Recurrent lentigo maligna in a young patient.

Lentigo maligna (LM) is usually diagnosed in sun-damaged skin of elderly patients and a correct excision of the lesion determines a complete healing from the disease. LM is very rare in young patients and, for this reason, it can be commonly misdiagnosed. We describe the case of a locally recurrent LM in a 19-year-old male patient, which initially arose at the age of 17 years. In order to avoid diagnostic pitfalls, clinicians have to put more emphasis on diseases which previously were prerogative only of elderly patients and that now could begin to engage a younger age, according to climate and behavior changes.

Protein Oxidative Damage in UV-Related Skin Cancer and Dysplastic Lesions Contributes to Neoplastic Promotion and Progression.

The ultraviolet (UV) component of solar radiation is the major driving force of skin carcinogenesis. Most of studies on UV carcinogenesis actually focus on DNA damage while their proteome-damaging ability and its contribution to skin carcinogenesis have remained largely underexplored. A redox proteomic analysis of oxidized proteins in solar-induced neoplastic skin lesion and perilesional areas has been conducted showing that the protein oxidative burden mostly concerns a selected number of proteins participating to a defined set of functions, namely: chaperoning and stress response; protein folding/refolding and protein quality control; proteasomal function; DNA damage repair; protein- and vesicle-trafficking; cell architecture, adhesion/extra-cellular matrix (ECM) interaction; proliferation/oncosuppression; apoptosis/survival, all of them ultimately concurring either to structural damage repair or to damage detoxication and stress response. In peri-neoplastic areas the oxidative alterations are conducive to the persistence of genetic alterations, dysfunctional apoptosis surveillance, and a disrupted extracellular environment, thus creating the condition for transformant clones to establish, expand and progress. A comparatively lower burden of oxidative damage is observed in neoplastic areas. Such a finding can reflect an adaptive selection of best fitting clones to the sharply pro-oxidant neoplastic environment. In this context the DNA damage response appears severely perturbed, thus sustaining an increased genomic instability and an accelerated rate of neoplastic evolution. In conclusion UV radiation, in addition to being a cancer-initiating agent, can act, through protein oxidation, as a cancer-promoting agent and as an inducer of genomic instability concurring with the neoplastic progression of established lesions.

Linear ectopic sebaceous hyperplasia of the penis: the last memory of Tyson's glands.

Pathologists who find ectopic glands on the glans and/or on the prepuce, often describe them as Tyson's glands. In this regard, the term Tyson's glands can be replaced by two different descriptive expressions: papillomatosis corona penis and ectopic sebaceous glands. A 15-year-old Caucasian male patient presented to our Institute with multiple and asymptomatic circular skin colored-to-yellowish papules at the level of the foreskin, also affecting the shaft of the penis, where they assumed a linear feature. The histological examination revealed hyperplastic and dilated sebaceous glands, while in some areas these glands showed also a direct attachment with the epidermis. A lymphocytic infiltrate was also observed in one of the two specimens. A final diagnosis of linear ectopic sebaceous hyperplasia of the penis was made. According to the current report, the ectopic sebaceous hyperplasia of the penis can have a circular and a linear patter, as well as the presence and the absence of a lymphoid infiltrate. A correct clinical and pathological diagnosis are necessary to avoid unnecessary treatments and worries in the patients. In fact, not infrequently, this condition is confused with dermatological diseases as molluscum contagiosum, epithelioid granuloma, lymphangioma circumscriptum, multiple syringomas, lichen planus, and bowenoid papulosis.

Resolution of Benign and Malignant Sebaceous Neoplasms, in a Renal Transplant Patient Treated With Everolimus.

Nonmelanoma skin cancers are the most common malignancies in transplant recipients under immunosuppression; nevertheless, appendage tumors also may appear. The onset of several cutaneous neoplasms in transplant patients can cause deterioration in quality of life of these patients. A 62-year-old white woman patient developed several malignant and benign sebaceous neoplasms during an immunosuppressive treatment for a renal transplant. The genetic study showed a mutation in MSH6-eson 1 (c116G>A), without mutations in MLH1 gene and MSH2. A final diagnosis of multiple sebaceous tumors in an immunosuppressed patient without Muir -Torre syndrome was made. The spreading of further cutaneous neoplasms led to a change in immunosuppression: namely, that clinicians suspended tacrolimus and add everolimus. After 2 months, all tumor lesions on the face and on the limbs have disappeared, and no further lesions occurred. Everolimus could represent a valid therapeutical treatment for transplant patients at high risk for cutaneous tumors. A genetic consult and a consequent study of the genetic profile should be performed on each of these patients, to avoid risks of recurrent cutaneous tumors and negative effects on the quality of life.

Galli-Galli Disease Presenting as a Lentigo-like Eruption: A Further Clinical Feature in the Wide Spectrum of Reticulate Pigment Disorders.

Dear Editor, Reticulate pigmentary disorders (RPD) is a term used to classify a spectrum of several acquired and congenital disorders. Different clinical features can be present, including a reticular pattern and a freckle-like pattern with hyper- or hypo-pigmented macules (1). Dowling-Degos disease (DDD), an autosomal dominant genodermatosis, is the main type of RPD (2). Clinically, DDD presents with pigmented, reticulate, flexural macules and comedo-like papules on the back and neck. Galli-Galli disease (GGD) is a very rare variant of DDD, from which is clinically indistinguishable (3). A 65-year-old Caucasian male patient presented to our Department with a 6-year history of diffuse maculopapular lesions involving the trunk and the extensor and flexor regions of the upper and lower extremities (Figure 1). These lesions were small, monomorphous, erythematous macules and papules, some covered by discrete scales. Numerous brown lentiginous macules were also observed. The patients did not present with comedo-like lesions, reticulate pigmentation, pitted acneiform facial scars, palmar pits, or nail changes. Furthermore, the oral mucosa showed no lesions. The patient's familial history was negative for dermatoses. Laboratory routine tests were all negative. Topical and oral steroids as well as systemic retinoids were unsuccessful. Therefore, a punch biopsy was performed. Histologic examination showed a digitate elongations of rete ridges, with small foci of acantholysis (Figure 2, a). The epidermis showed a finger-like projections extending into the papillary dermis with increased melanin pigment. The epidermis was atrophic above the digitate proliferations and above the acantholytic foci, where necrotic and dyskeratotic keratinocytes also were found (Figure 2, b). In the papillary dermis, a lymphohistiocytic infiltrate with perivascular distribution was detected (Figure 2, a). According to the clinical and histological findings, a final diagnosis of Galli-Galli disease with lentigo-like macular lesions was established. The patients started 25 mg/day acitretin with only partial improvement. GGD is now considered a variant of DDD, from which is clinically indistinguishable (2,3). Several differential diagnosis can be considered, including Darier's and Groover's disease (2-9) (Table 1). Because of the absence of digitate proliferation of the rete ridges and the presence of yellow or brown macules, Darier's disease can be distinguished from GGD. In our patient, the involvement of the lower legs and the presence of unusual brown, lentigo-like macules were accurately evaluated, because of the major diagnostic pitfall with an extensive kind of Grover's-like eruption with lentiginous freckling (6). However, the involvement of sun-shielded areas and the histological presence of a lentiginous elongation of rete ridges led us to a final diagnosis of GGD. Regarding the pathogenesis, the alteration of the keratine 5 gene (12q13.13) may be the main factor in GGD. In GGD, a reduced amount of functional keratin 5 impairs the structure of keratin intermediate filaments (10). As a result, the structure of the epidermis is affected, leading to alterations in desmosomes and hemidesmosomes (2). Regarding the lentigo-like pattern of our patient, the additional diffusion of lentigos over shield-sites and the absence of extreme sun exposure in the patient's history ruled out the ultraviolet radiation as the main etiopathogenetic factor. In this regard, as reported by Girard et al., lentigos could represent a post-inflammatory pigmentation of the papular acantholytic lesions (10). However, as emphasized by Coper et al. (6), the persistence of lentigos for several years would contrast with this hypothesis. It is indeed known that a failure of keratin 5 may disrupt the movement of pigment-carrying melanosomes into keratinocytes. The disruption of melanosome transport is thought to be the cause of the pigmentation abnormalities seen in DDD as well as in GGD. These aspects could explain the elongated rete ridges and the altered pigmentation clinically and pathologically observed in GGD and DDD.

Atrophic and Annular Scarring Alopecia of the Scalp as a Finding in Underlying Systemic Sarcoidosis.

Cutaneous sarcoidosis is not an uncommon disorder, and the skin can be the sole manifestation in about 10% of patients. However, when the involved anatomical area of the cutaneous sarcoidosis is the scalp and it presents as a scarring alopecia, there is an increased risk of a systemic disease (1,2). A 79-year-old Caucasian male patient presented to our Institute with annular and painless plaques of the scalp, with variable diameter, showing a reddish and yellowish color (Figure 1, a). Furthermore, a scleroderma-like atrophy of the skin with an exposure of the underlying vasculature was present (Figure 1, b). The patient reported that these lesions began to appear 2 years ago, with a worsening in the last 6 months. He also reported a chronic cough and dyspnea. According to the patient's medical history, he was treated for tinea capitis with radiotherapy of the scalp at the age of 7, with temporary hair-loss and subsequent total re-growth. Additionally, during the last 7 years he was diagnosed with mental depression and treated accordingly. The histology revealed typical epithelioid cell granulomas without central necrosis in association with a sparse lymphocytic infiltrate. Elastosis with ectatic vessels, sclerosis, and edema was also present in the upper dermis (Figure 1, c, d) A diagnosis of cutaneous sarcoidosis of the scalp was established. Laboratory investigations, including hepatitis B and C viral serology, anti-nuclear antibodies, antibodies to extractable nuclear antigen, cardiolipin, beta2 glycoprotein immunoglobulin G antibodies, and lymphoid subsets were all in normal ranges, whereas the angiotensin converting enzyme level was 124 (range: 65-114) IU/L. The chest radiography showed diffuse interstitial nodulations with bilateral and right para-tracheal lymphadenopathies, and the histology revealed pulmonary sarcoidosis (Figure 2). As of this writing, the patient is undergoing steroidal treatment with periodical clinical and instrumental follow-up, with poor response from the cutaneous lesions but an improvement of the pulmonary symptoms. Scalp sarcoidosis is a not frequent finding (1). Most of the reported cases are Afro-American female patients. Although the main clinico-pathological differential diagnosis is atypical necrobiosis lipoidica, this entity differs from cutaneous sarcoidosis by an absence of scalp scarring alopecia and by the fact that the annular lesions are often limited to the face, without involving the scalp (1-4). Additionally, histologically atypical necrobiosis lipoidica does not reach the typical features of a sarcoid granuloma. Other potential misdiagnoses are morphea, discoid lupus erythematosus, and lichen plano-pilaris (1-4). Sarcoidosis is most likely driven by a putative antigen in genetically susceptible individuals (5). Although radiation exposure is one of the possible causes of sarcoidosis, the radiotherapy used for the fungal infection did not have any role in the onset of the disease in our patient, as confirmed by the normal total regrowth of the hairs and the long-time interval. Regarding the therapy (mainly steroids, azathioprine, and hydroxychloroquine), if compared to other anatomical sites, the grade of atrophy in the scalp is always too high to allow an objective clinical response, as observed in our patient. This case emphasizes that in cutaneous annular sarcoidosis of the scalp, an underlying systemic sarcoidosis is often present.

Vitamin D receptor immunohistochemistry variability in sun-exposed and non-sun-exposed melanomas.

Ultraviolet rays are one of the leading factors in the development of melanoma (MM); however, ultraviolet rays seem not to play a role in non-sun-exposed MM, where systemic immunosuppression, anatomical, and physiological features may contribute toward the development of the malignancy. Our aim was to evaluate vitamin D receptor (VDR) expression in shield-site melanoma (ST-MM) and non-shield-site melanoma (NST-MM) to find features that could explain the different biological behavior of MM according to the area of onset. We reviewed 118 specimens of MM. VDR expression was assayed using immunohistochemistry by dividing the specimens according to the anatomical area. We included MM of the soles, feet, hands, gluteus, scrotum, skin of the penile shaft, and large vaginal labia in the ST-MM group. The NST-MM group was divided into two main categories: NST-MM of chronic sun-exposed areas, including MM of the face, scalp, neck, back of the hands, and NST-MM of intermittent sun-exposed areas, including MM of the trunk, lower, and upper limbs. In shield sites, 66.67% of MMs showed VDR expression; in intermittent sun-exposed areas, 33.3% showed VDR expression; and in chronic sun-exposed areas, only 4.66% showed VDR expression. A similar behavior was observed for Breslow's thickness, where VDR staining intensity was higher in thicker lesions, ranging between 60 and 100%. We found that VDR expression decreased from ST-MM to NST-MM. These findings confirm the hypothesis that different pathways are involved in ST-MM and NST-MM.

Folliculotropic Cutaneous Metastases and Lymphangitis Carcinomatosa: When Cutaneous Metastases of Breast Carcinoma Are Mistaken for Cutaneous Infections.

Dear Editor, Cutaneous metastases (CM) are detected in about 0.6-10.4% of patients with an internal malignancy (1-3). Excluding melanoma, breast and lung carcinomas are the main source of CM in women and men, respectively (1,4,5). CM can have different clinical features, and a diagnosis of CM is usually suspected before performing a biopsy. However, this can be a pitfall for clinicians when the clinical presentation is not the typical inflammatory nodule or mass. Herein we report 2 cases of cutaneous metastases of breast carcinoma, initially treated as a common skin infection. Case 1 A 51-year-old Caucasian woman presented to our Institute with a four-month history of diffuse and erythematous pustular, lesions on the right arm that were painless and non pruritic (Figure 1). The patient had undergone excision for a breast adenocarcinoma (stage IIIA) 5 years earlier. An initial diagnosis of folliculitis was established, and the patient started systemic and topical antibiotics without any improvement. Based on the clinical features and the patient medical history, we performed a skin biopsy. Pathologically dermal nests of tumor cells, arranged in a glandular-like pattern and involving the perifollicular and follicular areas (Figure 2, Figure 3), were highlighted. The tumor cells were positive to cytokeratin (CK) 7, CK19, and carcinoembryonic antigen (CEA) and negative for CK20, CK5/6, CD10, and thyroid transcription factor-1 (TTF-1) (Figure 4). According to the clinical history and pathology, a final diagnosis of folliculotropic metastatic breast carcinoma was established. Unfortunately, the patient died after 10 months. Case 2 A 61-year old Caucasian woman presented to our Department with a two-month history of pink/violet macular lesions with diffuse telangiectasia on the left breast and arm (Figure 5, Figure 6). Five years earlier she had undergone excision for a breast adenocarcinoma (stage II A). A previous diagnosis of cellulitis had been made, and systemic antibiotic therapy had been started without any improvement. Based on the clinical features and the patient medical history, a punch biopsy was performed. Examination of skin biopsy showed a diffuse, sclerotic, and mixoid stroma with several dense ectatic lymphatic vessels (Figure 7, Figure 8). The dermal and hypodermal lymphatic lumens were filled with neoplastic cells. Thus, a diagnosis of cutaneous lymphangitis carcinomatosa (CLC) was established. Unfortunately, the patient died after 8 months. Discussion CM are present after breast carcinoma in about 23.9% of patients, often involving the chest and abdomen and manifesting on average 5 years after surgical removal of the first malignancy (1,6). CM of breast cancer are usually solitary or multiple nodular pinkish lesions (ranging between 1 and 3 cm) (1). However, several clinical features have been reported in the literature, including telangiectatic carcinoma, erythema-like, erythema annulare centrifugum-like, morphea-like, erysipelas-like, dermatofibroma-like, herpes-zoster-like, and alopecia-like lesions (1,7-10). Clinical and pathological images of folliculitis-like metastases are rarely reported in the literature, especially after breast cancer (11,13) Clinically, folliculitis-like metastases could resemble a zosteriform-like metastatic lesion (7,14,15) although they do not follow a dermatome and are pustular lesions rather than violaceous indurate papules and/or nodules (13,14) Pathologically, our cases showed an infiltration of the dermis and pilosebaceous units growing through the pilosebaceous unit in a "pseudo-eruptive way". In this regard, folliculitis-like CM could be similar to alopecia neoplastica, where the metastatic process involves and destroys the pilosebaceous units completely, leading to scarring alopecia (9,10). However, in our case, the pilosebaceous unit was still slightly recognizable, and clinically there were no scar-like features. The mechanism of folliculitis-like metastasis formation is currently unknown. As reported in zosteriform-like metastases, the lymphatic and hematogenous spread of malignant cells or the koebnerization at the site of a previous viral and/or bacterial infection could lead to metastasis (7,14-16). However, unlike zosteriform-like metastases, the spread of neoplastic cells from the dorsal root ganglia was not a plausible mechanism of metastasization in our cases because of the absence of dermatome involvement. Furthermore, there were no signs of possible koebnerization in a previous bacterial and/or viral infection site (7,13) In our opinion, folliculitis-like metastasis may be a result of the skin extruding malignant cells through the pilosebaceous unit to limit the neopalstic proliferation. This could explain the clinical and pathological features of folliculitis-like metastasis. Alternatively, the adnexotropic behavior of malignant cells may be explained by homing mechanisms, involving the up-regulation of the intercellular adhesion molecule 1 (ICAM-1) on the follicular epithelium, such as folliculotropic mycosis fungoides (17). In our patient, the folliculitis-like eruption was the first sign of recurrence after 5 years of disease-free survival. It is evident that the unusual folliculitis-like eruption of CM led to a delay in the diagnosis. CLC is a rare presentation of skin metastasis, characterized by an occlusion of dermic lymphatic vessels by neoplastic cells (18). CLC has been reported in the literature in association with several malignancies, including lung, breast, and ovarian cancer (19). CLC shows pink/violet macular lesions with diffuse telangiectasias, often associated with itching and burning sensation. The main differential diagnoses are erysipelas and cellulitis. However, CLC is not associated with fever, chills, and leukocytosis. Furthermore, CLC shows no response to antibiotic therapies. Several clinicopathological types of cutaneous metastasis have been reported in the literature, including telangiectatic metastatic breast carcinoma (TMBC) and carcinoma erysipelatous (CE). TMBC is characterized by yellowish/reddish or violaceous papulo-vesicular lesions. CE usually shows blistering erythematous eruptions resembling erysipelas. However, CLC, TMBC, and CE are different clinical expressions of the same metastatic process, pathologically characterized by edema of the dermis and ectatic lymphatic vessels. Positivity to CD31 and podoplanin in the endothelial cells shows that the tumor metastatises predominantly via lymphatic vessels (20). In conclusion, we stress that every cutaneous lesion should be studied and examined carefully in patients with a personal history of cancer. Indeed, a correct diagnosis remains the pivotal point for a better management of these patients.

Early Angiosarcoma of the Scalp: A Clinicopathological Pitfall.

Angiosarcoma (AS) is a rare malignant vascular tumor, which affects mainly elderly patients. After the diagnosis, the mean overall survival of patients is 30 months. The variable presentation of the malignancy, the benign appearance of the cutaneous lesions, and the minimal histological changes in early lesions can sometimes delay the correct diagnosis. The authors report a case of an 80-year-old white male patient, with a painless and ecchymotic lesion of the scalp, which histologically showed minimal pathological atypia, conclusive for a diagnosis of AS with minimal histological changes. The authors discuss the main and most emblematic cases of AS initially misdiagnosed for other cutaneous diseases reported in the literature, noting that in some cases, also the histology can be treacherous and a trap for the dermatopathologist. The recent findings on MYC, FLT4 and KDR amplification, and the relative therapeutic perspectives are also discussed. Finally, the authors draw up some pathological cornerstones, which could improve the diagnosis, above all in early lesions with minimal atypia.

Purely cutaneous sclerosing IgG4-related disease of the cephalic region: case report and a mini-review of the clinical and pathological aspects.

IgG4-related disease is a recently defined emerging entity. Many different organs may be affected by this disease: pancreas, salivary and lacrimal glands, liver, peritoneum and lung. Also the skin may be affected, as secondary localization, while as primary cutaneous localization it has been rarely described. A male patient presented at our Institute with a two-year history of sclerosing erythematous nodules of the scalp. Histological examination showed a T-lymphocyte (CD3+) infiltrate with interspersed plasmacytoid cells and the interposition of a fibrosclerotic tissue. We found numerous IgG4+ cells at the periphery of the nodular structures, while the serum levels of IgG4 and the remaining blood chemistry analysis were normal. Only a few cases of primitive cutaneous pseudo-lymphomatous IgG4-related disease have been described in the literature. Our case showed the same clinical and histologic features of those previously described; the etiology of IgG4-related diseases remains to be elucidated.