Merkel Cell Carcinoma of Unknown Primary Origin.

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary cutaneous neuroendocrine carcinoma most often occurring in the elderly. Risk factors include chronic sun exposure and immunosuppression (1). MCC is associated with frequent recurrences and a high metastatic potential and mortality rate (1). It is the second most common cause of skin-cancer-related death after melanoma. At primary diagnosis with an apparent cutaneous tumor, loco-regional metastases are present in up to 30% of patients, and 6-12% have distant metastatic disease (2-3). Up to 5% of cases present with unknown primary origin (4). Five-year overall survival for patients with advanced or metastatic disease is 13-18% (4). We report two cases of MCC presenting without primary cutaneous involvement; first at an unusual location in the adipose tissue of the right breast, and the second one with only a clinically positive left inguinal lymph node. In October 2018, a 78-year-old woman presented with a 15-week history of a painless solitary mass in the upper outer quadrant (UOQ) of the right breast with no visible cutaneous involvement. Her medical history included hypertension, dyslipidemia, and plaque psoriasis. She underwent ultrasound guided biopsy, and histopathology confirmed the diagnosis of metastatic MCC (mMCC). Positron emission tomography/computed tomography (PET/CT) scans showed increased standardized uptake values in the mass in the UOQ and an additional mass in the lower inner quadrant (Figure 1A). The patient underwent mastectomy and lymph node dissection of the right axilla. Histopathology confirmed mMCC and negative axillary lymph nodes. Regular follow-up (clinical examination, PET/CT scan, ultrasound, mammography) every 6 months revealed no disease recurrence during this 4-year period (Figure 1B). In September 2021, a 66-year-old man was referred to our Clinic with clinically detectable painful left inguinal lymphadenopathy. Excisional biopsy was performed, and histopathology confirmed the diagnosis of mMCC (Figure 2). After an extensive clinical and imaging evaluation (PET/CT scan), which confirmed disseminated disease (Figure 3A), initial treatment with the programmed cell death ligand 1 inhibitor (anti PD-L1) avelumab was proposed. The first cycle consisting of seven intravenous applications, and was applied in October 2021. After one year and completion of the third cycle of therapy, imaging assessment (PET-CT scan) detected a solitary lesion in the pancreas. Fine needle aspiration biopsy confirmed a distant metastasis of MCC that was later treated with stereotactic radiosurgery. The fourth cycle of immunotherapy was completed in March 2023. No treatment-related adverse events were noted during these 18 months of follow-up. Recent PET/CT scans demonstrated scaring tissue in the pancreas with no signs of locoregional or distant metastatic disease (Figure 3B). Management of MCC should be individualized based on the specific pattern of disease presentation. The presence of nodal disease is one of the most powerful predictors of overall survival and risk for developing distant metastatic disease (3-4). Multidisciplinary tumor board discussions are mandatory for the management of advanced MCC. New emerging treatment options have once again returned focus to this rare and highly-aggressive entity. Until recent years, mMCC was managed with extensive surgery, radiotherapy, or chemotherapy, but responses were not durable (1). Based on new clinical trials, immunotherapy has now become a rational and promising treatment option and is considered as first-line treatment in patients with advanced MCC (5). The management of patients with MCC of unknown primary origin should adhere to that for patients with an identifiable primary tumour (6). Although cutaneous manifestations are the hallmark of MCC, only a minority of cases have been reported in the literature without any cutaneous involvement (7-10). Our cases highlight this unusual presentation of MCC that could be misleading and contribute to delayed diagnosis. We therefore emphasize the importance of considering rare forms of malignancies such as MCC even in the absence of a primary cutaneous lesion.

Adverse Reaction to Cetuximab, an Epidermal Growth Factor Receptor Inhibitor.

Dear Editor, Inhibition of the epidermal growth factor receptor (EGFR) is a new strategy in treatment of a variety of solid tumors, such as colorectal carcinoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and pancreatic cancer (1). Cetuximab is a chimeric human-murine monoclonal antibody against EGFR. Cutaneous side effects are the most common adverse reactions occurring during epidermal growth factor receptor inhibitors (EGFRI) therapy. Papulopustular rash (acne like rash) develop with 80-86% patients receiving cetuximab, while xerosis, eczema, fissures, teleangiectasiae, hyperpigmentations, and nail and hair changes occur less frequently (2). The mechanism underlying these skin changes has not been established and understood. It seems EGFRI alter cell growth and differentiation, leading to impaired stratum corneum and cell apoptosis (3-5). An abdominoperineal resection of the rectal adenocarcinoma (Dukes C) was performed on a 43-year-old female patient. Following surgery, adjuvant chemo-radiotherapy was applied. After two years, the patient suffered a metastatic relapse. Abdominal lymphadenopathy was detected on multi-slice computer tomography (MSCT) images, with an increased value of the carcinoembryonic antigen (CEA) tumor marker (maximal value 57 ng/mL). Hematological and biochemical tests were within normal limits, so first-line chemotherapy with oxaliplatin and a 5-fluorouracil (FOLFOX4) protocol was introduced. A wild type of the KRAS gene was confirmed in tumor tissue (diagnostic prerequisite for the introduction of EGFRI) and cetuximab (250 mg per m2 of body surface) was added to the treatment protocol. The patient responded well to the treatment with confirmed partial regression of the tumor formations. Three months after the patient started using cetuximab, an anti-EGFR monoclonal antibody, the patient presented with a papulopustular eruption in the seborrhoeic areas (Figure 1) and eczematoid reactions on the extremities with dry, scaly, itchy skin (Figure 2). Furthermore, hair and nail changes gradually developed, culminating with trichomegaly (Figure 3) and paronychia (Figure 4). The patient was treated with oral antibiotics (tetracycline) and a combination of topical steroids with moisturizing emollients due to xerosis, without reduction of EGFRI therapy and with a very good response. Trichomegaly was regularly sniped with scissors. Nail fungal infection was ruled out by native examination and cultivation, so antiseptics and corticosteroid ointments were introduced for paronychia treatment. During the above-mentioned therapy, apart from skin manifestations, iatrogenic neutropenia grade IV occurred, with one febrile episode, and because of this, the dose of cytostatic drugs was reduced. After 10 months of therapy, progression of the disease occurred with lung metastases, so EGFRI therapy was discontinued and the patient was given second-line chemotherapy for metastatic colorectal carcinoma. This led to gradual resolution of all aforementioned cutaneous manifestations. Since the pathogenesis of skin side-effects due to EGFRI is not yet fully understood, there are no strict therapy protocols. Therapy is mainly based on clinical experience and follows the standard treatments for acne, rosacea, xerosis, paronychia, and effluvium. The therapeutic approach for papulopustular exanthema includes topical and systemic antibiotics for their antimicrobial as well as anti-inflammatory effect, sometimes in combination with topical steroids. Topical application of urea cream with K1 vitamin yielded positive results in skin-changes prevention during EGFRI therapy, especially with xerosis, eczema, and pruritus (6). Hair alterations in the form of effluvium are usually tolerable, and if needed a 2% minoxidil solution may be applied. Trichomegaly or abnormal eyelash growth can lead to serious complications, so ophthalmologic examination is needed. At the beginning of the growth, regular lash clipping may reduce possibility of corneal abrasion (7,8). Nail changes can just be a cosmetic problem (pigmentary changes, brittle nails), and in the occurrence of paronychia or onycholysis (of several or all nails) they result in high morbidity and impair daily activities. Nail management should be started as soon as possible because of slow nail growth and the relatively long half-life of EGFRI. Combination of topical iodide, corticosteroids, antibiotics, and antifungals with avoidance of nail traumatization will yield the best results (9). EGFRI are potentially life prolonging therapies, and our goal as dermatovenereologists is to provide optimal patient care and improve their quality of life in a multidisciplinary collaboration with oncologists, radiotherapists, and ophthalmologists.

The Most Common Cutaneous Side Effects of Epidermal Growth Factor Receptor Inhibitors and Their Management.

The use of epidermal growth factor receptor inhibitors (EGFRI) for the treatment of solid tumors is increasing due to elevated expression of epidermal growth factor receptors (EGFR) in the stimulation of tumor development. EGFR inhibitors have shown to be effective in the treatment of neoplasms of the head, neck, colon, and lung. Inhibition of EGFR may cause cutaneous reactions in more than 50% of patients. The most common skin manifestations are papulopustular lesions in the seborrhoeic areas (upper torso, face, neck, and scalp). Other cutaneous side effects include xerosis and hair and nail changes. The onset of eruption is usually within one to three weeks after starting therapy, although in some cases it may occur much later. All dermatologic side effects are reversible and generally resolve after adequate therapy. However, for a minority of patients side effects are severe and intolerable, demanding dose reduction or even interruption of therapy. A positive correlation has been demonstrated between the degree of cutaneous toxicity and the antitumor response. For dermatologists the goal is to provide treatment of symptoms, so that the patient may continue to benefit from the EGFRI therapy. However, frequent cutaneous manifestations, even though related to a better antitumor response, may limit use of the therapy considering the interference with patient quality of life. Early management of cutaneous side effects of EGFRI may prevent severe, extensive symptoms, the need for dose reduction, or antitumor therapy interruption. This indicates a dermatologist should play a role in early stages of treatment.

Psoriasis: female skin changes in various hormonal stages throughout life--puberty, pregnancy, and menopause.

Psoriasis is one of the most prevalent immune mediated skin diseases worldwide. Despite the large prevalence in both men and women, the pathogenesis of this disease has not yet been fully clarified. Nowadays, it is believed that psoriasis is most likely a T helper Th1/Th17 induced inflammatory disease. Stressful life situations are known to cause flare-ups and psoriasis activity may be linked to stress from major life events. We know that stress greatly affects both the hormone and immune systems and that there are many different hormonal phases throughout a woman's lifetime. The severity of psoriasis may fluctuate or be influenced by each phase and this relationship can be seen as disease frequency seems to peak during puberty, postpartum, and menopause when hormone levels fall, while symptoms improve during pregnancy, a state when hormone levels are increased.

Laser therapy of pigmented lesions: pro and contra.

Although frequently performed, laser removal of pigmented lesions still contains certain controversial issues. Epidermal pigmented lesions include solar lentigines, ephelides, café au lait macules and seborrheic keratoses. Dermal lesions include melanocytic nevi, blue nevi, drug induced hyperpigmentation and nevus of Ota and Ito. Some lesions exhibit both an epidermal and dermal component like Becker's nevus, postinflammatory hyperpigmentations, melasma and nevus spilus. Due to the wide absorption spectrum of melanin (500-1100 nm), several laser systems are effective in removal of pigmented lesions. These lasers include the pigmented lesion pulsed dye laser (510 nm), the Q-switched ruby laser (694 nm), the Q-switched alexandrite laser (755 nm) and the Q-switched Nd:YAG laser (1064 nm), which can be frequency-doubled to produce visible green light with a wavelength of 532 nm. The results of laser therapy are usually successful. However, there are still many controversies regarding the use of lasers in treating certain pigmented lesions. Actually, the essential question in removing pigmented lesions with lasers is whether the lesion has atypical features or has a malignant potential. Dermoscopy, used as a routine first-level diagnostic technique, is helpful in most cases. If there is any doubt whether the lesion is benign, then a biopsy for histologic evaluation is obligatory.

Ablative laser resurfacing: is it still the gold standard for facial rejuvenation?

A new era in dermatological cosmetology, especially in the field of nonsurgical skin rejuvenation, started with ablative resurfacing, at first by carbon dioxide laser and later by Er:YAG or their combination. Although ablative lasers result in major improvements in photodamaged skin, the related postoperative recovery time and side effects are currently unacceptable for most patients. During the last forty years, skin resurfacing has changed dramatically. After ablative laser systems, nonablative and now fractional laser systems have been developed, fulfilling the new demands for a lesser risk of side effects and minimal or no downtime.

Why don't we have more effective treatment for keloids?

Numerous treatment modalities have been used to treat keloids and hypertrophic scars, but optimal treatment has not yet been established. The failure of achieving better therapeutic results in treating keloids highlights the essential problem that the pathogenetic mechanisms causing keloids remain unclear. Increased understanding at the molecular level will lead to the development of new therapies. Prevention is the first rule in keloid therapy. Conventional and experimental therapeutic approaches are presented in this review but further investigation is needed in relation to safety, adverse effects, and therapeutic efficacy. Because of the high recurrence rate of keloid scars, a follow-up period of at least 1 year is required to enable the start of treatment of recurrences as expediently as possible and to evaluate long-term success.

Comparison of diagnostic value of indirect immunofluorescence assay and desmoglein ELISA in the diagnosis of pemphigus.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases characterized by intraepidermal separation as the result of autoantibodies directed to desmoglein 1 and desmoglein 3, adhesion molecules that have a pathogenic role in blister formation. Both PV and PF are diagnosed according to clinical picture, histopathologic, immunopathologic and molecular biologic features. In the present study, the value of indirect immunofluorescence (IIF) and enzyme linked immunosorbent assay (ELISA) for desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) at baseline visit was compared. The study was performed as a retrospective study that included 22 patients, 19 of them with PV and three with PF. Patient sera were tested with IIF and Dsg 1 and Dsg 3 ELISA. In the group of 19 PV patients, 12 patients had positive IIF, Dsg 3 and Dsg 1 ELISA; two had positive IIF and positive anti Dsg 3 but negative anti Dsg 1; three had negative IIF but positive both Dsg 1 and Dsg 3 antibodies; and two had negative IIF and Dsg 1 but positive Dsg 3 antibodies. In the group of PF patients, all three patients had positive IIF, positive Dsg 1 ELISA and negative Dsg 3 ELISA. Results of our study supported previous reports confirming Dsg 1 and Dsg 3 ELISA to be a sensitive and specific tool for the diagnosis of PV and PF.

Halo phenomenon with regression of acquired melanocytic nevi: a case report.

We report a case of halo-phenomenon in excisional biopsy of junctional nevi in a 19-year-old girl. The diagnosis was established histopathologically because of the lack of clinical halo and unspecific dermoscopic features. Clinicopathologic difficulties in establishing the diagnosis of these pigmented lesions, etiopathogenesis and differential diagnosis of halo nevi are emphasized. Dermatologists should be familiar with the possible changes in benign melanocytic nevi, halo reactions and possible complete regression of melanocytic nevi. Diagnostic difficulties are seen in the ultimate phase of regression when melanocytes are diminished or destroyed with immune reaction.

Small and large bowel manifestation of leukocytoclastic vasculitis.

Leukocytoclastic vasculitis is a disease mostly limited to the skin. Extracutaneous manifestations that include visceral involvement are normally self-limiting and not life-threatening. We describe a 44-year-old man with palpable purpura, polyarthritis and microhematuria who developed severe vasculitis of the small and large bowel. Initial laboratory tests confirmed leukocytosis, slightly elevated C-reactive protein and mildly increased erythrocyte sedimentation rate. Skin biopsy revealed histological features typical of leukocytoclastic vasculitis. The search for trigger factors revealed urogenital infection with Ureaplasma urealyticum. Severe abdominal pain followed cutaneous symptoms eight days after admission. Abdominal x-ray showed several air-fluid levels in the lower right abdomen and an abdominal CT scan revealed thickening of the intestinal wall in several segments of jejunum, ileum and colon. C-reactive protein rose from 32 mg/l to 107 mg/l. Methylprednisolone pulse therapy rapidly improved gastrointestinal, cutaneous and articular symptoms. The aim of this report is to show the unpredictability of vasculitic disease and the difficulties in its classification. The report emphasizes the importance of adapting diagnosis and treatment according to disease severity rather than to the type of vasculitis. The specific etiological trigger remains unknown in this case, although a causal relationship with U. urealyticum infection is speculated.