Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Lentigo Maligna Melanoma With Local and Distant Blue Nevus-like Metastases.

Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically, presenting a diagnostic pitfall for both the clinician and the dermatopathologist. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases followed by a distant metastasis, heralding widespread systemic metastases.

Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature.

Melanomas arising in association with blue nevi or mimicking cellular blue nevi comprise a relatively rare and heterogeneous group of melanomas. It remains controversial which prognostic indicators predictive of outcome in conventional cutaneous melanomas are applicable to this type of melanoma. Here, we describe the clinical and histopathologic features of 24 melanomas arising in association with blue nevi and correlate these with clinical outcome. The mean patient age was 49 years (range: 23-85) with a slight female predominance (15 females:9 males). The most common anatomic locations included the head and neck region (50%), the trunk (21%), and the buttock/sacrococcygeum (17%). Histologically, the tumors were typically situated in the mid to deep dermis with variable involvement of the subcutis, but uniformly lacked a prominent intraepithelial component. The mean tumor thickness (defined as either the standard Breslow thickness or, if not available due to the lack of orientation or lack of epidermis, the largest tumor dimension) was 20.9 mm (range: 0.6-130 mm). The mean mitotic figure count was 6.5/mm(2) (range: 1-30/mm(2)). Perineural invasion was common (38%). Follow-up was available for 21 cases (median 2.1 years). The median overall survival, recurrence-free survival, time to local recurrence, and time to distant recurrence were 5.2, 0.7, 2.6, and 1.6 years, respectively. Logistic regression analyses demonstrated a significant association between tumor thickness and recurrence-free survival (hazard ratio=1.02 per mm; P=0.04) and reduced time to distant metastasis (hazard ratio=1.03 per mm; P=0.02) with a similar trend toward reduced time to local recurrence (hazard ratio=1.02 per mm; P=0.07). No other parameters (age, anatomic location, mitotic figures, lymphovascular or perineural invasion, or type of associated blue nevus) emerged as significant. In addition, we provide a comprehensive review of 109 cases of melanoma blue nevus type described in the English literature and summarize our findings in this context.

Malignant neurocristic hamartoma: a tumor distinct from conventional melanoma and malignant blue nevus.

Neurocristic hamartomas are rare pigmented lesions comprised of melanocytes, Schwann cells, and pigmented dendritic spindle cells that involve the skin and soft tissue. Malignant transformation can rarely arise within neurocristic hamartomas. Up to date, there has been only 1 series of 7 cases of malignant neurocristic hamartomas (MNHs), with 3 cases that developed metastases. We present the histology and clinical course of 3 additional cases of MNH, 2 of which were metastatic. CD117 was strongly positive in all cases with available archival materials--the tumors and background neurocristic hamartoma of 3 cases, and 1 lymph node metastasis; however, KIT sequencing for exons 11, 13, 17, and 18 was negative. Mutational analyses of recurrent mutations of 17 cancer genes, including BRAF and KIT, were also negative. Although our series is small, KIT overexpression in MNH does not seem to correlate with gene mutation. The lack of BRAF, NRAS, GNAQ, and KIT mutations seems to support the notion that MNH may be distinct from conventional melanoma and from other dermal melanomas, such as malignant blue nevi and melanoma arising in congenital nevi.

Multiple bilateral ocular metastases from malignant melanoma associated with blue nevi.

PURPOSE: Malignant melanoma associated with a blue nevus is a rare diagnosis. Additionally, only a handful of cases of malignant melanoma associated with blue nevi involving the ocular structures have been reported. We report a probable case of malignant melanoma associated with a blue nevus with metastasis to multiple bilateral ocular structures. METHODS: Observational case report. RESULTS: We report a case of a 27-year-old man with lymph node biopsy-proven malignant melanoma as well as a separate skin biopsy of a blue nevus, who developed multiple bilateral pigmented ocular lesions on the sclera, iris, trabecular meshwork, and choroid. CONCLUSIONS: Although ocular histopathologic evidence could not be obtained, our case likely represents a case of explosive widespread metastasis probably originating from a blue nevus of unknown location, which involved both eyes and adnexae.

Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008.

Several reports demonstrated the difficulties and lack of agreement in the histopathologic diagnosis of particular melanocytic tumors (atypical Spitz tumors, atypical blue nevi, deep penetrating nevi). These lesions are often referred to as "melanocytic tumors of uncertain malignant potential" (MELTUMP). We studied a large number of such tumors to find out whether repeatable histopathologic criteria for distinction of benign from malignant cases exist. Fifty-seven cases of MELTUMP were classified within 3 groups according to behavior as follows: (a) favorable (no evidence of metastatic disease after a follow-up of > or = 5 y), (b) unfavorable (tumor-related death and/or large metastatic deposits in the lymph nodes and/or visceral metastases), (c) borderline (small nodal deposits of tumor cells < or = 0.2 mm). There were no significant differences in tumor thickness and presence or absence of ulceration between the different groups. The only 3 histopathologic criteria that were statistically different between the groups of favorable and unfavorable cases were presence of mitoses, mitoses near the base, and an inflammatory reaction, all of them found more frequently in cases with unfavorable behavior. The major outcome of this study of a series of "MELTUMPs" suggests as a preliminary observation that these lesions as a group exist and that they may be biologically different from conventional melanoma and benign melanocytic nevi. The terminology remains highly controversial, reflecting the uncertainty in classification and interpretation of these atypical melanocytic tumors.

Pigmented epithelioid melanocytoma: favorable outcome after 5-year follow-up.

Pigmented epithelioid melanocytoma (PEM) is a recently described entity encompassing epithelioid blue nevus (of Carney complex) and most tumors earlier considered as so-called "animal-type melanoma". Loss of expression of a Carney complex gene, cyclic adenosine 3',5' monophosphate-dependent protein kinase regulatory subunit 1alpha, is observed in the majority of PEMs. Initial reports with short-term follow-up have suggested that although PEMs frequently metastasize to lymph nodes, they have a more favorable outcome than conventional melanomas. In this report, we present the results of long-term follow-up in 26 patients with PEMs from North America and Australia. There were 9 males and 17 females, with a median age of 20 years. The tumors involved the trunk (6 cases), extremities (12 cases), genitalia (1 case), and the head and neck region (7 cases) had a median Breslow thickness of 2.2 mm (range 0.80 to 10.0 mm) and a median Clark level of 4. Eight of the patients developed lymph node metastases. After a median follow-up period of 67 months (range 39 to 216 mo), all patients are alive and free of disease. These findings provide further evidence that PEM is a unique low-grade melanocytic tumor with limited metastatic potential (to lymph nodes), but a favorable long-term clinical course.

Malignant blue nevus with lymph node metastases.

BACKGROUND: Malignant blue nevi arise within cellular blue nevi and contain atypical mitoses, necrosis, nuclear pleomorphism and prominent nucleoli. Malignant blue nevus has been described as a distinct identity, a rare form of malignant melanoma, and a misdiagnosed melanoma. METHODS: We present a patient with metastatic malignant blue nevus and studies on the histopathologic, immunohistochemical, and molecular features of the neoplasm. RESULTS: Histology showed a malignant blue nevus arising in a combined intradermal and cellular blue nevus. CD117 (c-kit) staining showed diffuse cytoplasmic expression within the cellular blue nevus, decreased staining in the malignant component, and variable positivity within the lymph node metastases. Molecular loss of heterozygosity analysis showed different allelic patterns at the hOGG-1 locus between the melanoma and control skin specimens with a varying heterozygous allelic pattern in both the benign and malignant blue nevus. CONCLUSIONS: Our case of malignant blue nevus with lymph node metastasis involved mutation of the hOGG-1 DNA repair gene. CD117 showed decreased staining of the primary malignant blue nevus with marked upregulation in the metastatic lesion, unlike most metastatic melanomas. Further study is needed to determine if hOGG-1 mutation or c-kit upregulation play a role in the pathogenesis of dendritic melanocytic lesions (either benign or malignant).

Primary invasive melanoma and basal cell carcinoma (collision tumor) with blue nevus-like cutaneous metastases.

The simultaneous presence of two disparate neoplasms occurring in the same specimen has been well documented, albeit uncommonly. The juxtaposition of malignant melanoma and basal cell carcinoma (BCC) has been rarely reported in case reports, with most cases describing melanoma in situ and BCC. We present two cases of invasive melanoma (Clark level IV, no microscopic satellites present) intimately associated with BCC, and in areas distinction of the two lesions was difficult. Immunohistochemical studies delineated the two cell populations. In addition, one patient presented with multiple cutaneous metastases, all simulating blue nevi. The metastases occurred in the same anatomical region as the primary tumor, and histologically consisted of pigmented dendritic melanocytes and melanophages in the superficial and mid-dermis and arranged in a blue nevus-like lesion. Histologic clues suggesting the possibility of a metastatic melanoma included a sparse lymphocytic infiltrate, the presence of an epithelioid component and atypia of the dendritic melanocytes. However, without appropriate clinical history, the lesions could be overlooked as ordinary blue nevus. Collision tumors containing invasive melanoma and BCC are rare and this is the first report of a collision tumor with blue nevus-like metastasis. Awareness of this phenomenon and pattern of metastasis, together with the clinical findings will aid in the correct classification of these lesions.

Malignant blue nevus: a case report and molecular analysis.

Malignant blue nevus is a rare melanocytic tumor that is described by some authors as a variant of malignant melanoma, whereas others regard it as a distinct entity. To our knowledge no molecular studies of this tumor have been performed, although the molecular pathogenesis of conventional melanomas has been extensively described. We present a case of malignant blue nevus that developed in a 15-cm congenital blue nevus on the back of a 41-year-old man. Subsequent regional lymph node and lung metastases developed within 1 and 29 months, respectively. We performed a molecular analysis for loss of heterozygosity on microdissected samples from the spectrum of benign to malignant blue nevus, using a panel of eight genes (MTS1, MXI1, CMM1, p53, NF1, L-myc hOGG1, and MCC), many of which are commonly associated with conventional melanomas. No loss of heterozygosity was detected, despite informativeness in seven genes. We suggest that malignant blue nevus may represent a distinct entity with a different molecular pathway to tumorigenesis than that of conventional melanomas.

Cellular blue naevus of the scalp with brain invasion.

A case of a 28 year old woman with an intracranial cellular blue naevus (CBN) which was believed to be the extension from a pigmented skin/scalp lesion is reported. There was no similar pigmented skin lesion noted on other parts of her body. Radical intervention, including wide excision of the affected skin of the scalp, removal of the underlying pigmented skull bone and wide excision of the pigmented dura, together with wide excision of the intracranial mass, were performed. The skin defect was covered by rotation flap and free skin graft. The dura was closed by grafting with fascia lata. The skull defect was left open and would be repaired later at a second planned surgery.

Malignant blue nevus of the scalp.

A 70-year-old woman had noticed, at the age of 30, a single blue nodule of about 1 cm in size on her scalp. The lesion remained stable until 1991, when it became larger and ulcerated and, because of the sudden onset of additional macules and nodules around it, the patient presented at our Dermatological Division in August 1992. Physical examination showed a blue-black plaque, 2 x 2 cm in size, on the left parietal area of the scalp, surrounded by several blue-grey pigmented nodules and macules (Fig. 1). Chest X-ray, abdomen scan, and a total body computed tomography (CT) scan were negative for metastatic disease. A wide resection of the scalp lesion was performed. The histologic evaluation revealed a dense collection of spindled melanocytes in the dermis and in the subcutaneous fat. Nuclear and cytoplasmic pleomorphism, some mitotic figures, and necrosis foci were present (Figs 2 and 3). Pictures of cellular blue nevus were found in the surrounding lesions. Ten months later, new blue macular and papular lesions appeared in proximity to the surgical scar. The patient refused any additional surgery, and so was treated with dacarbazine (DTIC) 800 mg intravenously (every 20 days) and 2 alpha interferon (3 million units subcutaneously, three times weekly). The growth of the lesions slowed down for a few weeks, and then increased again to become a wide, blue-black vegetating mass (Fig. 4). In June 1995, a total body CT scan revealed multiple focal nodules on the lungs and two metastatic masses on the eighth segment of the liver. A palliative polychemotherapy, with vindesin 3 mg/m2 and DTIC 400 mg/m2, was started, but did not stop the progression of the disease, and the patient died in December 1996.

Metastatic malignant blue nevus: a case report.

This report presents a 63-year-old Caucasian woman with a malignant blue nevus, which is an extremely rare form of melanoma originating from or associated with a preexisting blue nevus. The background blue nevus on the left upper arm, which had been present for 5 to 6 years, increased in size and darkened in color for 3 months prior to histological diagnosis of malignant blue nevus. Although the tumor looked much like a nodular melanoma clinically, the diagnosis of malignant blue nevus was established histologically. The patient had a poor outcome due to metastatic spread of the tumor to the visceral organs 1 year following the initial excision of the tumor. To distinguish this rare tumor from other melanocytic lesions, strict histological criteria are needed to make the diagnosis of malignant blue nevus. Differential diagnosis includes cellular blue nevus, atypical cellular blue nevus, primary malignant melanoma, and metastatic melanoma to the dermis. Malignant blue nevus is most commonly seen on the scalp. The tumor has an aggressive behavior and metastasizes in the majority of patients. This paper describes the second reported case of malignant blue nevus involving the upper arm. Clinical and histological features of this uncommon tumor are presented, along with a review of the literature.

Malignant blue naevus with distant subcutaneous metastasis.

Malignant blue naevus is a distinct but rarely documented variant of malignant melanoma, and we describe the triple recurrence of a suprapatellar cellular blue naevus over 12 years in a middle-aged woman. Staging investigations revealed a distant subcutaneous metastasis of the right thigh. Immunohistochemistry of the primary lesion and all recurrences showed S-100, HMB-45, NKI/C-3 and Ki-67 positive cells. However, non-malignant cellular blue naevi from five consecutive other patients were all Ki-67 negative. The change from negative to positive Ki-67 responsivity may therefore be a valuable marker of malignant and metastatic potential in early cellular blue naevi.

[Malignant blue nevus with metastasis to lymph nodes and brain]. / Maligner blauer Nävus mit Metasierungen in Lymphknoten und Gehirn.

We report a patient who developed malignant transformation of a cellular blue nevus. At the age of 19 years the congenital, pigmented tumor on the left buttock was histopathologically diagnosed as cellular blue nevus. Thirty years later the tumor dramatically increased in size, involving the entire left buttock within several months. Multiple biopsies revealed the presence of a cellular blue nevus within the papillary dermis and an invasive, pleomorphic pigmented sarcoma in the depth of the tissue spreading into subcutis and skeletal muscle. Both benign and malignant cells were S100+, vimentin+ and HMB-45+, but only the malignant tumor cells stained positive for the proliferating cell nuclear antigen. General examination disclosed multiple metastases in the paraaortal lymph nodes and the retroperitoneum as well as a single brain metastasis. Despite palliative therapy with ionizing radiation and chemotherapy, the patient developed generalized metastases and died within weeks. This case clearly confirms that cellular blue nevi have the potential for malignant transformation and that the malignant variant may behave aggressively just as a malignant melanoma.

Cellular blue nevus with massive regional lymph node metastases.

BACKGROUND: Small, well-differentiated groups of nevus cells have been found occasionally in the marginal sinuses and parenchyma of regional lymph nodes that drain sites of cellular blue nevi. OBJECTIVE: The histologic, immunohistochemical, and karyometric description of a pigmented cutaneous lesion, with the features of cellular blue nevus and located on the leg of a 14-year-old woman, that was accompanied by synchronic presentation of massive inguinal lymph-node metastases. METHODS: The excised specimens were processed routinely, embedded in paraffin, and sectioned into 4-microm-thick slices. The sections were stained using hematoxylin-eosin and the ABC immunohistochemical method for demonstrating S-100 and HMB-45. Karyometric analysis was performed in a static cytometer using Feulgen-stained sections. RESULTS: The cutaneous lesion had the cytologic and architectural features of cellular blue nevus. The lymph nodes showed massive invasion by pigmented cells and contained extensive necrotic foci. After 3.5 years of clinical follow-up, the patient is free from disease. CONCLUSIONS: The absence of malignant features in the cutaneous lesion and the bland nuclear features of the pigmented cells in the regional lymph node metastases suggest that this case could be interpreted as an unusual form of benign cellular blue nevus with metastases. Nonetheless, other possibilities, such as malignant melanoma mimicking a cellular blue nevus or primary malignant melanoma of the lymph nodes with concomitant cutaneous cellular blue nevus, cannot be definitively excluded. A conservative surgical approach with close follow-up was recommended.

Malignant cellular blue nevus: a clinicopathological study of 6 cases.

BACKGROUND: Malignant cellular blue nevus (MCBN) is a rare entity due to the malignant transformation of a preexisting cellular blue nevus (CBN). OBJECTIVE AND METHODS: The clinical and pathologic features of 6 patients with MCBN are described. RESULTS: Three tumors were located on the scalp, 2 on the trunk and 1 on the neck. The lesions, present from birth or childhood, had enlarged rapidly in the last months before excision. Histologically, there was a dermal proliferation of spindle and epithelioid atypical melanocytic cells. Some of them were heavily pigmented. Numerous atypical mitoses were seen. In 2 cases, foci of necrosis were detected. In 2 cases, remnants of CBN were also noted. MCBN has a poor prognosis and may be difficult to differentiate from so-called atypical blue nevus, metastasis of malignant melanoma and malignant transformation of combined nevus. CONCLUSIONS: CBN may represent a precursor of malignant melanoma. In MCBN, malignant changes seem to occur in clear cells.

Malignant blue nevus with neurosarcoma-like lymph node metastases.

We report a case of malignant blue nevus (MBN) of the foot with unusual morphologic presentation of nodal metastases. Their structure resembled neurosarcoma, and differed from the appearance of the primary tumor. This case confirms the mutual close histogenic relationship between MBN and neurosarcoma, both tumors originating from the structures of the neural crest. We also discuss the problem of so-called "benign" metastases of malignant melanoma.