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Here we describe the case of a 65-year-old Caucasian female who presented with an amelanotic malignant conjunctival melanoma and highlight the clinical and pathological features of this rare entity that displayed exclusive corneal invasive growth without evidence of conjunctival tumors other than primary acquired melanosis. Impression cytology aided in the initial diagnosis. The patient underwent surgical treatment. Histopathology and immunohistochemistry revealed an invasive amelanotic melanoma limited to the cornea and exhibiting S-100, Melan A, and HMB-45 positivity. The absence of pigmentation delayed early clinical detection and treatment. Awareness of this nonpigmented melanoma is important for early recognition and appropriate management.

Amelanotic melanoma, a renowned impersonator, has taken on a new persona. A 63-year-old woman was seen in the emergency room with a chief complaint of back pain after a fall and was discovered to have a 15-cm fungating mottled gray mass independent of bone on the right elbow. Initial workup discovered lytic calvarial lesions, anemia (Hb 7; Hct 20%), and circulating plasma cells consistent with plasma cell myeloma. Biopsy of the elbow mass displayed sheets of plasmacytoid cells, some reactive for CD138. Flow cytometry revealed a substantial portion of the plasma cells in the tumor that were kappa restricted consistent with cutaneous plasmacytoma. The elbow mass was initially signed out as extramedullary involvement by her myeloma. Reevaluation of the mass after the patient experienced an explosive growth of multinodular jet black malignant melanoma on ipsilateral breast revealed MART-1 and S-100 reactivity of the majority of the cells. In retrospect, the elbow mass was a neglected primary amelanotic malignant melanoma with neoplastic plasma cells participating in its chronic inflammatory infiltrate.

Excessive amounts of melanin pigments may hamper histopathological assessments of melanocytic lesions by obscuring cellular morphology and hindering antibody-antigen interactions. To determine the optimal melanin-bleaching conditions for histopathological examination, heavily pigmented melanomas were treated with warm hydrogen peroxide (H2O2) diluted with various diluents (1% disodium hydrogen phosphate 12H2O (Na2 HPO4); phosphate buffer 0.05 M, pH 7.4 (PB); and PBS 0.05 M, pH 7.4) at varying temperatures (50°C, 55°C, and 60°C) and for varying incubation times (0.5, 1, 2, and 3 h). The effect of the sequential order of antigen retrieval and bleaching on preserving tissue morphology was then evaluated. Additionally, the effect of melanin bleaching using warm diluted H2O2 on the antigenicity of melanoma-related markers (HMB-45, MART-1, and S-100) and other markers used for histopathology was examined in amelanotic melanomas and tonsil tissue. Optimal and complete bleaching was achieved using warm 3% H2O2 in PB treatment at 55°C for 2 h following antigen retrieval with microwaving or digestion with trypsin. Under these conditions, the tissue morphology and antigenicity of various immunohistochemical markers were also well preserved. Bleaching with warm 3% H2O2 PB is a fast and efficient method of bleaching melanin pigments and performing immunohistochemical examination in heavily melanin-pigmented lesions., (© 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

Amelanotic vulvar melanoma is a rare type of malignant melanoma. This paper describes a case of an asymptomatic ulcerated nodule 20 mm in size. The tumor cells from the nodular lesion showed positive staining immunohistochemically for Melan-A, but negative staining with HMB-45. The cells showed negative reactivity to S-100 except in one region. The melanoma cells in the epidermis were detected in one of the specimens from the excised tumor nodule. The cells in the epidermis showed positive staining for Melan-A and S-100 and partial staining with HMB-45. The tumor was diagnosed as malignant melanoma of the vulva and immunohistochemically shown to have intratumor histological heterogeneity. This case suggests the importance of viewing non-pigmented nodules on the vulva of elderly females as potentially malignant melanoma, and that a combination of immunohistochemical stains may be useful for recognizing the stage of the melanosomes in the melanoma cells.

Amelanotic malignant melanoma in the oral region is extremely rare and has not previously been reported in the parotid gland. This present case report describes an amelanotic malignant melanoma in the parotid gland, with no other primary lesion detectable. The medical history, pathology and immunohistochemical analysis of the case are described and the relevant literature is reviewed in order to help in the recognition of this uncommon tumour. Amelanotic malignant melanoma is a melanoma subtype with little or no pigmentation and, because of this lack of pigmentation and its wide-ranging clinical appearance, it often defies clinical diagnosis. A high level of vigilance is, therefore, necessary in diagnosing such a tumour in the parotid gland. Where it is suspected, positive expression of S-100 protein and human melanoma black 45(HMB45) using immunohistochemical analysis can be considered reliable methods of confirming diagnosis.

Small cell melanoma is a recognized rare variant of malignant melanoma. We report a case of a brown, ulcerated papule on the left third finger of an 80-year-old woman. Microscopic examination revealed the presence within the epidermis of diffuse sheets of monomorphic small to medium-sized cells. The nuclei were round or oval, and hyperchromatic with inconspicuous nucleoli. Melanin pigment was either absent or minimal. This case report draws attention to the difficulties encountered in the histological diagnosis of this rare variant of malignant melanoma.

Purpose: To report a case of metastatic malignant amelanotic melanoma to the skin from a patient diagnosed with bilateral diffuse uveal melanocytic proliferation (BDUMP). This dermatological finding is a unique phenomenon associated with BDUMP., Design: Retrospective case report., Methods: We studied the case of a 66-year-old Caucasian woman with gradual onset of blurred vision in her right eye followed by her left eye. She had previously been diagnosed with ovarian carcinoma, and findings of funduscopic examinations were consistent with BDUMP. Metastatic examination revealed no evidence of liver involvement. Clinical and histopathological examinations of both enucleated eyes were consistent with BDUMP., Results: The hematoxylin and eosin, S-100, and HMB-45 stains were consistent with metastatic malignant amelanotic melanoma to the skin., Conclusions: Although believed to have a low potential for metastasis, patients should be monitored and evaluated regularly to detect any new lesions not associated with their primary inciting carcinoma.

A 3-year-old, neutered, male Golden Retriever was presented for evaluation of a 10 X 9 X 5 mm, firm, red, raised, cutaneous mass located over the left cranial thorax and noted incidentally by the owner. On cytologic evaluation of a fine-needle aspirate of the mass, the interpretation was a malignant tumor with predominantly mesenchymal features. Differentials included liposarcoma, atypical amelanotic melanoma, anaplastic sarcoma, and anaplastic carcinoma. Following complete excision of the mass, a diagnosis of sebaceous adenocarcinoma was made based on histologic features, positive immunostaining for pancytokeratin, and negative staining for vimentin, Melan-A, and S-100. There was no evidence of metastasis on physical examination or thoracic radiographs, and the prognosis was good. The unique and previously unreported cytologic features of this small, sebaceous adenocarcinoma were the extreme pleomorphism, including marked anisocytosis, anisokaryosis, and multinuclearity, and the paucity of epithelial features.

Case Report: We report an unusual case of cavitary choroidal melanoma. The results of ultrasonography, magnetic resonance imaging, computed tomography, and immunohistochemical studies are presented for a 38-year-old woman who developed an amelanotic tumor in the posterior choroid. B-scan ultrasonography disclosed intratumoral cavitations. Systemic and extraocular extension studies were negative. Enucleation was performed and histopathologic examination showed a choroidal melanoma of spindle cell type, with intratumoral cavitations lined by flattened tumor cells., Comments: The majority of previous reports of intraocular cavitary tumors describe cavitary ciliary body tumors. Uveal melanoma should be included in the differential diagnosis of choroidal cavitary lesions. As far as we know, this is the second documented clinicopathologic correlation of a cavitary choroidal melanoma.

Objective: To characterize a murine model of spontaneous amelanotic melanoma arising in the uvea of transgenic mice bearing a targeted deletion of the Ink4a/Arf tumor suppressor locus (exons 2 and 3) and expressing human H-ras controlled by the human tyrosinase promoter., Methods: Ocular lesions developed in 20 (15.7%) of 127 male albino Tyr-RAS+ Ink4a/Arf-/- transgenic FVB/N mice within 6 months, and were evaluated histologically and ultrastructurally., Results: Uveal melanomas were locally invasive but confined to the eye, with no evidence of metastasis. Tumor cells exhibited epithelioid and spindle-shaped morphological features and closely resembled the human counterpart. Melan-A, S100 and neuron-specific enolase expression were detected immunohistochemically. Melanosomal structures were detected using electron microscopy. The retinal pigment epithelium was intact above small melanomas, and electron microscopy of the tumors failed to show the presence of basement membrane formation or desmosomes., Conclusion: Spontaneous uveal malignant melanomas occurring in male Tyr-RAS+ Ink4a/Arf-/- transgenic mice arise within the choroid or ciliary body and share histopathological features characteristic of human uveal melanoma., Clinical Relevance: Uveal melanoma research has benefited from xenograft models, but engineered mouse models of spontaneous uveal amelanotic melanoma will undoubtedly further our understanding of the genetic underpinning for this disease.

The electrical resistance breakdown assay provides a novel approach for the quantification of cytotoxic activity of platinum based anticancer drugs. It is a functional assay system for cancer cell invasion that detects nanoscale alterations of an epithelial test barrier prior to microscopic morphometric changes. We measured changes in transepithelial electrical resistance (TEER) of a tight epithelial MDCK-C7 monolayer in response to highly invasive amelanotic melanoma cells (A7-clone) in combination with different platinum complexes (cis-, oxali- and carboplatin). The efficiency of the electrical resistance breakdown assay was compared a standard method for measurement of cytostatic activity, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The MTT-assay utilizes mitochondrial enzymatic activity to draw conclusions from a functional cell metabolism to the number of living cells in a sample. When human melanoma cells were seeded on top of an electrically tight MDCK-C7 monolayer, electrical leakage occurred within 48 h of co-culture. Electrical resistance breakdown was effectively prevented by cisplatin and its analogs (no significant difference between 100 microM cisplatin and corresponding controls with non-invasive cells). The results of the electrical resistance breakdown and MTT-assay were linearly dependent. Significance of both tests was equivalent, but the electrical resistance breakdown assay gave additional functional information. Compared to oxali- and carboplatin, cisplatin was more effective in preventing TEER-breakdown than reducing the number of tumor cells, giving rise to the assumption that cisplatin can reduce tumor cell number as well as invasiveness. In conclusion the electrical resistance breakdown assay provides a sensitive, continuous and cell-based assay system for the quantification of cancer cell invasiveness and evaluation of chemotherapeutics under physiological conditions., (Copyright 2004 S. Karger AG, Basel)

We describe a 76-year-old white male with subungual amelanotic melanoma. The lack of pigmentation of the lesion may cause misdiagnosis and aggravate its poor prognosis.

Metastatic neoplasms to the breast are relatively rare. Spindle-cell lesions of the breast are also uncommon. Here we present a case of fine-needle aspiration (FNA) of an amelanotic, spindle-cell melanoma metastatic to the breast and axillary lymph node. The patient was a 47-yr-old female who presented with a right breast mass, left axillary adenopathy, and a pigmented skin lesion on the back. FNA of the right breast and left axilla showed malignant, nonpigmented spindle cells that were weakly positive for HMB-45 on immunocytochemistry. The skin biopsy showed a pigmented malignant melanoma with epithelioid features, and also weak positivity for HMB-45. Although malignant melanoma is one of the more common tumors to metastasize to the breast, this is the first known case that showed exclusive spindle-cell morphology. History and physical examination were crucial in making the correct FNA diagnosis. The cytologic differential diagnosis of spindle-cell tumors of breast and the discordant morphology between the primary and metastatic melanotic lesions observed in this case are discussed.

Using the spin labelling method we studied changes in the structure and dynamics of molecular mobility in the plasmatic membrane accompanied by a spontaneous alteration of a melanotic melanoma line into an amelanotic form with a higher growth rate, changed antigenicity and immunogenicity. The calculated ratio of the low-field line (A) intensity to the central line (C) intensity of the spectrum showed statistically significant differences in the order of parameters in the plasmatic membranes of both forms of melanocytes. The significantly broader central line (deltaW0) in the spectra of labelled amelanotic melanoma cells than in the original cell line indicated changes in the membrane structure leading to a lowering of the degree of order in the phospholipid bilayer. It has been suggested that a progression of transplantable melanomas is accompanied by an increase in membrane fluidity and reduction in molecular mobility dynamics within it.

Background: The cytologic diagnosis (CD) of metastatic amelanotic melanomas (MAM) is challenging because the tumor cells may mimic those of a carcinoma or a sarcoma in cytologic materials obtained by fine-needle aspiration biopsy (FNAB)., Methods: Thirty-five well documented cases of MAM at different anatomic sites with cytologic evaluation by FNAB were reviewed., Results: In 31 cases a correct CD was made based on the cytologic and immunocytochemical (IM) findings. The MAMs were characterized by abundant dyshesive pleomorphic malignant cells containing prominent nucleoli and occasional intranuclear cytoplasmic inclusions. The tumor cells stained positively with S-100 and/ or HMB-45 antibodies. There were four cases with unusual cytologic manifestations and equivocal IM characteristics requiring electron microscopic examination (EME) of the aspirated tumor cells to identify intracytoplasmic melanosomes, pre-melanosomes, or microtubules within cisternae of rough endoplasmic reticulum (MCRER) to establish a diagnosis of MAM., Conclusions: A correct CD of MAMs may be made in a large number of cases by routine cytologic findings and IM staining with S-100 protein and HMB-45 antibodies. However, EME is necessary to demonstrate melanosomes, premelanosomes, or MCRER in cases with unusual cytologic and equivocal IM manifestations.

Background: The authors describe an amelanotic malignant melanoma of the conjunctiva in association with primary acquired melanosis (PAM) sine pigmento, and highlight the clinical and pathologic features of this rare entity., Methods: Histopathologic and immunohistochemical studies were performed on a conjunctival tumor in a 54-year-old white woman., Study Design: Case report., Results: Histopathologic examination revealed an invasive amelanotic melanoma of the conjunctiva, with anterior orbital extension arising from intraepithelial dysplastic melanocytes that lacked melanin pigment (PAM sine pigmento). Both the malignant melanoma cells and the intraepithelial dysplastic melanocytes in the areas of PAM exhibited S-100 and HMB-45 positivity. The patient underwent an orbital exenteration that disclosed tumor within the anterior orbit inferiorly., Conclusions: Amelanotic invasive malignant melanoma can arise in association with PAM sine pigmento, as seen in our patient who had orbital invasion necessitating exenteration. This aggressive form of conjunctival melanoma is often associated with a poor prognosis and risk of metastatic disease. Absence of conjunctival pigmentation in PAM sine pigmento prevents early clinical detection of this variant of PAM. This lack of pigmentation also makes clinical diagnosis virtually impossible, and diagnosis can only be established histopathologically. Awareness of this nonpigmented variety of PAM is crucial for early recognition and appropriate management of the associated melanoma.

Cutaneous malignant melanomas in cats, both melanotic and amelanotic, were diagnosed in 57 of 1.530 skin tumors during the period 1991-1995. All melanomas occurred in domestic shorthaircats of ages 3-19 years (mean = 11.5 years). Postmortem examination was performed on 16 cats. All had metastases in the regional lymph node and several organ systems. The average time of survival after surgical removal of the tumor was 4.5 months. Histologically, five types of melanomas could be distinguished: epithelioid, spindle, mixed, signet-ring, and balloon cell. Whereas all epithelioid, spindle, and mixed epithelioid/spindle cell types showed pigmentation, signet-ring and balloon cell types were often amelanotic. Immunohistochemical examination of the melanomas revealed a positive staining for S-100, vimentin, and neuron-specific enolase. The melanomas were negative for muscle cell markers, except in some of the signet-ring cell melanomas; 13 of 21 tumors showed a weak positive staining for polyclonal desmin. Electron microscopic examination of signet-ring cell melanomas revealed an abundance of intermediate filaments, whereas in some of these tumors a few cells with melanosomes were found. Nonisotopic in situ hybridization for mRNA encoding for tyrosinase verified the melanocytic origin of the amelanotic signet-ring and balloon cell melanomas.

Previous reports from this laboratory have shown marked cytocidal effects of the ISIS-3466 antisense phosphorothioate oligodeoxynucleotide to the human nucleolar protein p120 on human cancer cell lines in vitro and inhibition of tumor growth in vivo in an i.p/i.p. LOX cell model (L. Perlaky et al. Anti-Cancer Drug Design 8:3-14, 1993). In this study, light and fluorescence microscopy showed that the number of LOX cells in mitosis decreased by 50% after incubation for 4 h in 0.2-0.4 microM antisense oligonucleotide; a 70% reduction in cell number was found from 8-72 h post-treatment. In addition, marked unravelling of nucleolar structures and chromatin fragmentation was found after a 4-h incubation. The nucleolar unravelling occurred in varying degrees ranging from partial unfolding to almost complete separation of the strands of nucleolar residues. Twenty four hours post-treatment, immunofluorescence staining with the anti-p120 monoclonal antibody showed reduced nucleolar protein p120 and translocation of the p120 protein from the nucleoli to the nucleoplasm. Analysis of the mechanisms of the nucleolar unravelling and inhibition of mitosis will provide further understanding of the cytocidal effects of the ISIS-3466 antisense oligonucleotide.

A case of amelanotic melanoma arising in the upper molar region, which was difficult to diagnose histologically, is reported. The patient was a 79-year-old woman, who complained of a painful swelling in the gingiva of the left upper molar region. Routine histological examination showed that the lesion was composed of diffusely scattered atypical cells with round, spindle-shaped and irregular nuclei and scanty fibrous connective tissue. A fascicular arrangement was often found in the lesion, and no cancer nests were observed. Immunohistochemical study demonstrated positive staining for S-100 protein in both the nuclei and cytoplasm of the tumor cells. Electron microscopic examination revealed that cell organelles were abundant, and an interrupted basal lamina was often found along the cell membrane. The preliminary diagnosis was a non-epithelial malignant tumor. After surgery, histological examination of metastases in lymph nodes from the submandibular region revealed that the tumor cells contained melanin pigment in the cytoplasm, as confirmed by Masson's melanin stain. The final pathological diagnosis was therefore amelanotic melanoma. Immunohistochemical staining for S-100 protein may be useful for differential diagnosis of amelanotic melanoma in conjunction with electron microscopic examination.