Pigmented lesions on the palms and soles during PUVA therapy

Pigmented skin lesions due to PUVA are well recognized. They include freckles, mottled skin, naevus spilus-like lesions and 'PUVA lentigines' (Kietzmann & Christophers, 1984). The PUVA lentigo appears to be common, occurring in up to 53% of patients (Rhodes, Stern & Melski, 1983). These discrete brown macules, 2–5 mm in diameter, may become very widespread, particularly in those patients who have had many PUVA treatments. They tend to spare the face and have not previously been reported on the palms or soles.
We have now seen three female patients who have developed pigmented lesions on their palms (and in one case also on the sole) whilst receiving long-term oral PUVA therapy for psoriasis. The lesions were of two types: ill-defined light grey-brown macules (histologically a freckle, with no increase in number of basal melanocytes), and discrete dark brown macules. The latter showed focal proliferation of dendritic melanocytes at the dermo-epidermal junction, with increased pigmentation throughout the epidermis and also in the superficial dermis. These lesions developed after a minimum of 70 PUVA treatments (over 18 months) in one case, but only appeared after 5 years' PUVA (330 treatments) in another.
Ultrastructural studies (Rhodes, Harrist & Momtaz, 1983) have demonstrated that the melanocytes in PUVA lentigines may show cytological atypia. PUVA lentigines may also persist for up to 2 years (and probably longer) after stopping PUVA. Patients undergoing prolonged PUVA therapy to the palms and soles should be warned about the possibility of developing pigmented lesions which may persist after cessation of therapy.     

Atypical pigmented lesions following extensive PUVA therapy

We report a 38-year-old woman with psoriasis who developed multiple atypical lentigines following psoralen photochemotherapy (PUVA). The lentigines first appeared 12 years ago, 3 years after she commenced intermittent PUVA treatment. New lesions continued to develop over the subsequent years with further photochemotherapy. Clinically, the lentigines were strikingly atypical, deeply pigmented, dark brown or black, large stellate macules. Histology of a representative lesion was consistent with a PUVA lentigo and no atypical melanocytes were seen. At present, a link between malignant melanoma and PUVA lentigines has not been established. Instead, limited evidence suggests that PUVA lentigines may be more closely linked with the risk of nonmelanoma skin cancer.     

Atypical pigmented penile macules

Two patients with pigmented lesions of the penis are described. The lesions consisted of asymptomatic, multifocal, irregular macules, with variegated pigmentation. The main differential diagnostic problem was with mucocutaneous melanoma. Histologic examination of the lesions showed basal layer hyperpigmentation. No cytologic atypia of melanocytes was detectable. The diagnosis in both cases was melanotic macules. Because of their atypical clinical appearance, genital melanotic macules are often misinterpreted as mucocutaneous melanoma. However histopathologic study solves the problem because genital melanotic macules show no melanocytic proliferation nor melanocytic atypia.     

UVA-induced melanocytic lesions

The occurrence of melanocytic lesions following PUVA therapy is well documented. We describe a patient who developed similar lesions after cosmetic use of a home sun-bed without psoralen administration. Histological examination showed increased numbers of large and sometimes atypical melanocytes, which may theoretically act as precursors for melanoma.     

Pigmented plexiform neurofibroma: Distinction from a large congenital melanocytic nevus

The substantial clinical and histologic overlap between neurotized congenital melanocytic nevi and the subset of plexiform neurofibromas with hyperpigmentation and hypertrichosis of the overlying skin (pigmented neurofibroma) has led to considerable confusion in the literature. A dark-brown, hypertrichotic plaque covered much of the right lower aspect of the trunk of a 1-year-old girl with a diffuse and plexiform neurofibroma in the same area, numerous café-au-lait macules, and intertriginous freckling. The latter findings were diagnostic of neurofibromatosis-1, which was further supported by the presence of unidentified bright objects on magnetic resonance imaging of the brain. Histologic examination of the hyperpigmented plaque revealed melanocytic hyperplasia at the dermoepidermal junction and a proliferation of rounded, pigmented melanocytes dispersed individually and in occasional small nests in the papillary dermis and scattered within underlying neurofibromatous tissue. Immunohistochemical staining with A103 (Melan-A/MART-1) and PNL2 confirmed the melanocytic differentiation of the pigmented cells, whereas glial fibrillary acidic protein and Leu-7 were detected only within plexiform areas and slender neuroid spindle cells. This case draws attention to the pigmented neurofibroma as a distinct clinicopathologic entity resulting from proliferation of melanocytes and neurosustentacular cells in the setting of neurofibromatosis-1.     

Histological analysis of intraepidermal proliferations of atypical melanocytes

Fifty cutaneous pigmented lesions characterized by an intraepidermal proliferation of atypical melanocytes were reviewed. Several histological parameters (position of melanocytes in the epidermis, nuclear melanocytic atypia, presence or absence of pagetoid melanocytes, nucleoli, and others) were evaluated. On the basis of the results, the investigated cases were classified into three groups. In group 1, pagetoid melanocytes were present, melanocytic atypia was severe and continuous, all epidermal layers were involved by melanocytic proliferation, and a pattern of epidermal infiltration was recognized. In group 2, pagetoid melanocytes were absent, melanocytic atypia was mild-moderate and discontinuous, the lower epidermis only was involved by melanocytic proliferation, and a pattern of epidermal pseudoinfiltration was recognized. Group 3 cases were in an intermediate area between the two major groups. The results showed that intraepidermal proliferations of atypical melanocytes lie on one line, in which groups 1 and 2 account for the extremes.     

Morphologic alterations of epidermal melanocytes and melanosomes in PUVA lentigines: a comparative ultrastructural investigation of lentigines induced by PUVA and sunlight

Ultrastructural studies were conducted in order to determine morphologic and functional differences in melanocytes and melanosomes in PUVA lentigines and solar lentigines, and light-protected buttock skin. Compared to melanocytes in solar lentigines from 7 subjects and light-protected buttock skin from 5 subjects (none of these subjects had received UV radiation therapy), melanocytes in PUVA lentigines from 6 subjects generally had longer and more numerous dendrites, and showed more active melanogenesis. Basal keratinocytes in PUVA lentigines had a significantly increased frequency of large, single melanosomes, and revealed significantly larger individual melanosomes within compound melanosomes. Other findings in some PUVA lentigines included the close apposition of Langerhans cells to melanocytes, and atypical nuclear, cytoplasmic and melanosomal alterations, including melanosomal pleomorphism and melanin macroglobules. The presence of relatively large and predominantly single melanosomes in basal keratinocytes of PUVA lentigines suggests more active melanogenesis and/or an irreversible somatic alteration. It will be important to determine the clinical course and ultrastructural findings of PUVA lentigines that persist long after PUVA is discontinued.     

Malignant melanoma in situ on the sole of the foot. Its clinical and histopathologic characteristics

This clinical and histologic study of 122 macular melanocytic lesions on the soles of the feet of Japanese subjects revealed ten in situ malignant melanomas. Clinically, the lesions were broad pigmented macules or patches with asymmetric, angular, irregular shapes, and notched borders. The lesions appeared brownish black, and most were variegated from tan to black. The largest diameters were greater than or equal to 9 mm. The demargination of most lesions was not even; that is, one part of the lesion border was vague while another part was sharp. Histologically, an increased number of atypical melanocytes, mainly arranged as solitary units, were observed within the epidermis. Intraepidermal nests of melanocytes were found in five cases. The great majority of malignant melanomas in non-Caucasians affect acral regions--especially the sole of the foot--so, to improve their prognosis, the characteristics of malignant melanoma in situ on the sole must be elucidated.     

Malignant melanoma in situ in two patients treated with psoralens and ultraviolet A

Two patients are reported who were treated with 8-methoxypsoralen and ultraviolet A (PUVA) for psoriasis and developed cutaneous lesions of malignant melanoma in situ (atypical melanocytic hyperplasia). One patient received 324.5 joules/cm2 of UVA. Seven months after discontinuing therapy, he developed a superficial spreading melanoma in situ in association with an intradermal nevus on the left posterior thoracic area. The second patient received 2,802 joules/cm of UVA. While on PUVA therapy she developed an in situ lentigo melanoma on her lower lip. To our knowledge only one other psoriatic patient and one patient with vitiligo have developed malignant melanomas after PUVA therapy, so that an increased incidence of malignant melanomas after PUVA therapy, so that an increased incidence of malignant melanoma following PUVA is not documented.     

Eruptive melanotic macules and papules associated with adenocarcinoma

BACKGROUND: Malignancies may be associated with paraneoplastic cutaneous manifestations, including pigmentary disorders. METHODS: The clinical findings were reviewed. Skin and tumor tissue samples were examined by routine histology, immunohistochemistry, and in one case also by electron microscopy. RESULTS: Two patients developed diffuse melanotic macules and papules associated with visceral adenocarcinoma. One patient was a 64-year-old man with advanced carcinoma of the distal esophagus. The other was a 62-year-old man with metastatic pulmonary adenocarcinoma. The detection of the primary tumor in both patients was preceded by the rapid onset of melanotic macules and papules in the anogenital region and in one patient also around both nipples. The pigmented lesions were histologically characterized by a lentiginous melanocytic proliferation of large and heavily pigmented melanocytes associated with hyperpigmentation of adjacent keratinocytes. Both patients had been misdiagnosed as having epidermotropic metastatic malignant melanoma. None of them had prior, concurrent, or subsequent cutaneous or extracutaneous invasive melanoma. Both patients died of metastatic adenocarcinoma. CONCLUSION: Eruptive melanotic macules and papules represent an under-recognized paraneoplastic syndrome. The cases illustrate a diagnostic pitfall for clinicians and pathologists unaware of this phenomenon.     

Intraepidermal epidermotropic metastatic melanoma: a clinical and histopathological mimicker of melanoma in situ occurring in multiplicity

The distinction between primary melanoma and melanoma metastatic to the skin has major prognostic implications. We report a case of a 67-year-old male with a diagnosis of a superficial spreading melanoma (stage IB) rendered 6 years earlier who presented clinically with an atypical nevus on his left thigh. Histopathological examination showed an intraepidermal melanocytic proliferation that was interpreted as melanoma in situ. Subsequently, 45 additional pigmented macules appeared in crops over a 9-month period. Clinically and dermoscopically, these lesions were extremely polymorphic. Histopathological findings were compatible with melanoma in situ, as each lesion consisted of a wholly intraepidermal proliferation of markedly atypical melanocytes arranged singly and in nests. A complete gastrointestinal study showed multiple pigmented metastatic lesions throughout the stomach and small bowel, which supported a diagnosis of metastatic melanoma with gastrointestinal and epidermotropic skin involvement. Monosomy of chromosome 9 and a BRAF V600E mutation were detected in the primary tumor sample and in macro-dissected secondary lesions. No CDKN2A or CDK4 germline mutations were found. Intraepidermal epidermotropic metastases of melanoma have been rarely described in literature. In this case, histopathology alone was insufficient to distinguish metastatic melanoma from multiple in situ melanomas. The recognition of epidermotropic metastases should be based on the correlation between clinical, dermoscopic, histopathological and molecular findings.     

Genital lentiginosis: a clinical and histopathologic study

We studied the clinical and histopathologic characteristics of melanotic macules of the penis and vulva. The 10 lesions studied were relatively large (up to 2 cm), multifocal, irregular in outline, and had variegated pigmentation. Most were regarded as clinically atypical in appearance. Histologic examination of the lesions showed basal layer hyperpigmentation, slight melanocytic hyperplasia, epithelial hyperplasia, and stromal melanophages. No cytologic atypia of melanocytes was detectable. Information is insufficient at present to predict the natural history of genital lentiginosis or its relation to mucocutaneous melanoma.     

Primary malignant melanoma of the oral cavity: case report

An 80-year-old-female patient had a pigmented lesion on: the hard palate, the soft palate, the alveolar mucosa and the vestibular mucosa of the maxillary gingiva. Pigmented macules and patches had been persistent and asymptomatic for many years (Fig. 1). The lesion exhibited irregularities of pigmentation, border and surface contour. About 1 year later the patient had noticed an extension of the pigmented macules and plaques; there was also the appearance of nodules of the maxillary gingiva accompanied by swelling. Loosening of teeth as a result of extensive destruction of bone was further noted (Fig. 2). The histological examination showed a downward streaming in the dermis of the tumor cells and a disintegration and ulceration of the epidermis (Fig. 3). An increased number of large round or polygonal cells resembling atypical epithelioid cells were found on the submucosa. The atypical cells had enlarged, pleomorphic nuclei with prominent and sometimes multiple nucleoli. Mitoses were observed at various tissue levels (Fig. 4). Abundant pigmented melanin was present in the tumor cells (Fig. 5). Many cells had fine, dusty melanin particles. The tumor cells showed great variations in size. Immunohistochemical staining, with S100 protein and HMB45 antibodies, stained many of the spindleshaped cells, indicating that they were melanocytic cells. An inflammatory infiltrate of lymphocytes was seen in a band beneath the invading tumor cells.     

Numerous,small, darkly pigmented melanocytic nevi: the cheetah phenotype

BACKGROUND: The presence of multiple atypical nevi or numerous melanocytic nevi increases the risk for the development of cutaneous melanoma. OBJECTIVE: We sought to describe a distinct clinical phenotype characterized by numerous (>100), small (< or =4 mm), darkly pigmented melanocytic nevi that are uniform in color. METHODS: Biopsy specimens from 6 patients (3 men and 3 women; age range, 44 to 81 years) with this clinical phenotype were reviewed and compared with a database of melanocytic lesions analyzed by the Yale Dermatopathology Laboratory (YDL) in the year 2000. RESULTS: Of the 6 patients, 4 had multiple primary melanomas develop (n = 2-4), ranging from in situ to 1.0 mm in depth. The other 2 patients each had 1 nevus with severe cytologic atypia. When compared with the YDL database, our patients were more likely to have the following pigmented lesions: junctional melanocytic nevi, junctional lentiginous nevi, junctional nevi with cytologic atypia, and simple lentigines (P <.001). CONCLUSIONS: The longitudinal evaluation of patients with this phenotype can be challenging because similar-appearing pigmented lesions (small and uniformly dark-brown to black) had a range of histologic diagnoses from simple lentigo to junctional lentiginous nevus to thin melanoma.     

Melanocytic lesions of the genital area with attention given to atypical genital nevi

Melanocytic lesions of the genital area are rare. They arise mainly in the vulva, although they can also occur less frequently in the perineum, mons pubis and male genitalia and represent 10-12% of pigmented lesions of White women. These pigmented lesions include melanocytic nevi, lentigines, melanocytic nevi with architectural disorder and atypia of melanocytes (dysplastic nevi) and melanomas with microscopic features similar to those seen elsewhere on the body. There is a small subset of benign nevi named atypical melanocytic nevi of the genital type (AMNGT) that occur in young women, with distinctive histologic features in some cases overlapping morphologically with those of melanoma. Thus, it is important to distinguish AMNGT from melanomas in terms of prognosis and treatment. We retrieved 58 cases of genital pigmented lesions diagnosed at our hospital from 1986 to 2008 to evaluate their clinicopathologic features with especial consideration to those cases with atypical features. Thirty-two cases (55%) were common nevi, 10 (17%) lentigines, 6 (10%) melanomas, 3 (5%) dysplastic nevi and 1 blue nevus. Six cases (10%) corresponded to AMNGT and were taken from women with a median age of 21 years. All cases showed symmetry, and the melanocytic proliferation was well demarcated at the lateral margins. The junctional component was very prominent and formed by round or fusiform nests with common retraction artifact and/or cellular dyshesion or as a single cell proliferation with mild (33%) to moderate (67%) cytologic atypia, focal pagetoid spread (17%) and a benign-appearing dermal component (83%) with maturation and dense eosinophilic fibrosis in the superficial dermis. Neither nuclear atypia of melanocytes in the superficial dermis nor dermal mitoses were observed. AMNGT were excised, and no recurrences were recorded in the follow up (median 10.5 years). Therefore, it seems that there is no evidence that AMNGT are precursors of dysplastic nevi or melanomas.     

Genital melanotic macules: clinical, histologic, immunohistochemical, and ultrastructural features

BACKGROUND: Genital melanotic macules are poorly recognized lesions, which appear as isolated discrete macules. Their occurrence, usually as new pigmented lesions in adult life, can cause concern because they can mimic early melanoma. OBJECTIVE: Our purpose was to define the clinical, histologic, immunohistochemical, and electronmicroscopic features of genital melanotic macules. METHODS: History and clinical features of 10 patients (5 female, 5 male) were assessed in detail. Histologic findings were reviewed in 5 cases, and immunohistochemistry, with the use of the HMB-45 antibody, in 4 cases and electron microscopy in 3 cases. RESULTS: Clinically the lesions varied in color, tan to dark brown/black, and size (0.5-2 cm). Histologic findings showed increased basal pigmentation without atypical features. HMB45 antibody staining was negative. Electron microscopy showed normal morphology and number of melanocytes but increased melanosomes and dermal melanophages. CONCLUSION: Genital melanotic macules are benign, asymptomatic, discrete areas of hyperpigmentation that occur equally in men and women. Histologic, immunohistochemical, and electronmicroscopic study confirms their benign nature.     

Matrical carcinoma with melanocytic hyperplasia mimicking nodular melanoma in an elderly Mexican male

Matrical carcinoma with melanocytic hyperplasia (MCMH), previously referred to as malignant melanocytic matricoma, is a rare variant of the uncommon pilomatrical carcinoma, occurring most often on the head/neck and upper backs of middle‐aged men. Nodular lesions may resemble pigmented basal cell carcinoma or melanoma clinically. We present a case of MCMH in a Hispanic patient with history of melanoma. Histopathological clues to appropriate diagnosis include basaloid cells, numerous atypical mitotic figures, matrical differentiation, shadow cells, strong diffuse nuclear and cytoplasmic expression of ß‐catenin, and interspersed pigmented dendritic melanocytes.     

Diagnosis and therapy of streaked nail pigmentation

Melanonychia striata longitudinalis is due to a focal increase in number and/or activity of melanocytes in the nail matrix, resulting in the continuous production of large amounts of melanin which are transferred to the nail cells and grow out with the nail plate. Histologically, either benign melanocytic hyperplasia, lentigo simplex, nevocellular nevus, atypical melanocytic hyperplasia or acral lentiginous melanoma may be found. Longitudinal pigmented streaks in the nails of Caucasians tend to be malignant rather than benign. Thus a biopsy for proper histological diagnosis is strongly advised. Melanonychia striata may also occur as a symptom of rare syndromes and diseases or be due to therapy. Differentiating this condition from subungual hematoma and infections with chromogenic bacteria and fungi may be difficult.     

Atypical moles in a patient undergoing chemotherapy with oral 5-fluorouracil prodrug

We present a patient with multiple pigmented lesions on the palms, soles, oral mucosa and nails after chemotherapy with oral 5-fluorouracil (5-FU) prodrug. Dermoscopically, most of the macules showed similar features, with pigmentation present predominantly on the crista superficialis, while a large, dark macule also showed pigmentation along the sulcus superficialis with irregular hyperpigmentation and depigmentation, suggesting malignancy. However, histologically, both types of lesion showed basal hyperpigmentation and the presence of a small number of large atypical melanocytes. We diagnosed these lesions as pigment flecks induced by 5-FU, and the pigmented lesions gradually diminished after the cessation of chemotherapy. Our findings suggested that immunosuppression and 5-FU led to the development of the atypical pigmented lesions.