Primary cutaneous follicular helper T-cell lymphoma: diagnostic pitfalls of this new lymphoma subtype.

The recently proposed entity of cutaneous follicular helper T (T(FH)) cell lymphoma (CT(FH)CL) harbors distinct clinical and histopathologic features. Here, diagnostic pitfalls are exemplified in a case report and by review of the literature. A 45-year-old patient developed rapidly growing nodules and plaques on upper arms and buttocks, which were initially misdiagnosed as primary cutaneous follicle center B-cell lymphoma (CFCL). Consequently, systemic therapy with rituximab failed and consecutive skin biopsies revealed CT(FH)CL (CD3+CD4+CD10+PD-1+bcl6+ICOS+CXCL13+). Interestingly, the prima vista PD-1-positive and CD10-positive tumor cells lost PD-1 expression in follow-up biopsies while retaining CD10, ICOS and CXCL13 expression. All biopsy specimens displayed an identical clonal T-cell population. Initially, nodules were controlled by local radiotherapy and oral psoralen combined with ultraviolet A (PUVA) therapy. However, disease recurred and progressed rapidly with disseminated nodules. Treatment with bexarotene, methotrexate and polychemotherapy failed to stop disease progression. Finally, modified total skin electron beam radiation resulted in complete remission. Disease stabilized on maintenance therapy with bexarotene in combination with ultraviolet A (UVA) therapy. The case highlights that because of concomitant B-cell stimulation, CT(FH)CL clinicopathologically is prone to be mistaken for CFCL. Importantly, CT(FH)CL might lose PD-1 while retaining CD10 expression in later stages, which may lead to confusion in distinguishing CT(FH)CL from CFCL.

Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma.

BACKGROUND: Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. PATIENTS AND METHODS: This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). RESULTS: Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. CONCLUSION: Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.

Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German Central Malignant Melanoma Registry.

BACKGROUND: Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow-up examinations. OBJECTIVES: This study aimed to analyze stage- and time-dependent hazard rates (HR) and discusses current surveillance recommendations. METHODS: Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan-Meier estimates and HRs were calculated. RESULTS: Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. LIMITATIONS: As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. CONCLUSION: For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account.

An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells.

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-positive MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-positive MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the observed effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-positive MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.

Blood vessel density in Basal cell carcinomas and benign trichogenic tumors as a marker for differential diagnosis in dermatopathology.

In order to get insight into the density of blood vessels in the stroma of benign and malignant trichogenic neoplasms, immunohistological quantification of CD 31 positive vessels was performed in 112 tumors, comprised of 50 BCCs of nodular (35) or morphoeic (15) growth patterns, 17 Pinkus' tumors, as well as 17 trichoepitheliomas of which 6 were desmoplastic, 8 trichofolliculomas, and 20 trichoblastomas. Methods. Vessel density was counted within the tumors, in the tumor-surrounding stroma, and, as a control, in the normal skin of the operation specimen. The results were compared using statistical methods. Results. Whereas, irrespective of the patients' age and location of tumors, the vessel density in normal skin showed no significant differences (8.8 ± 2.7), the counts in the peritumoral stroma revealed significant differences between the different tumors investigated. The highest counts were obtained in BCC (24.7 ± 6.7) and the lowest in benign trichogenic neoplasms (around 14) Pinkus' tumors revealed intermediate counts (19.7 ± 6.6). The vessel densities within the tumors were generally low, and no correlation to the dignity was found. Conclusion. Determination of blood vessel density in the peritumoral stroma may be an additional parameter for differential diagnosis of trichogenic tumors of uncertain dignity.

Pigmentation, Melanocyte Colonization, and p53 Status in Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5-8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.

Dermal schwannoma (neurilemmoma): a peculiar foreign body reaction?

Schwannoma is usually a subcutaneous benign neoplasm that derives from nerve sheath. Pain and neurologic symptoms are uncommon, and exclusively dermal tumors are very rare. Solitary schwannoma has a traumatic origin in some cases, and rarely occur as a part of neurofibromatosis or schwannomatosis. An association of deeply located schwannoma with foreign material has been reported in very few cases. To our knowledge, we present the first case of a painful dermal schwannoma in association to foreign material.

Mycosis fungoides bullosa: a case report and review of the literature.

INTRODUCTION: Mycosis fungoides, the most common type of cutaneous T-cell lymphoma, can manifest in a variety of clinical and histological forms. Bulla formation is an uncommon finding in mycosis fungoides and only approximately 20 cases have been reported in the literature. CASE PRESENTATION: We present a case of rapidly progressive mycosis fungoides in a 68-year-old Caucasian man who initially presented with erythematous plaques characterised by blister formation. CONCLUSION: Although mycosis fungoides bullosa is extremely rare, it has to be regarded as an important clinical subtype of cutaneous T-cell lymphoma. Mycosis fungoides bullosa represents a particularly aggressive form of mycosis fungoides and is associated with a poor prognosis. The rapid disease progression in our patient confirms bulla formation as an adverse prognostic sign in cutaneous T-cell lymphoma.

Cutaneous metastases as the first clinical sign of metastatic gastric carcinoma.

Cutaneous metastases from gastric cancer are uncommon with a frequency of 7 % but can rarely be the presenting sign. A 54-year-old man complained of multiple pea-sized scalp nodules which had been present for four months. Histology showed a metastatic adenocarcinoma. Initial evaluation revealed liver metastases and gastroscopy then identified a tumor involving the distal esophagus and gastric cardia that was diagnosed as a gastric tubular carcinoma. The patient had a good response to polychemotherapy. While gastric carcinoma generally metastasizes to the abdominal wall or lymph nodes, our patient showed an exceptional variant with distant cutaneous metastases as the first clinical sign.

Multiple pilomatricomas and gliomatosis cerebri--a new association?

Pilomatricomas are benign skin tumors originating from hair follicle matrix cells. In 2% to 3.5% of cases they occur in multiplicity and then may be associated with genetic diseases, such as myotonic dystrophy Curschmann-Steinert, familial adenomatous polyposis (Gardner syndrome), and Rubinstein-Taybi syndrome. A 15-year-old boy treated with temozolomide and oxcarbazepine for gliomatosis cerebri with symptomatic epilepsy developed four firm cutaneous nodules on his face and right upper arm in the course of 1 year. All four tumors were excised under local anesthesia. Histological examination confirmed the clinical diagnosis of pilomatricomas. This is the first published case of a patient suffering from gliomatosis cerebri and developing multiple pilomatricomas. Whether this observation represents a new association or is a mere coincidence cannot be clarified at present.

Therapy of metastasized Merkel cell carcinoma with liposomal doxorubicin in combination with radiotherapy.

BACKGROUND: Merkel cell carcinoma is a rare skin cancer of neuroendocrine origin, which is characterized by a high rate of recurrence, metastatic spread and mortality. Because of its rarity, evidence-based therapeutic regimens are difficult to establish. Merkel cell carcinoma is known to be both radio- and chemosensitive. Toxicity is a key factor in assessing any regimen, as the patients are usually elderly and likely to have other significant medical problems. PATIENTS AND METHODS: We retrospectively evaluated five patients with metastatic Merkel cell carcinoma to see if liposomal doxorubicin (Caelyx) or Myocet) in combination with radiotherapy exhibited clinical anti-tumoral effects accompanied by acceptable side effects. RESULTS: The outpatient chemotherapy regimen was tolerated without major side effects and produced good response rates. All patients achieved at least tumor stabilization; four of five had a partial remission. Effects of therapy were usually seen in the first cycle of therapy but the responses were of short duration with an average interval of two months until progression. CONCLUSIONS: As combined radiochemotherapy with liposomal doxorubicin is well tolerated even in older patients with other illnesses and can be given on an outpatient basis, it is an attractive option for metastatic Merkel cell carcinoma. Based on response rate or overall survival, it offers no advantages compared to polychemotherapy.

Anetodermic pilomatricoma.

A pilomatricoma, or Malherbe's calcifying epithelioma, is an uncommon tumor originating from hair matrix cells. It is clinically characterized by a solitary, firm nodule. As the skin overlying the pilomatricoma may change in color and texture, its clinical presentation can vary. We report an unusual case of pilomatricoma with associated anetoderma on the lower extremity of a 12-year-old girl. Histology revealed a thinned dermis replaced by myxomatous tissue between the surface and a deep-seated tumoral mass. This mass is formed of irregular islands of basaloid cells, shadow cells, calcified areas and discrete inflammatory and foreign-body reactions surrounding it. Anetodermic cutaneous changes may occur in pilomatricomas without histological evidence of triggering factors.

Management of allergy to heparins in postoperative care: subcutaneous allergy and intravenous tolerance.

Itching erythematous or eczematous plaques around injection sites are quite frequent side effects of heparin treatment and are clinical symptoms of a delayed-type hypersensitivity to heparins. In most cases, changing the subcutaneous therapy from unfractionated to low molecular weight heparin or treatment with heparinoids does not provide improvement, due to extensive cross-reactivity. Interestingly, it has been demonstrated that patients with delayed-type hypersensitivity to subcutaneously injected heparins tolerate intravenous application of heparin in controlled challenge tests. A patient with known delayed-type hypersensitivity to heparins received the heparinoid, danaparoid, subcutaneously for thrombosis prophylaxis after orthopedic surgery. After the first few injections, eczematous plaques developed; administration of the anticoagulant was continued and gradually resulted in generalized eczema despite treatment with topical and oral glucocorticoids. However, the patient required further anticoagulation. After discontinuation of subcutaneous injections and a switch to intravenous heparin, rapid improvement and clearing of skin lesions occurred. Therefore, in cases of delayed-type hypersensitivity to subcutaneously injected heparins, the switch from subcutaneous to intravenous heparin administration may be justified.