULTS: Review of the additional 6 slides from level sectioning revealed a greater maximum tumor thickness than was evident from the original slide in 43% of the cases. In 10 of these cases, the new maximum tumor thickness measurements changed the surgical management of the patients. Ulceration was observed in 6% of cases on the initial slides, and an additional 3% of lesions were found to have ulceration on levels. The level of invasion was deeper than originally found in 10% of the cases.
CONCLUSIONS: Level sectioning through an entire block of a melanoma specimen provides additional information in the classification and management of melanomas. Extensive block sampling will result in more accurate information regarding histologic parameters of melanoma, but the yield must be balanced with the extra cost of materials, time, labor, and the potential disadvantage of not retaining tissue for future use.
- Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma.
Karimipour DJ, Schwartz JL, Wang TS, Bichakjian CK, Orringer JS, King AL, Huang CC, Johnson TM.
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Am Acad Dermatol. 2005 May;52(5):798-802. Abstract quote
BACKGROUND: A significant portion of cutaneous melanoma may remain after subtotal incisional biopsy. The accuracy of microstaging and impact on clinical practice in this scenario are unknown.
OBJECTIVE: Our purpose was to examine microstaging accuracy of an initial incisional biopsy with a significant portion of the clinical lesion remaining (> or =50%).
METHODS: Patients with cutaneous melanoma, diagnosed by incisional biopsy with > or =50% of the lesion remaining, were prospectively evaluated for microstaging accuracy, comparing initial Breslow depth (BD1) to final depth (BD2) after excision of the residual lesion. Impact on prognosis and treatment was also evaluated.
RESULTS: Two hundred fifty of 1783 patients (14%) presented with > or =50% residual clinical lesion after incisional biopsy. The mean BD1 was 0.66 mm; the mean BD2, 1.07 mm (P = .001). After complete excision of the residual lesion, upstaging occurred in 21% and 10% became candidates for sentinel node biopsy.
CONCLUSION: An incisional biopsy with > or =50% clinical lesion remaining afterward may be inadequate for accurate microstaging of melanoma. This scenario is relatively uncommon but clinically significant.FROZEN SECTIONS Are En Face Frozen Sections Accurate for Diagnosing Margin Status in Melanocytic Lesions?
Victor G. Prieto, MD, PhD,
Zsolt B. Argenyi, MD, Raymond L. Barnhill, MD, etal.Am J Clin Pathol 2003;120:203-208 Abstract quote To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly.
Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per dermatopathologist and per case.
One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (6.8%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (k range per dermatopathologist, –0.1282 to 0.6615).
If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions.SECOND OPINION
Pitfalls in the diagnosis of malignant melanoma: findings of a risk management panel study.
Troxel DB.
Department of Pathology, Mt. Diablo Medical Center, Concord, CA, USA.
Am J Surg Pathol. 2003 Sep;27(9):1278-83. Abstract quote
The misdiagnosis of melanoma is a major cause of malpractice claims involving pathologists and dermatologists.
A detailed analysis of individual surgical pathology and cytology claims (excluding Pap smears) reported to The Doctors Company from 1995 through 2001 revealed that 46 of 362 claims (13%) involved the misdiagnosis of melanoma; 70% of these claims were for false-negative diagnoses. Melanoma claims were second only to claims involving breast biopsy. A Melanoma Risk Management Panel of expert dermatopathologists was convened to discuss recurrent "problem areas" identified by the author in claims reviewed from 1998 through 2001.
The purpose was to devise useful strategies that pathologists and dermatologists could use in their practices to reduce the risk of diagnostic error and/or patient mismanagement when dealing with melanocytic lesions. The panel's findings and recommendations are the subject of this review.
Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.
Scolyer RA, Shaw HM, Thompson JF, Li LX, Colman MH, Lo SK, McCarthy SW, Palmer AA, Nicoll KD, Dutta B, Slobedman E, Watson GF, Stretch JR.
Department of Anatomical Pathology, and Sydney Melanoma Unit, and the Melanoma and Skin Cancer Research Institute, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Am J Surg Pathol. 2003 Dec;27(12):1571-6. Abstract quote
BACKGROUND: The prognosis for patients with localized primary cutaneous melanoma is known to depend principally on tumor thickness, and to a lesser extent on ulcerative state and Clark level. We have recently found in an analysis of 3661 patients that tumor mitotic rate (TMR) is also an important prognostic parameter, ranking second only to tumor thickness. However, few studies have assessed the accuracy and reproducibility with which these features of a melanoma are recorded by histopathologists. AIM: To assess interobserver reproducibility of major pathologic prognostic parameters in cutaneous melanoma.
METHODS: Single hematoxylin and eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were circulated among six pathologists with differing experience in the assessment of melanocytic tumors. The observers independently determined the tumor thickness, Clark level of invasion, ulcerative state, and TMR for each lesion. Intraclass correlation coefficients and kappa scores for multiple ratings per subject were calculated.
RESULTS: The intraclass correlation coefficients were 0.96 for tumor thickness and 0.76 for TMR. The kappa scores were 0.83 for ulcerative state and 0.60 for Clark level. These results indicated excellent agreement among the pathologists for measurements of tumor thickness, ulcerative state, and TMR and fair to good agreement for Clark level.
CONCLUSIONS: Appropriately trained and experienced histopathologists can assess prognostically important features of melanomas accurately and reproducibly. Given our recent finding of the significance of TMR in determining prognosis, it is important that this feature be assessed by a standardized method and documented for all primary cutaneous melanomas.Quality assessment by expert opinion in melanoma pathology: experience of the pathology panel of the Dutch Melanoma Working Party.
Veenhuizen KC, De Wit PE, Mooi WJ, Scheffer E, Verbeek AL, Ruiter DJ.
Institute of Pathology, University Hospital Nijmegen St. Radboud, The Netherlands.
J Pathol 1997 Jul;182(3):266-72 Abstract quote
Some cutaneous melanocytic lesions are notoriously difficult to diagnose by histopathology. For that reason, the Pathology Panel of the Dutch Melanoma Working Party was instituted and is regularly approached to provide an expert opinion on problem cases.
In order to identify the most common diagnostic problems, 1069 consecutive referral cases of submitted lesions (1992 to 1994 inclusive) were analysed. About 60 per cent of the requests came from small laboratories, with up to three consultant pathologists. Two-thirds of the lesions reviewed concerned women and nearly 50 per cent of the patients were 30 years of age or younger. In 8 per cent of the cases, the referring pathologists felt unable to make a confident diagnosis; in 14 per cent, melanoma was suspected; and in 12 per cent, a differential diagnosis only had been formulated. The panel felt able to provide an unequivocal diagnosis in 93 per cent of the requests. Of the 158 lesions classified as 'invasive melanoma' by the referring pathologists, 22 were considered to be benign by the panel. Conversely, 108 invasive melanomas (panel diagnosis) had originally been considered as benign lesions, dysplastic naevi or melanoma in situ. These high numbers of discordancies reflect the intrinsic difficulty of the differential diagnoses in this selected material submitted to the panel.
Diagnostic difficulties were most often encountered with Spitz naevi and dysplastic naevi. Although the rate of overdiagnosis and underdiagnosis is quite high, in the majority of cases the diagnosis of the referring pathologist matched the diagnosis of the panel. This may reflect a proper awareness of difficult melanocytic lesions in pathology practice. The activities of the Pathology Panel of the Dutch Melanoma Working Party contribute to the improvement of the quality of diagnosis in cutaneous melanocytic lesions, as they increase the number of unequivocal diagnoses and reduce the number of incorrect diagnoses. On the basis of the systematic comparison of the diagnosis by the referring pathologist and the panel, postgraduate teaching and quality control can be more focused on specific diagnostic problems.
Pathology Review of Cases Presenting to a Multidisciplinary Pigmented Lesion Clinic.McGinnis KS, Lessin SR, Elder DE, Guerry D IV, Schuchter L, Ming M, Elenitsas R.
Department of Dermatology, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104.
Arch Dermatol 2002 May;138(5):617-621 Abstract quote OBJECTIVES: To determine if pathology review, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis of melanocytic lesions and to ascertain if the change in diagnosis altered clinical management and outcome.
METHODS: Retrospective review of pathology reports, progress notes, and diagnoses entered in the University of Pennsylvania (Philadelphia) Pigmented Lesion Clinic database.
RESULTS: A total of 5136 primary melanocytic lesions from patients referred to the pigmented lesion clinic between 1991 and 1999 were reviewed by a single pathologist. Of these, 559 (11%) had diagnoses that were changed significantly from the submitting diagnosis, with 120 (2.3%) undergoing a "critical" revision, 63 (1.2%) defined as a change from malignant to benign, and 57 (1.1%) from benign to malignant; 171 (3.3%) remained within the same category (benign or malignant) but had a downgrade in diagnosis (less severe) that would have a significant impact on treatment, prognosis, and research. Likewise, 268 (5.2%) remained within the same category but had an upgrade in diagnosis (more severe) that would have a significant impact on the same parameters. In addition, 257 reexcisions of melanocytic lesions were reviewed, of which 15 (5.8%) were changed from clear to involved margins, while another 16 (6.2%) were changed from involved to clear margins, for a total of 12%. Of the lesions with a critical revision, follow-up was obtained in 98 (83%). The patients in the malignant-to-benign category were followed up for an average of 2.6 years while those in the benign-to-malignant category were followed up for an average of 4.2 years. The change of diagnosis from malignant to benign resulted in 9 patients (17%) being spared a reexcision while 12 patients (23%) were downgraded from a radical to moderate reexcision. The change in diagnosis from benign to malignant resulted in 45 patients (98%) requiring a reexcision after review. Twenty-five of these patients were found to have residual disease in their reexcision specimens or had already had recurrence at the excision site. Furthermore, 7 patients (15%) underwent lymph node dissection or sentinel lymph node biopsy after review. However, none of the nodes were positive for metastatic disease. During this time, 8 patients (17%) in the benign-to-malignant category, and 1 patient (1.9%) in the malignant-to-benign category (who had previously had 4 primary melanomas) developed metastatic disease.
CONCLUSIONS: Pathology review of primary melanocytic lesions, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis in a significant proportion of cases. These changes have important implications for clinical decision making, patient outcome, and research data collection.
VERTICAL GROWTH PHASE
Relevance of Vertical Growth Pattern in Thin Level II Cutaneous Superficial Spreading Melanomas.Lefevre M, Vergier B, Balme B, Thiebault R, Delaunay M, Thomas L, Beylot-Barry M, Machet L, De Muret A, Bioulac-Sage P, Bailly C.
Am J Surg Pathol. 2003 Jun;27(6):717-24. Abstract quote Thin (</=0.76 mm) level II cutaneous superficial spreading melanomas (SSMs) are known to be of excellent prognosis and very few recur, metastasize, or are lethal. Although many prognostic features at this stage have been studied, none appears to be statistically significant.
The concept of tumor growth phase is correlated with Clark's level except for level II. SSM level II show either an invasive vertical growth phase or an invasive radial growth phase. The aim of our study (retrospective, multicenter, and case-control type) was to investigate the prognostic impact of vertical growth phase in thin level II cutaneous SSM. We identified 12 patients of poor outcome with complete initial excision. Each case was matched with three controls for gender, age, location, tumor thickness, and follow-up period since diagnosis. Independent pathologists studied all cases and controls. Univariate analyses were performed with a conditional logistic regression method. A kappa test was used to assess reproducibility between pathologists. Our study is the first and largest that shows that vertical growth phase is the only statistically significant prognostic factor for thin level II cutaneous SSM.
We propose that growth phase evaluation (a minimum of eight serial sections being mandatory not to underdiagnose vertical growth phase) should be added to the recommendations for melanoma histologic report, at least for level II SSM.
Problems in the interpretation of apparent 'radial growth phase' malignant melanomas that metastasize.Abramova L, L Slingluff C, Patterson JW.
Departments of Pathology and Dermatology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA Division of Surgical Oncology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
J Cutan Pathol 2002 Aug;29(7):407-14 Abstract quote BACKGROUND: The delineation of radial and vertical growth phases in primary cutaneous malignant melanomas has contributed to our understanding of melanoma progression and has enhanced the ability of pathologists to provide clinicians with meaningful prognostic information. Vertical growth phase (VGP) lesions have the potential to metastasize, but radial growth phase (RGP) melanomas are believed to lack competence for metastasis.
METHODS: We have identified three cases in which metastasis occurred in association with lesions initially interpreted as RGP melanomas. To determine whether these cases truly represented exceptional metastasizing RGP melanomas or VGP lesions incorrectly identified as RGP lesions, careful microscopic re-review of these cases was performed.
RESULTS: In one case, additional microscopic sectioning revealed a focus of vertical growth that was not evident on the original sections. In the other two cases, only radial growth was found. In one of these cases there was melanoma in situ with regressive changes, but no evidence for invasive melanoma. In the other, a RGP lesion was associated with an adjacent compound nevus with periadnexal involvement.
CONCLUSIONS: These cases suggest that, while true RGP melanomas have an excellent prognosis, caution must be exercised in defining a lesion as having no metastatic potential when multiple sections of the primary lesion are unavailable, when the lesion is accompanied by regressive changes, or when there is an associated melanocytic nevus. It is possible that strictly defined RGP melanomas may metastasize in very rare cases. Our observations also suggest that metastatic potential is a function of numerous factors, and may not be evaluable on morphological grounds alone.
CYTOLOGY
Cytopathology of malignant melanoma in conventional and liquid-based smears.Morrison C, Young DC, Wakely PE Jr.
Department of Pathology, Ohio State University College of Medicine, Columbus 43210, USA.
Am J Clin Pathol 2002 Sep;118(3):435-41 Abstract quote We evaluated 62fine-needle aspiration (FNA) biopsy specimens of metastatic malignant melanoma (MM) from 62 patients and compared 84 smears with the corresponding tissue sections.
Melanin is found more often in FNA smears than in corresponding tissue sections of metastatic MM but is significantly less abundant in smears. Melanin is present more often in liquid-based than in conventional smears. Pseudoinclusions were almost twice as frequent in tissue sections as in corresponding aspirates, regardless of the preparation method.
There was no statistical difference for cell type or cytoplasmic features in the tissue sections and aspirates or between the type of preparation and/or stain used. With the exception of melanin, direct comparison of liquid-based and conventional smears showed higher cellularity in the former as the only difference.
MAIN HISTOLOGIC VARIANTS MELANOMA IN SITU
LENTIGO MALIGNA INVASIVE MELANOMAS
5-15%
Usually occurs on sun-exposed surfaces of elderly people, usually the face and upper extremities
Lentigo maligna (melanoma in situ) is the precursor lesion and presents as an irregular darkly pigmented macule
About 5% of lentigo malignas become invasive lentigo maligna melanomasEpidermal atrophy occurring on sun-damaged skin
Pleomorphic melanocytes are usually confined to the basal epidermal layer with little tendency for upward intraepithelial pagetoid spread
Usually considerable downward extension along adnexal epithelium.
50-75%
Occur anywhere on the body but particularly on the trunk in males and lower extremities in females
Proliferation of melanocytes through all layers of the epidermis (pagetoid spread)
If the melanoma is invasive into the underlying dermis, it may be present as solid masses
NODULAR MELANOMA
15-35%
Nodules or polypoid in appearance and are characterized by having no antecedent radial growth phase.
Expansile nodule of malignant melanocytes fills the dermis
By definition, a nodular melanoma is a level III melanoma and acks an adjacent intraepidermal component or radial growth phase
Usually epidermal involvement as the underlying melanoma may secondarily invade the epidermis
- Early detection of thick melanomas in the United States: beware of the nodular subtype.
Demierre MF, Chung C, Miller DR, Geller AC.
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
Arch Dermatol. 2005 Jun;141(6):745-50. Abstract quote
BACKGROUND: Incidence and mortality of melanoma in the United States have risen steeply. Part of this mortality increase may be related to late detection of biologically aggressive nodular melanomas. We determined trends in distribution of thin and thick melanoma, with emphasis on the histopathologic subtype nodular melanoma.
METHODS: Surveillance, Epidemiology, and End Results melanoma incidence data for whites were obtained for 1988 through 1999 and stratified according to histologic subtype: lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, other, and not otherwise specified (NOS); thickness: 0-0.99 mm, 1.00 mm-1.99 mm, and > or =2.0 mm; patient age (0-49, 50+); gender; and year (1988-1991, 1992-1995, 1996-1999). Comparison of tumor thickness between strata was defined by year of diagnosis, sex, age, and histologic subtype.
RESULTS: The number of new melanoma cases in a 3-year period increased 60% from 1988-1991 (n = 9132) to 1996-1999 (n = 14 575). The proportion of thick melanomas (> or =2 mm) remained relatively stable during the 12 study years. Nodular melanoma comprised 9% of all recorded cases but 34% of melanomas 2 mm or larger, including melanoma not otherwise specified (NOS), and nearly 50% of all melanomas 2 mm or larger when NOS cases were excluded. In contrast, superficial spreading melanoma was almost uniformly diagnosed as an early tumor, mostly (77%) presenting as thin melanoma (<1 mm) and with only 7% presenting as thick melanoma (> or =2 mm).
CONCLUSIONS: A substantial number of thick melanomas in the United States are of the nodular subtype, and median thickness of nodular melanoma has not changed during the 12 years of study. New strategies are needed to decrease the incidence of thick melanoma in the United States.
Nodular melanoma: Patients' perceptions of presenting features and implications for earlier detection.Chamberlain AJ, Fritschi L, Kelly JW.
Victorian Melanoma Service, Alfred Hospital, and the Department of Public Health, University of Western Australia.
J Am Acad Dermatol 2003 May;48(5):694-701 Abstract quote BACKGROUND: The incidence of thick melanoma and related mortality is largely static despite advances in early detection during the last 20 years. Nodular melanoma (NM) accounts for the majority of thick lesions and is difficult to recognize in the early stages of its evolution.
OBJECTIVE: The purpose of this study was to identify historic or clinical features that may facilitate earlier detection of NM.
METHODS: A questionnaire was administered to 125 patients attending the Victorian Melanoma Service between 1998 and 2000 with superficial spreading melanoma or NM. Parameters were compared by tumor type and thickness.
RESULTS: NMs are more often symmetric, elevated, uniform in color, and nonpigmented. Color change is uncommon.
CONCLUSION: NM often fails to fulfill the ABCD diagnostic criteria. Biopsy after a set period of observation should aid differentiation from inflammatory lesions and enable earlier detection of this subtype.ACRAL LENTIGINOUS MELANOMA 5-10%
Occur on the palms, feet, and the nailbeds
Lentiginous growth pattern with considerable upward intraepithelial scatter and nuclear pleomorphism
More common in Japanese and blacks
*Department of Anatomical Pathology ‡Sydney Melanoma Unit, Sydney Cancer Centre ¶Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital §Melanoma and Skin Cancer Research Institute ∥Discipline of Surgery, Faculty of Medicine **Discipline of Pathology, Faculty of Medicine, The University of Sydney ♯Skin and Cancer Foundation, Australia, Sydney, Australia †Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, Singapore.
Subungual melanoma (SUM) is an uncommon variant of melanoma that is often difficult to diagnose, both clinically and pathologically. In an attempt to provide pathologic clues to diagnosis, especially in early lesions or small biopsies, and to provide practical advice to pathologists in reporting, the clinicopathologic features of 124 cases of SUM were reviewed, the largest series reported to date.
The features of 28 cases of subungual melanoma in situ (MIS), comprising 4 cases of MIS and 24 cases where areas of MIS were present adjacent to dermal-invasive SUMs, were compared with those of a similar number of acral nevi to identify useful distinguishing features. The median age of the patients was 59 years and the most common site was the great toe (24%). Nine percent of cases were AJCC stage 0, 14% were stage I, 41% were stage II, 32% were stage III, and 4% were stage IV at initial diagnosis. The commonest histogenetic subtype was acral lentiginous (66%), followed by nodular (25%) and desmoplastic (7%). The majority of tumors were locally advanced at presentation with 79% being Clark level IV or V. The median Breslow thickness was 3.2 mm. The median mitotic rate was 3 per mm and 33% of cases demonstrated primary tumor ulceration. Seven of 29 patients (24%) who underwent a sentinel lymph node biopsy had nodal disease. Multivariate Cox-regression analysis showed higher disease stage to be the only significant predictor of shortened survival. In comparison to acral nevi, MIS more frequently showed lack of circumscription, a prominent lentiginous growth pattern, predominance of single cells over nests, moderate-to-severe cytologic atypia, a dense and haphazard pagetoid intraepidermal spread of melanocytes, and the presence of junctional/subjunctional lymphocytes ("tumor infiltrating lymphocytes"). Tumor infiltrating lymphocytes have not been highlighted previously as a feature of subungual MIS and represent a useful diagnostic clue.
Guidelines for the reporting of SUMs are also presented. Knowledge and recognition of the pathologic features of SUMs and the important features that distinguish them from nevi should reduce the frequency of misdiagnosis.
Acral lentiginous melanoma mimicking benign disease: The Emory experience.Soon SL, Solomon AR Jr, Papadopoulos D, Murray DR, McAlpine B, Washington CV.
Departments of Dermatology and Surgery-Surgical Oncology, Emory University School of Medicine, and the Bethesda Dermatopathology Laboratory.
J Am Acad Dermatol 2003 Feb;48(2):183-8 Abstract quote BACKGROUND: Plantar and subungual melanoma exhibits a higher misdiagnosis rate relative to other anatomic sites. Misdiagnosis and delay in diagnosis are statistically associated with poorer patient outcome. Awareness of atypical presentations of acral melanoma may, thus, be important to decrease misdiagnosis rates and improve patient outcome.
METHODS: We conducted a retrospective case review of plantar or lower-extremity subungual melanoma performed at Winship Cancer Center, a tertiary care, referral center affiliated with Emory University, between 1985 and 2001.
RESULTS: A total of 53 cases of plantar or lower-extremity subungual melanoma were identified. Of 53 cases with a final diagnosis of melanoma, 18 were initially misdiagnosed. Misdiagnoses included wart, callous, fungal disorder, foreign body, crusty lesion, sweat gland condition, blister, nonhealing wound, mole, keratoacanthoma, subungual hematoma, onychomycosis, ingrown toenail, and defective/infected toenail. Of the 18 misdiagnosed cases, 9 were clinically amelanotic.
CONCLUSION: Awareness that amelanotic variants of acral melanoma may assume the morphology of benign hyperkeratotic dermatoses may increase the rate of correct diagnosis and improve patient outcome.
Arch Otolaryngol Head Neck Surg 1989;115:374-9.
J Am Acad Dermatol 1995;32:717-25.
Cancer 1998;83:1128-35.Rare
Clinical presentation is that of a slow-growing (months to years), painless, innocuous, rarely ulcerating, frequently amelanotic nodule on sun-exposed areas on the head and neck and upper part of the trunk for male patients and the extremities for female patients.
Older men with a 2:1 male predilection
Melanoma cells usually have a bland spindled cell appearance and deceptively infiltrate deeply into the dermis
Usually a lentigo maligna junctional component which may provide a clue to the origin of the spindled cells
Usally amelanotic-immunoperoxidase stains are often needed to confirm the diagnosis. However, unlike most melanomas, 80% of these melanomas may be S-100 negative. In addition, HMB-45, a usually reliable melanoma specific marker is positive in only 0-20% of cases.
Occasionally, electron microscopy must be used in an attempt to identify premelanosomes, the diagnostic hallmark of melanocytes
Variant of desmoplastic melanomas known as neurotropic melanomas. These melanomas also have a spindled appearance with a propensity to form a circumferential arrangement around preexisting nerves. Both types of melanomas are prone to local recurrence.
- Expression of Melan-A and Ki-67 in desmoplastic melanoma and desmoplastic nevi.
Kucher C, Zhang PJ, Pasha T, Elenitsas R, Wu H, Ming ME, Elder DE, Xu X.
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Am J Dermatopathol. 2004 Dec;26(6):452-7. Abstract quote
BACKGROUND: Desmoplastic melanoma (DMM) is an uncommon melanoma variant with a distinct morphology, including a prominent spindle cell component with fibrosis, as well as a distinct immunohistochemical profile. Histologically, the spindle cell component of DMM can be confused with sclerotic/desmoplastic nevi, nonpigmented blue nevi, scar, and neural tumors. The histological distinction between sclerotic/desmoplastic/blue nevi and DMM using standard light microscopic techniques can be exceedingly subtle. Therefore, we investigated whether immunohistochemical staining for Melan-A and Ki-67 expression can be used to discriminate these lesions, distinguishing between epithelioid and spindle cell compartments of the lesions.
DESIGN: Fifty cases of DMM and 13 cases of sclerotic/desmoplastic/blue nevi were identified. Standard immunohistochemical techniques were used with antibodies towards HMB-45, Melan-A (A103), and Ki-67; 43 of 50 DMM cases were available for staining with Melan-A, 42 of 50 for HMB-45, and 31 of 50 cases were stained with Ki-67. All 13 nevi were stained for Melan-A and 8 for Ki-67. Immunoreactivity to Ki-67 antibody was scored as 0 to 5%, 6 to 10%, 11 to 30%, or greater than 30% positive tumor cells.
RESULTS: Only 3 of 43 and 3 of 42 of spindle cell compartments of DMMs were positive for Melan-A and HMB-45, respectively. Focal staining of epithelioid cells in the junctional component or superficial dermis was observed in 33% (14/43). In contrast, 100% of the 13 nevi were strongly positive for Melan-A (P < 0.001). Seventeen melanomas (55%) were 0 to 5% positive for Ki-67, five (16%) fell into the 6 to 10% category, three (10%) were between 11 and 30%, and six (19%) were at least focally greater than 30% positive. All 8 nevi (100%) had less than 5% positive cells for Ki-67 (P = 0.02), with only 2 cases having more than 2% positive cells.
CONCLUSION: The sclerotic/desmoplastic and hypopigmented blue nevi were uniformly positive for Melan-A, while the vast majority of DMM were negative in their spindle cell compartments. Melan-A is very useful in distinguishing between DMM and sclerotic nevi. Ki-67 appears to be an inconsistent marker for DMM. However, a high labeling index (over 5%) may be used as a clue in diagnosing DMM.
- Cutaneous Desmoplastic Melanoma: Reappraisal of Morphologic Heterogeneity and Prognostic Factors.
Busam KJ, Mujumdar U, Hummer AJ, Nobrega J, Hawkins WG, Coit DG, Brady MS.
From the Departments of *Pathology, daggerEpidemiology and Biostatistics, and double daggerSurgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
Am J Surg Pathol. 2004 Nov;28(11):1518-1525. Abstract quote
Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM).
We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1-4, >4 mitoses/mm; P = 0.01), and tumor thickness (<1 mm, 1-4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis.
Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.Desmoplastic malignant melanoma: diagnosis of early clinical lesions.
Wharton JM, Carlson JA, Mihm MC Jr. Division of Dermatopathology and Dermatology, Albany Medical College, NY 12208, USA.
Hum Pathol 1999 May;30(5):537-42 Abstract quote
Desmoplastic malignant melanoma (DMM) is an uncommon but potentially devastating malignancy that can be cured with early recognition and surgery. DMM has clinical as well as histological features that may be subtle and overlooked, or misdiagnosed as other benign or malignant lesions that would require less aggressive therapy for cure.
We have reviewed the preliminary clinical diagnoses and histological features of 18 cases of desmoplastic malignant melanoma, defined as either an inapparent lesion clinically, or a papule or small nodule less than 0.7 cm, which proved histologically to be DMM. Nine of 18 cases (50%) were clinically pigmented. Histologically, early lesions were characterized by superficial tumor fascicles, and random diffuse hypercellularity in the upper dermis identified as elongated hyperchromatic pleomorphic spindle cells with stromal myxoid change. Neuroidal melanocytic structures, invasion of adventitial dermis, islands of inflammation, and epidermal lentiginous melanocytic hyperplasia were often present.
The most reliable and characteristic features of an early lesion of DMM are aggregates of lymphocytes, tumor cell cytological atypia, stromal myxoid change, and poor circumscription of the dermal infiltrate. DMM is a disease best treated by complete excision at the time of initial surgery, but is also a lesion easily missed or misdiagnosed in the early stages. Features of early DMM are identified and illustrated to enable early diagnosis and cure of these lesions.
Desmoplastic and spindle cell melanomas express protein markers of the neural crest but not of later committed stages of Schwann cell differentiation.Huttenbach Y, Prieto VG, Reed JA.
Section of Dermatopathology, Departments of Pathology and Dermatology, Baylor College of Medicine, and Department of Pathology, UT-M.D. Anderson Cancer Center, Houston, TX, USA.
J Cutan Pathol 2002 Oct;29(9):562-8 Abstract quote BACKGROUND: The rare desmoplastic and spindle cell variants of malignant melanoma exhibit histological and biochemical features suggestive of early Schwann cell differentiation. These features include a spindle-shaped morphology, neurotropism, and the expression of the low affinity nerve growth factor receptor (p75NGFR).
METHODS: We evaluated by immunohistochemistry (using formalin-fixed, paraffin-embedded tissues) nine desmoplastic and three spindle cell melanomas for the expression of peripherin, p75NGFR, neural cell adhesion molecule (CD56/N-CAM), and growth-associated phosphoprotein-43 (GAP-43). Peripherin is expressed in the neural crest and in neurons, but not in cells committed to the Schwann cell lineage. p75NGFR and CD56/N-CAM also are expressed in early neural crest cells, but persist in unmyelinated and early premyelinating Schwann cells. GAP-43 is expressed in unmyelinated Schwann cells, but is downregulated in the later premyelinating to promyelinating stages of cells committed to the Schwann cell lineage.
RESULTS: Peripherin was expressed in 7/12 (58%), p75NGFR in 4/12 (33%), and CD56/N-CAM in 6/12 (50%) of the desmoplastic and spindle cell melanomas. GAP-43 was not expressed (0%) in any of the 12 melanomas (chi2, p = 0.05).
CONCLUSIONS: Desmoplastic and spindle cell melanomas express protein markers common to cells of the neural crest and to neurons similar to the immunophenotype previously reported for epithelioid cell melanomas. The expression of peripherin and the lack of expression of GAP-43 further define that these rare subtypes of melanoma do not recapitulate the later committed stages of Schwann cell differentiation.
Desmoplastic malignant melanoma of the lip: A report of 6 cases and review of the literature.Hui JI, Linden KG, Barr RJ.
Dermatopathology Laboratory, Department of Dermatology, University of California, Irvine.
J Am Acad Dermatol 2002 Dec;47(6):863-8 Abstract quote Desmoplastic malignant melanoma is a rare neoplasm consisting primarily of spindle-shaped melanoma cells embedded in a fibrous stroma, with approximately 6% of cases occurring in the lip. A literature search revealed that most reported cases occur in sun-exposed areas in older men. Few cases of desmoplastic malignant melanoma of the lip in young people (in their mid-twenties) have been described.
We report 6 previously undocumented cases of labial desmoplastic malignant melanoma occurring in young individuals and review 20 cases from the literature. Physicians should consider the possibility of desmoplastic malignant melanoma in young people who present with atypical lip lesions, which on histopathologic analysis demonstrate spindle-cell hyperplasia.
Although this diagnosis is rare and there have not been reports of such patients in the literature thus far, our findings should alert clinicians to the possibility of desmoplastic malignant melanoma as a diagnosis for lip lesions in young people.
ADDITIONAL VARIANTS-ALPHABETICAL
- Unusual histological variants of cutaneous malignant melanoma with some clinical and possible prognostic correlations.
Rongioletti F, Smoller BR.
Section of Dermatology, DISEM, University of Genoa, Italy.
J Cutan Pathol. 2005 Oct;32(9):589-603. Abstract quote
Malignant melanoma is known for the wide range of histological patterns it can assume mimicking other malignant tumors.
We present a review of most of the unusual histological variants of cutaneous melanoma and describe their immunohistochemical features, associate clinical findings, and possible behavior related to the histological subtype. In addition, we propose their classification into four groups corresponding to the (1) architectural patterns; (2) cytologic features; (3) stromal changes; and (4) the possible association of these findings (i.e. architectural + cytologic features).
Although most of these unusual variants have the same prognosis as conventional melanomas, with Breslow thickness and ulceration, being the most important predictor of survival in clinical stage I, some of them have a peculiar biologic behavior that the clinicians and the dermatopathologists should know in order to give melanoma patients all educational information available.ANIMAL TYPE MELANOMA
- Melanoma with prominent pigment synthesis (animal-type melanoma): a case report with ultrastructural studies.
Kazakov DV, Rutten A, Kempf W, Michal M.
Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen, Czech Republic.
Am J Dermatopathol. 2004 Aug;26(4):290-7. Abstract quote
Melanoma with prominent pigment synthesis or animal-type melanoma (ATM) is a very rare type of melanoma. Its histogenesis has not been elucidated and ultrastructural features have not been described in human beings.
We present an additional case of ATM in a 28-year-old woman with positive sentinel node biopsy and provide the results of electron microscopic studies. Histopathologically, the skin lesion was composed of heavily pigmented neoplastic cells mostly arranged as large sheets, focally also in a nodular growth pattern. After bleaching, the neoplastic cells demonstrated round nuclei with 1 or rarely 2 conspicuous nucleoli and a prominent nuclear membrane and abundant, gray, slate-like cytoplasm. Some cells demonstrated round cytoplasmic inclusions. There was no nuclear pleomorphism, and only a few mitotic figures could be found after extensive search. Multiple areas of necrosis en masse of tumor cells were seen.
The lymph node biopsy revealed a complete effacement of the lymph node architecture by the extensive proliferation of hyperpigmented cells in the parenchyma. Immunohistochemically, the same pattern of staining was seen on the bleached and unbleached slides both in the skin and in the lymph node. The neoplastic cells stained positively with MiTF (nuclei), NSE, NKI/C3, tyrosinase (weak), p53, and CD68. S-100 protein, HMB45, Melan A, Mac367, and lysozyme reacted negatively. Occasional cells (<1%) reacted with MIB-1.
Ultra-structural studies revealed that the neoplastic cells possessed a large, indented nucleus with a prominent nuclear membrane, a single (para) centrally located nucleolus, and peripherally marginated chromatin. The cytoplasm was abundant and contained numerous single melanosomes and rare compound melanosomes. The melanosomes were in stages II to IV of maturation, with a marked predominance of stage II and stage III melanosomes. There was a high number of aberrant melanosomes with a wide variety of configurations. Melanophages were a minor component of the lesion.
Our ultrastructural studies provide unequivocal evidence that ATM is a neoplasm of melanosome-producing cells. We also review the literature on ATM.Malignant melanoma with prominent pigment synthesis: "animal type" melanoma--a clinical and histological study of six cases with a consideration of other melanocytic neoplasms with prominent pigment synthesis.
Crowson AN, Magro CM, Mihm MC Jr.
Department of Laboratories, Misericordia General Hospital, Winnipeg, Manitoba, Canada.
Hum Pathol 1999 May;30(5):543-50 Abstract quote
Rare skin neoplasms in humans, comprising nodules of heavily melanized cells, mimic melanocytic neoplasms seen in horses and laboratory animals and thus are termed animal type melanomas. In part because of their rarity, behavior is unpredictable; many cases manifest a long indolent phase, and metastases are reportable.
Over 6 years, the authors encountered nine skin and one lymph node biopsy specimens from six patients in whom light microscopy of formalin-fixed, paraffin-embedded tissue sections stained with hematoxylin and eosin showed melanocytic neoplasms with prominent pigment synthesis. Clinical follow-up was obtained by telephone contact with clinicians. There were three women, two men, and one boy, aged 9 to 85 years, whose lesions were described as blue-black nodules with irregular borders from 1.0 to 4.0 cm in size, located on the scalp, lower extremities, back, and sacrum.
The dermatopathology comprised confluent dermal sheets of heavily melanized cells whose nuclei, where discernible, were large with irregularly thickened membranes, coarse chromatin, prominent, often spiculated nucleoli, and irregular parachromatinic clearing. Mitoses were infrequent. Four lesions had an epidermal component. One patient suffered metastases to regional lymph nodes, liver, and lungs with lethal effect, one experienced regional lymph node metastases but is still alive, one had local cutaneous metastases but was lost to follow-up, and one has a chest wall mass that has not yet been investigated.
This rare dermal-based melanocytic neoplasm with prominent pigment synthesis, the animal type melanoma, has a biological behavior difficult to predict on morphological grounds. We advise complete excision with a 1.0- to 2.0-cm margin of normal skin and clinical investigation for regional or distant metastases.
Animal Type Melanoma A Report of a Case with Balloon-cell Change and Sentinel Lymph Node Metastasis
Luis Requena, M.D.; Alberto de la Cruz, M.D.; Carmen Moreno, M.D.; Omar Sangüeza, M.D.; Celia Requena, M.D.
From Departments of Dermatology (L.R.) and Pathology (C.M.), Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Pathology (A. de la C.), Centro Oncológico de Galicia, La Coruña, Spain; Dermatopathology (O.S.), Wake Forest University, Winston Salem, NC, U.S.A. and Dermatology (C.R.), Hospital General, Valencia, Spain.
Am J Dermatopathol 2001;23:341-346 Abstract quote
Animal type melanoma is a rare histopathologic variant of melanoma characterized by sheets and nodules of heavily pigmented epithelioid melanocytes that involve the entire thickness of the dermis. This human neoplasm mimics melanocytic neoplasms seen in gray horses and laboratory animals; thus, is termed animal type melanoma. It is quite rare and, with only a few reported cases, its biological behavior is not well understood.
We report an example of animal type melanoma on the back of a 27-year-old man. The lesion showed areas of melanoma in situ, which ruled out the possibility of metastatic melanoma. Features of regression were also seen at dermo-epidermal junction and papillary dermis. In some areas, neoplastic melanocytes exhibited a balloon-cell appearance; in others the neoplasm was composed of sheets and fascicles of heavily pigmented epithelioid melanocytes that permeated the entire dermis and extended into the dermal-subcutaneous interface, mimicking a cellular blue nevus. Epithelioid melanocytes in deeper areas showed abundant, heavily pigmented cytoplasm and pleomorphic nuclei with prominent eosinophilic nucleoli and some mitotic figures. The neoplastic cells did not show evidence of maturation in deeper areas of the lesion. In some sections, a nodule of heavily pigmented epithelioid melanocytes was seen far from the main bulk of the lesion, at the dermal-subcutaneous interface, raising the possibility of a satellite lesion. A lymphoscintigraphy showed a sentinel lymph node in the right axilla and a subsequent axillary lymphadenectomy demonstrated that the architecture of the sentinel lymph node was effaced by metastatic melanoma. The patient received adjuvant chemotherapy with inteferon alfa-2b and four months after this treatment the patient is alive and well, without evidence of recurrences or additional metastases.
ANGIOMATOID MELANOMA Angiomatoid melanoma: a novel pattern of differentiation in invasive periocular desmoplastic malignant melanoma.
Baron JA, Monzon F, Galaria N, Murphy GF.
Jefferson Medical College and Thomas Jefferson University, Philadelphia, PA, USA.
Hum Pathol 2000 Dec;31(12):1520-2 Abstract quote
A case of locally invasive, long-standing desmoplastic and amelanotic malignant melanoma is described in an 84-year-old man.
Histologic examination of the involved periorbital tissue showed neoplastic foci exhibiting a novel pattern reminiscent of microvascular proliferation. These regions were characterized by malignant, S-100-positive tumor cells lining vessel-like spaces in transverse sections and forming tubuler-like structures in longitudinal sections.
Recent data indicate that melanoma cells may express genes and patterns of differentiation in vitro akin to endothelial cells. Because angiosarcoma often involves facial and scalp skin of elderly individuals, awareness of angiomatoid differentiation in melanoma has important diagnostic implications.
ANGIOTROPIC MELANOMA Angiotropic malignant melanoma: A rare pattern of local metastases
Anita Saluja, etal.
J Am Acad Dermatol 2001;44:829-32 Abstract quote
We report a case of angiotropic malignant melanoma and review previously reported cases. Vessel walls should be scanned for tumor cells in biopsy and re-excision specimens of melanoma.
BALLOON CELL MELANOMA Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.
Kao GF, Helwig EB, Graham JH.
Department of Pathology, Georgetown University Medical School, Washington, DC.
Cancer 1992 Jun 15;69(12):2942-52 Abstract quote Balloon cell malignant melanoma (BCMM) is a rare histologic variant of malignant melanoma (MM).
Thirty-four patients with BCMM from the files of the Armed Forces Institute of Pathology (AFIP) were studied by means of clinicopathologic correlation and histochemical, immunohistochemical, and ultrastructural methods to better define this entity.
The cytoplasmic features of the balloon cells observed in BCMM resemble those noticed in balloon cell nevus (BCN), but the presence of nuclear pleomorphism, atypia, and mitoses and the absence of intervening stroma help distinguish BCMM. The cells also show many histochemical, immunochemical, and ultrastructural features of conventional melanoma cells. Although it is generally believed that balloon melanoma cells represent a degenerative change, the immunohistochemical and electron microscopic findings suggest that the balloon tumor cells are most likely metabolically active melanocytic cells. Microscopically, BCMM also must be differentiated from other clear cell tumors such as clear cell sarcoma (MM of soft parts), hibernoma, xanthoma, sebaceous neoplasms, metastatic renal cell carcinoma, (malignant) clear cell acrospiroma, (malignant) granular cell tumor, granular (clear) cell basal cell carcinoma, clear cell syringoma, and atypical fibroxanthoma.
The prognosis of BCMM usually correlates with the tumor thickness similar to that in other histologic types of cutaneous MM. Nineteen (57.5%) of 33 patients with adequate follow-up information died of disseminated tumors from 2 months to 12 years after the initial treatment. Six (18.2%) patients developed local recurrences: four of these patients died of metastasis and two were alive with metastatic tumor at last contact.
Five (15.2%) patients were alive with metastatic tumors, and seven (21.2%) were alive without evidence of disease at last contact. Recognition of BCMM is important because of its malignant biologic behavior.
Glycogen-rich malignant melanomas and glycogen-rich balloon cell malignant melanomas: frequency and pattern of PAS positivity in primary and metastatic melanomas.
Nowak MA, Fatteh SM, Campbell TE.
Department of Pathology, Western Reserve Care System, Youngstown, Ohio 44501, USA.
Arch Pathol Lab Med 1998 Apr;122(4):353-60 Abstract quote
OBJECTIVE: After identifying a metastatic glycogen-rich balloon cell malignant melanoma, originally thought to be a benign clear cell tumor of the lung, we investigated the extent of positive reactions, or "positivity," of malignant melanoma to periodic acid-Schiff (PAS) staining.
METHODS: Frequency, intensity, and distribution of PAS positivity was studied in 61 excisional biopsy specimens from 58 patients with malignant melanoma. For comparison, 17 benign nevi from 10 patients were examined.
RESULTS: Positivity for PAS was seen in all cases. All malignant melanomas and benign nevi were characterized by weak, diffuse, diastase-resistant PAS positivity. Additionally, focal or diffuse, strong diastase-sensitive PAS positivity was observed in 9 of 61 melanomas (15%); 7 were metastatic and 2 were primary invasive melanomas. Strong diastase-sensitive PAS positivity was seen in all lesions with 30% or more balloon cell features and only in advanced primary or metastatic lesions. The presence of glycogen was confirmed by transmission electron microscopy.
CONCLUSIONS: Cutaneous malignant melanomas have weak, diastase-resistant PAS positivity. Strong diastase-sensitive PAS positivity, consistent with the presence of intracytoplasmic glycogen, is seen in many primary and metastatic melanomas with balloon cell features. Depending on the content of the balloon cells, these melanomas are best categorized as either glycogen-rich malignant melanomas or glycogen-rich balloon cell malignant melanomas. Because many tumors with clear cell features contain glycogen, such content often is an unreliable differential feature.
CHONDROID MELANOMA Primary chondroid melanoma
Christopher D. Ackley1, Victor G. Prieto1,2, Rex C. Bentley1, Marcelo G. Horenstein1, Hilliard F. Seigler3 and Christopher R. Shea1,2 1
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA, 2 Department of Medicine, Division of Dermatology, Duke University Medical Center, Durham, North Carolina, USA, 3 Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
Journal of Cutaneous Pathology 2001;28 (9), 482-485 Abstract quote
Background: Malignant melanoma is notorious for the wide range of histologic patterns it can assume, among the least frequent of which is chondroid melamona.
Methods: Two cases of primary chondroid melanoma of the distal lower extremity were studied. Tissue for light microscopy was fixed in formalin, embedded in paraffin, and processed routinely. In one case, transmission electron microscopy and immunohistochemical evaluation were performed.
Results: Both cases exhibited melanoma in-situ, a conventional (non-chondroid) invasive component, and areas of chondroid differentiation, as confirmed by strongly positive staining with Alcian blue at pH 2.5 and Safranin O. Immunohistochemically, one case expressed S-100 protein and vimentin, and did not express gp100 (HMB-45), tyrosinase, MART-1, the Mel-5 antigen, the NKI/C3 antigen, CD45Ro, cytokeratin, or desmin. Electron microscopy of the chondroid component revealed occasional tumor cells with rare, membrane-bound, electron-dense organelles; the extracellular compartment showed amorphous ground substance consistent with cartilaginous differentiation.
Conclusions: Chondroid change in the absence of osteogenic differentiation is extremely rare in malignant melanoma. Melanoma should be considered in the differential diagnosis of primary cutaneous neoplasms exhibiting cartilaginous differentiation.
DERMAL MELANOMA Primary Dermal Melanoma Distinct Immunohistochemical Findings and Clinical Outcome Compared With Nodular and Metastatic Melanoma
David S. Cassarino, MD, PhD; Erik S. Cabral, BS; Reena V. Kartha, PhD; Susan M. Swetter, MD
Arch Dermatol. 2008;144(1):49-56. Abstract quote Objective To provide an updated and expanded analysis of clinical outcome and immunohistochemical (IHC) findings unique to primary dermal melanoma (PDM) that may be used to differentiate this entity from primary nodular melanoma (PNM) and cutaneous metastatic melanoma (MM).
Design Cohort analysis and extensive IHC panel comparing PDM with PNM and cutaneous MM.
Setting Melanoma clinics and pathology departments of academic and VA medical centers.
Patients Thirteen patients with a solitary dermal or subcutaneous nodule of histologically proven melanoma, prospectively followed through April 30, 2007.
Interventions Clinical, pathologic, and IHC assessment of patients diagnosed as having PDM.
Main Outcome Measures Long-term clinical outcome and determination of unique clinical and IHC features in the study cohort compared with other melanoma subtypes.
Results Histologically, there was no evidence of an overlying in situ component, ulceration, or regression, and there was no associated nevus in any cases. Clinical history and findings from workup, including imaging studies, skin examination, and sentinel lymph node biopsy, were negative for evidence of melanoma elsewhere. The mean Breslow depth was 9.6 mm. Two patients developed satellite or in-transit recurrences, 1 developed pulmonary metastasis, and another died of liver metastases. Overall, the cohort showed a 92% melanoma-specific survival rate at a mean duration of follow-up of 44 months. The IHC findings showed that PDM exhibited lower levels of staining for the antigens p53 (P = .02), Ki-67 (Mib-1) (P = .002), cyclin D1 (P = .001), and podoplanin (recognized by D2-40 antibody) lymphovascular staining (P <.001) compared with MM and PNM. All other markers were comparable.
Conclusions Patients with PDM have remarkably prolonged survival compared with patients with MM or PNM of similar thickness. Preliminary results suggest that PDM may be characterized by lower levels of p53, Ki-67, cyclin D1, and D2-40 compared with histologically similar MM and PNM.
Primary dermal melanoma: a distinct subtype of melanoma.
Swetter SM, Ecker PM, Johnson DL, Harvell JD.
Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif., USA.
Arch Dermatol. 2004 Jan;140(1):99-103. Abstract quote
BACKGROUND: 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.
OBSERVATIONS: Seven patients had a single dermal and/or subcutaneous focus of melanoma. Metastatic staging workup findings were negative, including results from sentinel 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.
CONCLUSIONS: 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.EXTRAVASCULAR MELANOMA
- Angiotropism of Human Melanoma: Studies Involving In Transit and Other Cutaneous Metastases and the Chicken Chorioallantoic Membrane: Implications for Extravascular Melanoma Invasion and Metastasis.
Lugassy C, Vernon SE, Busam K, Engbring JA, Welch DR, Poulos EG, Kleinman HK, Barnhill RL.
Departments of *Pathology paragraph signDermatology, University of Miami School of Medicine/Jackson Memorial Hospital, Miami, FL daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 double daggerNational Institute of Dental and Craniofacial Research (HKK, JAE), National Institutes of Health, Bethesda, MD section signDepartment of Pathology and Comprehensive Cancer Center (DRW), University of Alabama, Birmingham, AL.
Am J Dermatopathol. 2006 Jun;28(3):187-193. Abstract quote
Melanoma cell migration along the outside of vessels has been termed "extravascular migratory metastasis" (EVMM), as distinct from intravascular dissemination. Previous studies in both human and experimental melanoma models have shown angiotropism of melanoma cells, suggesting EVMM.
Our objectives are to study the mechanism of dissemination of human melanoma cells in the chick chorioallantoic membrane (CAM) and to compare the histopathology in the CAM with that of patients with in transit and other cutaneous melanoma metastases.Human and murine melanoma cells were inoculated onto the CAM and observed over a 10-day period for tumor dissemination. Both human melanoma specimens from 26 patients and melanoma cells growing on the CAM showed the presence of tumor cell angiotropism at the invasive front of the tumor and at some distance from the tumor mass. In addition, a clear progression of melanoma cells spreading on the CAM was observed along the abluminal surface of vessels, where they occupied a perivascular location. By day 10 after injection, small micrometastases had developed along vessels, in a pattern similar to that in transit and other cutaneous melanoma metastases. In addition, the results suggested that the number of micrometastases directly correlated with increasing tumor volume.
Taken together, these data suggest that the CAM is a relevant model for studying tumor cell dissemination, and that EVMM may be a mechanism by which some melanoma cells spread to nearby and even distant sites.
FOLLICULAR
BACKGROUND: Seborrheic keratosislike melanoma could be one of the most problematic melanoma simulators, and it may be incorrectly treated by electrocautery or cryotherapy. Dermoscopic examination of pigmented tumors improves the diagnostic accuracy in these challenging lesions. In these tumors, numerous comedolike openings are present.
OBSERVATIONS: A 34-year-old man was seen for a conspicuous pigmented lesion on his back that clinically resembled a seborrheic keratosis because of the presence of multiple comedolike openings. Findings from dermoscopic examination showed distinct melanoma criteria (atypical pigmented network, asymmetric globules and dots, and a blue-whitish veil), in addition to multiple comedolike openings. Histopathological examination confirmed a peculiar melanoma variant characterized by prominent folliculotropism and minimal radial spreading. This tumor was not associated with chronic sun-damaged skin.
CONCLUSION: Dermoscopy was useful in identifying a particular case of seborrheic keratosislike melanoma with folliculotropism, thus avoiding incorrect treatment.
- Follicular Malignant Melanoma: A Variant of Melanoma to be Distinguished from Lentigo Maligna Melanoma.
Hantschke M, Mentzel T, Kutzner H.
Dermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany.
Am J Dermatopathol. 2004 Oct;26(5):359-363. Abstract quote
Follicular malignant melanoma can be regarded as a rare and unique presentation of melanoma. It is characterized by a deep-seated follicular structure in which atypical melanocytes extend downward along the follicular epithelium and permeate parts of the follicle as well as the adjacent dermis. The clinical diagnosis of follicular malignant melanoma may be difficult because the tumor mostly resembles a comedo or a pigmented cyst.
We studied five cases of follicular malignant melanoma in which the patients were between 61 and 82 years old. Three lesions were localized on the nose, one on the cheek, and one on the back of the neck. Clinically, all five cases measured distinctly less than 0.5 cm in size. While lentigo maligna is traditionally known as a pigmented macule in actinically damaged skin that gradually evolves in a slow process before invasive growth, three follicular malignant melanomas had developed in relatively short timeframes of 9 months to 1 ½ years. In all five cases the inconspicuous clinical appearance did not herald a malignant melanoma with invasive growth.
Follicular malignant melanoma underlines the importance of a correct excision technique with subsequent histologic workup and diagnosis. Superficial shave excision or even laser treatment in these specific cases may lead to a fatal prognosis for the patient.GANGLIO-
NEUROBLASTIC DIFFERENTIATION
Ganglioneuroblastic differentiation in a primary cutaneous malignant melanoma.Grayson W, Mare LR.
Am J Dermatopathol 2003 Feb;25(1):40-4 Abstract quote Ganglioneuroblastic differentiation in malignant melanomas is an exceedingly rare event. Although there has been a single report of this occurrence in a metastatic melanoma, divergent ganglioneuroblastic differentiation has not been documented previously in a primary cutaneous lesion of melanoma.
The present report describes an unusual case of invasive melanoma arising on the lower leg of a 61-year-old woman. The 16.9-mm thick tumor showed extensive ganglioneuroblastic differentiation, which was confirmed both immunohistochemically and ultrastructurally.
Although the prognostic significance of this observation remains uncertain, the unique case reaffirms the potential morphologic diversity of melanomas and suggests a shared histogenetic origin from a common neural crest derivative.
GIANT CELLS
- Malignant melanoma with osteoclast-like giant cells: an unusual host response: immunohistochemical and ultrastructural study of three cases and literature review.
Al-Brahim N, Salama S.
From St. Joseph's Hospital and McMaster University, Hamilton, Ontario, Canada.
Am J Dermatopathol. 2005 Apr;27(2):126-9. Abstract quote
Melanomas with unusual histologic features are very rarely reported in the literature and demonstrate the diversity of melanocytic expression. Three cases of malignant melanoma with osteoclast-like giant cells are reported. Two cases showed undifferentiated malignant cells without melanin pigment and one showed spindled cell morphology.
Immunohistochemistry showed that the osteoclast- like giant cells expressed CD68, but not melanocytic markers (HMB45, Melan-A, and S100). Ultrastructural analysis further supports that these cells are reactive histiocytes rather than transformed malignant cells. This suggests they represent an unusual host response, similar to those rarely observed in other neoplasms. Awareness of this entity is important to avoid misdiagnosis of melanoma as a histiocytic tumor.
Since only few cases have been reported, greater recognition and documentation may help to evaluate the prognosis of such cases with unusual morphology.LIPOBLAST-LIKE CELLS Primary cutaneous malignant melanoma with lipoblast-like cells.
Cruz J, Reis-Filho JS, Lopes JM.
Department of Pathology, Sao Joao Hospital, and Medical Faculty, University of Porto, Porto, Portugal.
Arch Pathol Lab Med 2003 Mar;127(3):370-1 MINIMAL DEVIATION MELANOMA Clin Lab Med 2000;20:745-758
Controversial term coined by Richard Reed, M.D., a noted dermatopathologist at Tulane Medical School. He has described several histologic variants:
Spitz nevus-like variant
Pigmented Spindle Cell Variants
Halo Nevus-like variant
Dermal-type minimal deviation melanomas
Nevus cell variant
Ki-67 and p53 expression in minimal deviation melanomas as compared with other nevomelanocytic lesions.Chorny JA, Barr RJ, Kyshtoobayeva A, Jakowatz J, Reed RJ.
Dermatopathology Laboratory, University of California Irvine Medical Center, Orange, California 92868-3201, USA.
Mod Pathol. 2003 Jun;16(6):525-9. Abstract quote Minimal deviation melanoma is a controversial entity encompassing a heterogeneous group of lesions cytologically in the spectrum between recognized subtypes of nevi and conventional "primary configuration" melanomas and reported to have a better prognosis than the latter.
To evaluate the distinctiveness of minimal deviation melanoma, Ki-67 proliferation rates and p53 expression in minimal deviation melanomas were compared with those in compound nevi, Spitz nevi, and vertical growth phase superficial spreading malignant melanoma. Twelve examples of each lesion were immunostained with antibodies to the Ki-67 and p53 proteins and evaluated by a pathologist who was blind to the diagnoses.
The mean Ki-67 (MIB-1) proliferation rates for the compound nevi, Spitz nevi, minimal deviation melanomas, and superficial spreading malignant melanomas were 0, 3%, 13%, and 25%, respectively. The mean Ki-67 proliferation rate was statistically greater in the minimal deviation melanomas than in the compound nevi or the Spitz nevi (P <.05), but the proliferation rates in the two melanoma subtypes were not statistically significant (P =.08). The mean p53 values for these lesions were 0, 9%, 9%, and 26%, respectively; the latter two were statistically different (P <.01).
Based on these Ki-67 and p53 immunophenotypes, minimal deviation melanoma may represent a distinct entity.MONSTER CELLS
- Monster Cells in Malignant Melanoma.
Boyd AS, Wu H, Shyr Y.
From the Departments of *Medicine (Dermatology), daggerPathology, and double daggerPreventive Medicine, Vanderbilt University, Nashville, Tennessee.
Am J Dermatopathol. 2005 Jun;27(3):208-210. Abstract quote
Cells with significantly enlarged nuclei have been described in basal cell carcinomas, dermatofibromas, and pleomorphic fibromas, to name a few. These cells are typically visible using low power microscopy and have been termed "pleomorphic" or "monster cells." They have not been previously described in cutaneous melanomas.
We sought to determine the prevalence of monster cells in otherwise conventional biopsies of primary cutaneous melanomas and its association with other histopathologic features of this malignancy. Ninety-nine superficial spreading melanomas, nodular melanomas, and acral lentiginous melanomas/lentigo malignas were retrospectively evaluated for the presence of monster cells, multinucleated giant cells, ulceration, inflammation, and depth of invasion (Breslow level).Thirteen cases of melanoma containing monster cells were found.
A statistically significant association was noted between the presence of these cells, the histologic subtype of nodular melanoma (P = 0.0125), ulceration (P = 0.0127), the depth of invasion (P = 0.0103), and the presence of multinucleated giant cells (P = 0.0016). The finding of monster cells is not an uncommon occurrence and is seen more often in nodular melanomas.MYXOID MELANOMA
- Cutaneous melanoma with pseudomyxoid features.
Urso C.
Dermatopathology Section - Pigmented Skin Lesions, S. M. Annunziata Hospital - ASL 10 Florence, Florence, Italy.
J Cutan Pathol. 2006 Apr;33(4):312-4. Abstract quote
A 96-year-old man presented with a polypoid melanoma, which showed a prominent clear stroma, similar to that of myxoid melanoma, but stained negative for Alcian blue at pH 2.5 and for colloidal iron. It is not clear whether melanoma displaying pseudomyxoid features (pseudomyxoid melanoma) may represent a distinct histological variant of melanoma.
However, it must be differentiated from true myxoid melanomas, in which Alcian blue-positive acid mucopolysaccharides are present.Cutaneous melanoma with myxoid features: twelve cases with differential diagnosis.
Hitchcock MG, McCalmont TH, White WL.
Department of Pathology, TheWake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Am J Surg Pathol 1999 Dec;23(12):1506-13 Abstract quote
Substantial myxoid change can occur in malignant melanoma, but its importance in primary disease has not been systematically evaluated.
This report describes the clinical, microscopic, histochemical, and immunohistochemical findings in 12 patients with primary cutaneous malignant melanoma with myxoid features.
The tumors presented as solitary lesions situated on the limbs (six lesions), trunk (four lesions), and head and neck (two lesions). The patients included six women and six men, whose ages ranged from 26 to 95 years, with a mean of 63 years. Breslow thickness varied from 0.48 mm to more than 12 mm, with a mean of more than 3.2 mm. Clinical follow-up for an average of 22 months showed one local recurrence, but no evidence of metastases yet. In all cases, there was a combination of myxoid and nonmyxoid areas. A minimum of 15% myxoid cross-sectional area was required for inclusion in the study, and up to 80% was observed. The pale blue mucin identified on hematoxylin and eosin staining was sensitive to hyaluronidase and positive for alcian blue in the 10 cases stained. Immunohistochemical staining was positive for S-100 in all 9 cases stained, positive for HMB-45 in 9 (90%) of 10, and negative for cytokeratin in all 9 cases in which myxoid melanoma remained in the block after previous sections.
The presence of myxoid stroma did not define a biologically significant subgroup of melanoma. Only in cases with extensive (>50%) myxoid stromal effacement of the melanoma was there a major diagnostic hurdle. The diagnosis of primary cutaneous melanoma with myxoid features was seldom as problematic as metastatic myxoid melanoma. Positive S-100 stains, negative cytokeratin immunohistochemical stains, and hyaluronidase-sensitive alcian blue staining assisted in the diagnosis of this entity.
Myxoid melanoma: Immunohistochemical studies and a review of the literature
Purvisha Patel, BA
Kimberly Levin, MD
Karen Waltz, MD
Klaus F. Helm, MD
Hershey, PennsylvaniaJ Am Acad Dermatol 2002;46:264-70 Abstract quote
Malignant myxoid melanoma (MMM) is a rarely reported variant of malignant melanoma, which can often be confused with other mucin-containing neoplasms.
A retrospective study of 3 cases of MMM and a review of the English-language literature was performed. MMM affects an older population and is frequently misdiagnosed. The major pathologic features are atypical spindle cells embedded in a myxoid stroma. Immunohistochemistry analysis of the tumor shows uniform staining of the spindle cells with S-100. In our 3 cases, there were noticeably more mast cells that could be detected with Giemsa stain and with antibody against transforming growth factor. The prognosis appears to be equivalent to other primary melanomas. Diagnosing MMM requires a high index of suspicion.
We hypothesize that mast cells and secretion of transforming growth factor stimulates fibroblast secretion of mucin, which contributes to the tumor's invasive potential.
NEVOID MELANOMA Metastatic nevoid melanoma in a 41/2-year-old child
David S. Cassarino, Douglas R. Fullen, Vernon K. Sondak and Paul H. Duray
J Cutan Pathol 2003;30:647-651 Abstract quote
Background: Childhood melanoma is a rare and controversial diagnosis.Methods: We present the case of a 4-year-old child found to have an expanding, elevated pigmented lesion on her back.
Results: The biopsy showed a symmetrical, well circumscribed lesion. However, higher magnification revealed sheets of nevoid cells infiltrating deep into the dermis, lacking maturation, and exhibiting a high mitotic rate (average 5/10 high-power field) with deep mitoses. The possibility of nevoid melanoma was raised, and re-excision and sentinel lymph node (SLN) biopsy were recommended. Two SLNs were positive for melanoma, verified by immunohistochemical staining. In order to further characterize this melanoma, we performed immunohistochemistry for the tumor-suppressor p53, proliferation marker MIB-1, and oncogenes Bcl-2, cyclin D-1, and MDM-2. Staining for p53 was diffusely positive in the primary and the metastasis; MIB-1 showed moderate proliferative rate in the primary (approximately 10%); Bcl-2 was weakly positive in the primary and showed focal staining in the metastasis; cyclin D-1 was strongly positive in the primary and metastasis; and MDM-2 staining showed scattered positive cells in both lesions.
Conclusions: These findings are consistent with a metastatic nevoid melanoma arising in the absence of predisposing disease in a young child, a distinctly unusual occurrence.
Nevoid melanoma: a clinicopathological study of seven cases of malignant melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus.
Wong TY, Suster S, Duncan LM, Mihm MC Jr.
Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Hum Pathol 1995 Feb;26(2):171-9 Abstract quote
We report seven cases of a distinctive type of malignant melanoma characterized by a deceptively benign histological appearance with an architecture resembling that of benign melanocytic nevi on scanning magnification.
Two predominant architectural patterns were observed: a dome-shaped pattern (two specimens) and a verrucoid pattern (five specimens).
The specimens with a dome-shaped pattern of growth were characterized by a smooth epidermal surface and a proliferation of epithelioid melanoma cells with an inconspicuous intraepidermal component resembling spindle and epithelioid cell nevi (Spitz nevi). Gradual diminution in the size of dermal nests toward the bases of the lesions simulating the maturation phenomenon of benign nevi was observed; however, the dermal organization in cords and strands of melanoma cells and the persistence of cellular atypia extending to the bases of the tumors allowed their recognition as malignant melanomas.
On the other hand, the specimens with a verrucoid growth pattern consisted of broad, exophytic tumors with a verrucous epidermal surface resembling that of papillomatous dermal nevi but distinguished from them by the presence of a continuous proliferation of melanocytes along the dermal-epidermal junction and by confluent sheets of melanoma cells in the dermis without evidence of true maturation.
Clinical follow-up showed local recurrence in three patients after intervals ranging from 5 months to 5 years and regional metastasis in one patient after 2 years.
The lesions described here may constitute a serious pitfall for diagnosis because of their innocent silhouette on scanning magnification and their superficial resemblance to spindle and/or epithelioid cell nevi and benign verrucous melanocytic nevi. Proper attention to cytological detail and subtle architectural features will aid in recognizing this unusual variant of malignant melanoma.
Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity.
McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J.
Department of Pathology, New York Hospital, Cornell University Medical Center, New York 10021, USA.
J Cutan Pathol 1995 Dec;22(6):502-17 Abstract quote
The term "nevoid malignant melanoma" (nevoid MM) is used here to describe rare nodular malignant melanomas that may escape detection in routine histological sections due to the lack of a prominent intraepidermal component, sharp lateral circumscription and evidence of partial maturation with descent in the dermis.
Nevoid MM mimic ordinary compound or intradermal melanocytic nevi when the melanoma cells are small, or Spitz's nevi when the cells are large. The patterns of HMB-45 staining in 12 nevoid MM were compared with those in 107 melanocytic nevi. HMB-45 staining was strong in the dermal component of the nevoid MM, even in the absence of a junctional component. In common acquired and congenital nevi, the upper dermal component stained less than the junctional component of the lesion. The deepest components of these nevi were negative. Spitz nevi and cellular blue nevi had positive dermal cells, even without a junctional component. Additional staining for a proliferation marker, such as cyclin (PCNA) or Ki-67 (with the antibody MIB-1), can help further in distinguishing a nevoid MM from a Spitz's nevus. Melanoma has strong nuclear staining throughout the lesion. In contrast, Spitz's nevi have more staining at the top of the lesion than at the bottom.
The patterns of HMB-45 and MIB-1 staining can be used along with standard histologic criteria for the diagnosis of nevoid MM. Clinicopathologic correlation is needed to distinguish some metastatic melanomas from primary nevoid MM.
Morphological Analysis of Nevoid Melanoma A Study of 20 Cases With A Review of the Literature
Artur Zembowicz, M.D.; Margaret McCusker, M.D.; Concetta Chiarelli, M.D.; Angelo P. Dei Tos, M.D.; Scott R. Granter, M.D.; Eduardo Calonje, M.D.; Phillip H. McKee, M.D.
From the Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital (M.M., P.H.M., S.R.G.), and Department of Pathology, Dermatopathology Unit, Massachusetts General Hospital (A.Z.), Boston, Massachusetts; Department of Pathology, San Martino Hospital, Belluno (C.C.), and Department of Pathology, Regional Hospital, Treviso, Italy (A.P.D.); and Department of Dermatopathology, St. John's Institute of Dermatology, St. Thomas Hospital, London, United Kingdom (E.C.).
Am J Dermatopathol 2001;23:167-175 Abstract quote
Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus.
Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and progn