Immunohistochemical distinction of epithelioid histiocytic proliferations from epithelioid melanocytic nevi

Histiocytic tumors can be confused with melanocytic nevi and malignant melanoma and vice versa. To explore the use of immunohistochemistry for this diagnostic problem, we examined the expression of S-100 protein, gp100 (the antigen recognized by HMB-45), tyrosinase (T311), Melan-A (A103), Factor XIIIa (FXIIIa), and CD68 in 10 juvenile xanthogranulomas (JXGs), five epithelioid histiocytomas (EHs), and 15 melanocytic nevi composed of large epithelioid cells. All epithelioid melanocytic nevi were immunoreactive for Melan-A, tyrosinase, and S-100 protein in most melanocytes. Four nevi were completely negative with HMB-45. Nine nevi had only a minor HMB-45-positive component in the superficial dermis. Two nevi were diffusely HMB-45-positive. Melanocytes in all nevi were completely negative for FXIIIa. Thirteen nevi were completely negative for CD68. Two nevi contained rare cells with weak staining for CD68. All 15 histiocytic proliferations were completely negative for Melan-A, tyrosinase, and gp100. They lacked expression of S-100 protein or had at most 10% immunopositive cells. In JXGs, most cells were strongly reactive for CD68, although only a few were positive for FXIIIa. In EHs, 40% to 60% of cells were immunoreactive for FXIIIa, and only 20% to 30% were positive for CD68. Our results demonstrate that Melan-A and tyrosinase are sensitive and specific markers to distinguish epithelioid melanocytic nevi from epithelioid histiocytic tumors.     

Giant congenital nevus with progressive sclerodermoid reaction in a newborn

Giant congenital melanocytic nevi are a rare occurrence in the pediatric population. The risk of malignant transformation associated with these lesions has been well established; however, the management strategies for giant congenital nevi remain controversial. We report an unusual sclerodermoid reaction in a giant congenital nevus in a 6-week-old Caucasian girl. Given its abnormal clinical appearance, the entire lesion was excised. The histology was consistent with an atypical compound/sclerosing spindle and epithelioid cell congenital nevus. No evidence of malignant change was seen histologically. The incidence of malignant transformation in giant congenital nevi has been difficult to calculate. Review of the literature yields an incidence of between 4 and 9%, favoring surgical excision of these lesions where possible. Atypical presentations of giant congenital nevi are rare, and we have found no other reported cases with a stromal change similar to that seen in our patient. We hypothesize that this change may represent an atypical host reaction to the nevus cells.     

先天性色素痣的诊疗进展

先天性色素痣又称为先天性黑素细胞痣,在出生时或出生后不久出现,并具有独特的临床和组织病理学特征。先天性色素痣根据尺寸可分为四类:小痣、中痣、大痣和巨痣。约1%的新生儿患有先天性色素痣,其中大多数属于小/中型痣,大/巨痣比较罕见。本文将从临床、并发症、病理、基因、治疗等多方面对先天性色素痣进行总结,以期提高临床诊疗水平。     

Expression of Melan-A and Ki-67 in desmoplastic melanoma and desmoplastic nevi

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.     

Histogenesis of congenital and acquired melanocytic nevi based on histological study of lesion size and thickness

The histogenesis of melanocytic nevi is poorly understood. It is important to determine the differences and similarities in histogenesis between congenital and acquired nevi. To clarify the histogenic differences between acquired melanocytic nevi (AMN) and congenital melanocytic nevi (CMN), diameter and depth of nevus cells (tumor thickness) were examined in histological specimens from 80 cases of CMN and 71 cases of AMN, and these nevi were classified according to Mark's pathological CMN criteria. In all cases, giant CMN nevus cells were found in the lower marginal portion of excised specimens. The mean diameter and lesional thickness were significantly higher in CMN than in AMN. AMN diameter showed a significant correlation (r = 0.567, P < 0.05) with lesional thickness, while no such relation was observed in CMN. In addition, a significant correlation between lesion diameter and thickness was observed in small (<10 mm) non-Mark's type CMN (r = 0.626, P < 0.05). CMN may be classified into three subtypes: (i) caused by increased proliferation of melanoblasts during the course of migration from the neural crest to the epidermis; (ii) proliferation of nevus cells after arrival at the epidermis, and nevus cell distribution affected by adnexa and dermal differentiation; and (iii) arising after completion of skin development before birth.     

Cutaneous granular cell tumor with epidermal involvement: a potential mimic of melanocytic neoplasia

BACKGROUND: Cutaneous granular cell tumor (GCT) may present with extension into the junctional region of the epidermis and thus may mimic melanocytic neoplasms. METHODS: We reviewed three cases of cutaneous GCT where a melanocytic neoplasm was either initially diagnosed or considered in the differential diagnosis. Histopathology was evaluated in regards to features associated with melanocytic neoplasms. Immunohistochemistry was performed to delineate a panel useful in the distinction of these and other entities. RESULTS: All cases consisted of spindle and epithelioid cells with granular cytoplasm and bland nuclei and were centered in the superficial dermis with extension into the epidermis. Two cases resembled Spitz nevi and one case demonstrated lentiginous growth. All cases stained positively with calretinin and inhibin. Two of the three cases stained diffusely with S100 and 2/2 cases with CD56. HAM56 and CD68 were positive in one case and another showed positivity for NSE and PGP9.5. HMB-45, tyrosinase, and Melan-A were non-reactive in all cases tested. CONCLUSIONS: GCT may involve the epidermis and has a growth pattern similar to melanocytic neoplasms. An immunohistochemical (IHC) panel including S100, Melan-A, tyrosinase, HMB-45, CD56, CD68, calretinin, inhibin, and PGP9.5 may aid in the distinction and may spare the patient from unnecessary morbidity.     

On the development of neurocutaneous units--implications for the histogenesis of congenital, acquired, and dysplastic nevi

This study of spontaneous abortions and fetal deaths in utero used immunostains to evaluate the structure of developing cutaneous nerves. Melan-A immunostains were also used to screen 25 cases of grossly normal fetal skin for occult fetal nevi. Discrete portions of epidermis were generally supplied by branches emanating from regularly spaced deep cutaneous nerves, producing a wedge shape, interpreted as neurocutaneous units (NCU). Deeper nerves embraced broader portions of epidermis. Some nerves ran parallel to epidermis, especially near the superficial vascular plexus at the junction of superficial and deep dermis. Nerve sheath stem cells in each NCU may supply the melanocytes needed by the corresponding portion of epidermis. Transformed nerve sheath stem cells may lead to formation of occult prenatal nevi, whose histology and histogenesis may best be understood in terms of NCUs. In particular, the size and shape of a nevus may be largely determined by its NCU of origin. Six fetal nevi were detected, and 3 occult lumbosacral Mongolian spots; all in deep dermis, no later than the middle of the second trimester, mainly with a pattern of singly dispersed deep dermal melanocytes. These findings suggest that congenital (prenatal) nevi begin as intradermal nevi. In addition to explaining congenital nevi, these findings have implications for the histogenesis of acquired (postnatal) nevi and dysplastic nevi.     

Cutaneous melanoma risk and phenotypic changes in large congenital nevi: A follow-up study of 46 patients

Background: Large congenital melanocytic nevi may undergo malignant transformation. Few prospective studies have evaluated the incidence of melanoma in large congenital nevi or have described how their phenotypic characteristics change over time. Objective: We attempted to ascertain the incidence of cutaneous melanoma in a cohort of patients with large congenital nevi and to evaluate the frequency and nature of several morphologic changes over time. Methods: Forty-six patients with large congenital nevi were prospectively followed up in our Pigmented Lesion Group. Large congenital nevi were defined as those occurring at birth and comprising 5% body surface area or greater in infants, children, and preadolescents and more than 20 cm in adolescents and adults. Information was obtained on location, satellitosis, changes in color and nodularity, and incidence of melanoma. The most atypical histologic findings from those who underwent biopsy were also noted. Standardized morbidity ratios (SMR) and 5-year cumulative risk were calculated and presented with corresponding 95% confidence intervals (CI). Results: Twenty-four male and 22 female patients (age range, 7 days to 36.7 years; mean, 8.4 years) with large congenital nevi were followed up prospectively for a total of 335 person-years (range, 0.17 to 17.5 person-years; mean, 7.3 person-years). Two patients (4.3%) experienced 3 cutaneous melanomas that originated in their primary congenital nevi. We found one case of neurocutaneous melanosis. No satellite, extremity, or extracutaneous melanomas were detected. The majority of nevi in our cohort were located on the posterior trunk, were accompanied by multiple satellite congenital nevi, and became lighter over time. In the 27 patients who underwent biopsies, the most atypical histologic findings included melanoma, atypical melanocytic dysplasia, neurocristic dysplasia, atypical neural crest hamartomas, atypical spindle cell tumors, and congenital nevi with dysplasia. The SMR comparing observed-to-expected melanoma incidence was 148 (95% CI 18, 535; P = .0002) indicating a substantially increased risk of melanoma in patients with large congenital nevi. The cumulative 5-year risk of cutaneous melanoma was 5.7% (95% CI 0%, 13.5%). Conclusion: Our findings are consistent with the previously observed increased risk for the occurrence of cutaneous melanoma in patients with large congenital nevi. Although the number of patients with melanoma in this study is small, our observations and those of previous studies suggest that location and age correlates with melanoma risk. The majority of large congenital nevi are located on the trunk and may undergo several clinical changes as these patients age. Additional prospective studies are needed to gain more insight into the natural history and optimal management of large congenital nevi. (J Am Acad Dermatol 1998;39:923-32.)     

Atypical cells in human cutaneous re-excision scars for melanoma express p75NGFR,C56/N-CAM and GAP-43: evidence of early Schwann cell differentiation

BACKGROUND: A common problem in the routine examination of melanoma re-excision scars occurs when a few or rare mildly atypical cells are present within the scar, raising the question of residual disease. Little is known about the derivation of these cells. Because the normal cutaneous wound-healing process is reparative, we hypothesized that these atypical cells may be reactive proliferating Schwann cell precursors. METHODS: The expression of the Schwann cell differentiation markers p75NGFR, CD56/N-CAM and GAP-43 was examined by immunohistochemistry in scars of wide local re-excisions for melanoma and non-melanoma tumors. Expression of S100, gp100 (with HMB45) and MART1 was also analyzed by immunohistochemistry. RESULTS: All melanoma and non-melanoma re-excision specimens contained mildly atypical, spindled or epithelioid cells within the scar. They varied in number from case to case and expressed S100, p75NGFR, CD56/N-CAM or GAP-43 but not gp100 (with HMB45) or MART1. Rare epithelioid non-melanoma cells within the superficial dermis expressed MART-1. CONCLUSIONS: Atypical cells are present in re-excision scars from melanoma and non-melanoma cases. They demonstrate early Schwann cell differentiation and appear to proliferate during the scarring process. The use of anti-MART-1 alone in the examination of melanoma re-excisions specimens may be inadequate as it may label rare, superficially located, non-melanoma cells within the scar.     

Atypical fibroxanthoma-like amelanotic malignant melanoma: A case report and literature review

Atypical fibroxanthoma (AFX)-like malignant melanoma is very rare. Here, we report a case of amelanotic AFX-like melanoma in a 72-year-old Taiwanese woman presenting with two separate, asymptomatic, enlarging erythematous nodules within a large hypopigmented patch on her left cheek. Histologically, both lesions showed cellular nodules in the reticular dermis separated from the overlying flattened epidermis by a zone of solar elastosis or fibrosis. The tumor consisted of sheets of atypical epithelioid cells arranged in a vague nesting pattern, as well as many atypical large or gigantic cells with one or more, large hyperchromatic, vesicular, or pleomorphic nuclei with prominent nucleoli, and moderate-to-abundant eosinophilic or foamy cytoplasm. Focal intraepidermal proliferation of atypical melanocytes with a pagetoid pattern was found only in the periphery of the main tumor. The tumor cells were moderately to strongly positive for S-100, Melan-A, and HMB-45. The pleomorphic giant cells were focally CD68-positive but CD163-negative. The patient underwent tumor excision followed by radiotherapy due to the narrow surgical margins. A sentinel lymph node biopsy revealed no metastasis of the melanoma. This case illustrates the importance of scrutinizing any subtle proliferation of atypical melanocytes in the epidermis in an AFX-like tumor in order to avoid misdiagnosis.     

Neonatal curettage of giant congenital nevi

OBJECTIVE: All agree upon the need for early treatment of giant congenital nevi, basically because of the risk of melanoma degeneration, estimated at about 5 p. 100. Another reason is the cosmetic, psychological and social impact of such nevi. The aim of this study was to assess neonatal curettage of giant congenital nevi as an alternative to classical surgery. PATIENTS AND METHODS: Between 1996 and 1999, the curettage technique was used in 14 newborns with giant congenital nevi. Three nevi were located on the scalp, 4 on lower limbs and 7 on the trunk with a jacket configuration in 1 case and a cape configuration in 4. RESULTS: Curettage achieved 70-95 p. 100 clearing of the giant nevi in 10 of the 14 children. Four of the children developed hypertrophic scar tissue which resolved with time. Secondary hair growth was observed in 5 cases. Outcome was better when the curettage was performed very early (before 2 weeks of life). DISCUSSION: Curettage is a surface technique proposed when surgical excision cannot be performed because the surface is too large or the localization is incompatible with surgery. Curettage is a simple low-cost technique which provides particularly satisfactory cosmetic results for very extensive giant congenital nevi. The risk of malignant transformation is greatly reduced although not totally. Regular clinical surveillance under conditions greatly improved by the clearing should help reduce the risk.     

Proliferative nodules in a giant congenital melanocytic nevus–case report and review of the literature

Malignant transformation of giant congenital nevi (GCN) is very rare, but may already occur in childhood. Benign proliferative nodules in GCN may clinically and histologically mimic a malignant melanoma. We report a newborn infant with large proliferative nodules and multiple satellite nevi in a GCN of the bathing suit type. The diagnosis in our patient was based on the smooth transition of the pre‐existing lesion and the nodule, the absence of strong atypical nuclei, the atypical mitotic figures, the ascension of melanocytes in the epidermis and the absence of necrosis. A review of the literature showed that the clinical and the histological features of benign (proliferative) nodules are variable. The awareness and the identification of this entity by clinicians and pathologist are imperative to prevent diagnostic errors. van Houten AH, van Dijk MCRF, Schuttelaar MLA. Proliferative nodules in a giant congenital melanocytic nevus–case report and review of the literature.     

Congenital pseudomelanoma

Benign congenital melanocytic nevi, removed shortly after birth, may histologically be misinterpreted as malignant melanomas. We present the criteria for the differential diagnosis. As a name for these unusual melanocytic tumors, which belong to the large group of pseudomalignancies of the skin, we suggest the term 'congenital pseudomelanoma'.     

Coexistence of Congenital Giant Melanocytic Nevus of the Scalp with Cranial Defect,Poliosis, and Hair Loss

Congenital melanocytic nevi (CMN) are pigmented lesions presenting on the skin in approximately 1% of all newborns at or shortly after birth. CMN have been described as being associated with several anomalies, including cranial bone hypertrophy, scoliosis, and spina bifida. This is the first report to describe a giant congenital melanocytic nevus on the scalp associated with cranial involvement, poliosis, and alopecia.     

Atypical distinctive dermal clear cell mesenchymal neoplasm arising in the scalp

Distinctive dermal clear cell mesenchymal neoplasm (DDCCMN) is a newly described entity characterized by a dermal proliferation of neoplastic cells with clear to reticulated cytoplasm and vesicular nuclei. Atypical features in the form of nuclear pleomorphism and mitoses may be found. The histogenesis of these neoplastic clear cells is not currently known but they are thought to be mesenchymal in origin. Immunohistochemically, they stain positively for NKI-C3 and negatively for melanocytic, epithelial and lymphoid markers. All five cases originally reported by Lazar and Fletcher occurred in the lower extremities. We report herein a case of DDCCMN with atypical features arising in the scalp.     

Epithelioid blue naevus of the genital mucosa: report of four cases

Epithelioid blue naevi are an unusual cytological variant of blue naevus that have been recently described mostly in patients with the Carney complex, although they may also occur in isolation. This variant of blue naevus is composed of melanin-laden polygonal epithelioid melanocytes situated within the dermis. The neoplastic cells show no maturation with progressive depth of dermal infiltration and, in contrast with the usual stromal changes in blue naevi, epithelioid blue naevi exhibit no dermal fibrosis. We describe four cases of epithelioid blue naevus located on the genital mucosa in four patients with no evidence of the Carney complex. Three male patients showed an epithelioid blue naevus on the mucosa of the glans penis and a female patient had a lesion of the right labium minoris. Histopathologically, the lesions consisted of entirely intradermal melanocytic naevi composed mostly of heavily pigmented epithelioid melanocytes involving the dermis of the genital mucosa. Immunohistochemically, in all cases, epithelioid melanocytes expressed immunoreactivity for S-100 protein, HMB-45, Melan-A and MiTF antibodies.     

HMB-45 staining in benign and malignant melanocytic lesions. A reflection of cellular activation.

The antibody HMB-45 used as an immunohistochemical reagent has often been labeled as a marker for melanoma, even though some benign lesions have been noted to show positive staining reactions with this reagent. Biopsy specimens from 225 benign and malignant melanocytic lesions were examined after immunoperoxidase staining for S-100 protein and HMB-45. The lesions studied included common acquired nevi, spindle cell and epithelioid cell nevi (Spitz nevi), cellular blue nevi, deep penetrating nevi, congenital nevi, nevi from hormonally reactive areas (genital), malignant melanoma, and desmoplastic malignant melanoma. A positive reaction for HMB-45 was seen in the dermal component in a high percentage of each of these types of lesions except for the common acquired nevi and the desmoplastic malignant melanomas that were uniformly negative for HMB-45 in the dermal component. HMB-45 correlates with melanosome production and thus a melanocytic origin of HMB-45-positive cells. HMB-45 may correlate best with factors that stimulate melanocytic proliferation and production of melanosomes.     

Epithelioid blue nevus: neoplasm Sui generis or variation on a theme?

The epithelioid blue nevus has recently been associated with the Carney complex, which is characterized by myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas. Using the general criteria proposed by Carney and Ferreiro, similar lesions were identified in 33 patients with no evidence of the Carney complex. Those lesions presented on the face, trunk and extremities of 15 males and 18 females. The mean age was 35 years, much older than those in the Carney complex (mean 16.3 years). Clinical diagnoses included malignant blue nevus, atypical nevus, melanoma, congenital nevus, and dermatofibroma. The lesions were symmetric, predominantly dermal melanocytic proliferations arranged as short fascicles, small nests, and single cells. Large polygonal and epithelioid melanocytes with moderate pleomorphism, and occasional nuclear pseudoinclusions were admixed with heavily pigmented dendritic and spindled melanocytes and melanophages. Rare mitotic figures were seen in some cases. The neoplasms showed a morphologic spectrum that encompassed a group of combined blue nevi with epithelioid melanocytes and other Spitz's nevus characteristics. These epithelioid combined nevi (ECN) fell into three phenotypes with morphologies that most closely paralleled those pictured by Carney and Ferreiro in the Carney complex: the classic or Carney complex pattern (ECN-CC), those that showed overlap with deep penetrating nevus (ECN-DPN), and those that have many dermal Spitz's nevus features, [BLue + SpITZ's nevus; (ECN-BLITZ)I. In six cases, there was such an admixture of features that it was difficult to ascribe them to one of the groups. Nine lesions had associated banal congenital nevus. Follow-up that averaged over 2.5 years (31 months) (range 6-162 months) showed no evidence of malignancy or recurrent disease after excision. Epithelioid combined nevus is a type of combined nevus with blue nevus and Spitz's nevus features, which may or may not be associated with the Carney complex. It shows morphologic overlap with the epithelioid blue nevus described by Carney (ECN-CC), deep penetrating nevus (ECN-DPN), and blue nevus with intradermal Spitz's (desmoplastic) nevus (ECN-BLITZ). Epithelioid combined nevus is thought to be a fitting nosologic designation for all of these lesions.