<div>Abstract<p>Deregulation of the sonic hedgehog (SHH) signaling pathway has been implicated in several cancers but has not been explored in T-cell lymphomas. Here, we report that the SHH/GLI1 signaling pathway is activated in anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma (ALCL). We show that <i>SHH</i>, but not its transcriptional effector <i>GLI1</i>, is amplified in ALK+ ALCL tumors and cell lines, and that SHH and GLI1 proteins are highly expressed in ALK+ ALCL tumors and cell lines. We also show that inhibition of SHH/GLI1 signaling with cyclopamine-KAAD, as well as silencing <i>GLI1</i> gene expression by small interfering (si)RNA, decreased cell viability and clonogenicity of ALK+ ALCL cells. Transfection of wild-type or mutant NPM-ALK into 293T cells showed that only wild-type NPM-ALK increased GLI1 protein levels and activated SHH/GLI1 signaling as shown by increase of <i>CCND2</i> mRNA levels. Inhibition of ALK tyrosine kinase and phosphatidylinositol 3-kinase (PI3K)/AKT or forced expression of pAKT down-regulated or up-regulated SHH/GLI1 signaling, respectively. Inhibition of GSK3β in 293T cells also increased protein levels of GLI1. In conclusion, the SHH/GLI1 signaling pathway is activated in ALK+ ALCL. SHH/GLI1 activation is the result of <i>SHH</i> gene amplification and is further mediated by NPM-ALK through activation of PI3K/AKT and stabilization of GLI1 protein. There is a positive synergistic effect between the SHH/GLI1 and PI3K/AKT pathways that contributes to the lymphomagenic effect of NPM-ALK. [Cancer Res 2009;69(6):2550–8]</p></div>
Giant basal cell carcinomas (GBCCs) are large basal cell carcinomas (BCCs; <5 cm) with a greater propensity to invade and metastasize than standard BCCs. The presence of 2 GBCCs in a single individual is rare. We present the case of a 71-year-old Caucasian male with bilateral GBCCs on the dorsal forearms, measuring 130 cm2 and 24 cm2, respectively, that developed over a 21-year period. Over this period, the patient treated the tumors with herbal remedies. Histologic evaluation showed a conventional nodular BCC for both tumors. Computed tomography and magnetic resonance imaging revealed a T4N0M0 stage for the larger lesion. Surgical excision and grafting and reconstruction were offered, but he declined. This case highlights a shared belief in holistic treatments and rejection of Western medical interventions that are common among many patients with GBCC. Studies reporting nonsurgical treatments for GBCCs, including radiotherapy, vismodegib, topical imiquimod, and acitretin are reviewed.
<p>Figure S1. Protein sequence alignment of HPyV6, HPyV7 and MCPyV small T antigens. Figure S2. Expression of HPyV sT induces p53-dependent senescence in human fibroblasts. Figure S3. Proliferation of BJ fibroblasts with expression of HPyV sT. Figure S4. Analysis of RNA-Seq from HPyV6, HPyV7, and MCPyV sT expressing BJ fibroblasts. Figure S5. Time course and extended analysis of additional SASP gene expression in BJ cells after sT expression. Figure S6. MCPyV sT shRNA confirms role of sT in SASP gene expression. Figure S7. Impact of LSD motif of MCPyV sT on gene expression and proliferation. Figure S8. MCPyV st, but not HPyV6/7 sT, stabilizes and activates c-Myc in an LSD motif dependent manner. Figure S9. Chromatin remodeling signatures induced by MCPyV sT. Figure S10. Mechanism of ncNF-κB and SASP induction by MCPyV sT. Figure S11. ncNF-κB signaling is required for SASP and EZH2 expression and affects cell proliferation. Figure S12. PyV sT conditioned media is not sufficient for growth in low serum. Figure S13. ST expression in VP-MCC lines and tumors. Figure S14. Impact of ncNF-κB inhibition on VP-MCC and VN-MCC. Figure S15. Summary Figure.</p>
Summary To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array‐based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene ( SHH ) at 7q36.2 (four cases), loss of protection of telomere 1 gene ( POT1 ) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 ( GLI1 ) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas‐associated via death domain gene ( FADD ) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH , respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.
Pagetoid reticulosis is a rare variant of mycosis fungoides. This rare condition typically presents as a solitary plaque located on the extremities with an indolent clinical course (Woringer-Kolopp disease) or as a more generalized presentation with diffuse cutaneous involvement and a more aggressive clinical course (Ketron-Goodman disease).To review the cutaneous manifestations, pathology, and treatment of localized pagetoid reticulosis.The authors describe a 24-year-old woman with a slowly enlarging, localized plaque of seven months duration, representing the localized form of pagetoid reticulosis with CD8+ immunophenotype.The histological, immunohistochemical, and clinical features of the patient's skin lesion were characteristic for a diagnosis of Woringer-Kolopp disease. Systemic work-up for lymphoma was negative.Woringer-Kolopp disease is most commonly seen in middle-aged men as a solitary lesion of the extremities, and it should always be considered in the differential diagnosis when a patient presents with such a lesion. A histological analysis demonstrated atypical lymphocytes preferentially localized to the epidermis with a CD4+, CD8+, or CD4-/CD8- phenotype. The treatment of choice for a solitary lesion may be localized radiation therapy, but newer therapies, such as bexarotene, may warrant further investigation.
A 60-year-old white male, who came from a rehabilitationassisted living facility in Miami, Florida, presented with multiple intensely pruritic migratory erythematous serpiginous tracks for 10 days over his left calf, left anterior leg, and right thigh.There were also hyper-pigmented macules around the tracks with overlying crust (Figure 1).Patient stated that he had been living some time in a bush and sleeping on the ground where stray animals defecate.He was previously treated for scabies with permethrin without success, otherwise unremarkable medical history.Based upon the typical characteristics of the lesions and epidemiologic history, a diagnosis of HrCLM was suspected, but due to the unusual multiple lesions, skin punch biopsies were performed from the left buttock and right posterior lower leg.Histologic sections showed several small intraepidermal cavities, likely corresponding to larva tracks (Figure 2A) associated with eosinophil-rich dermal mixed inflammatory cell infiltrates (Figures 2B and2C).Histology failed to demonstrate larvae itself.However, given the characteristic clinical presentation and overall histological features, the diagnosis of HrCLM was made.
To the Editor: Lymphomatoid papulosis (LyP) type D is a newly proposed LyP subtype.1,2 The diagnosis of this entity can be challenging to the dermatopathologists because it is histologically indistinguishable from primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and requires accurate clinicopathologic correlation.3 Most LyP type D cases are reported in young patients (median age 29 years) and express CD30.1,4 Here, we report a rare case of LyP type D affecting an elderly man where the tumor cells are negative for CD30. A 73-year-old white man, with unremarkable clinical history, presented with two 0.5-cm itchy papules in the abdomen and right leg, which was noticed a month ago and became ulcerated (clinical pictures never taken). He has a history of similar papules in different parts of his body since 5 years ago that either resolved spontaneously (within ∼3 weeks) or with topical betamethasone. Previous skin lesions were not biopsied. Skin examination showed 5 erythematous macules (spontaneously healing lesions) and 2 healed hyperpigmented scars (biopsy sites). Same topical treatment was recommended if needed and he has been followed for 6 months with no new lesions. The rest of physical examination and laboratory findings (immunoglobulins, β2-microglobulin, T4, complete blood cell count, electrolytes, liver function test, HIV1/2, human T-lymphotropic virus-1, PRP, cytomegalovirus, Hepatits B virus, Hepatits C virus) were unremarkable. Flow cytometry of the peripheral blood failed to detect aberrant T cells. Clinical staging showed no evidence of systemic lymphoma. Two skin biopsies (abdomen and right leg) showed similar histological features. The epidermis was ulcerated with striking epidermotropic lymphoid infiltrate. The lymphoid cells were atypical and medium to large cells (large cells representing >25% of all cells) (Figs. 1A, B) admixed with numerous eosinophils (Fig. 1C), neutrophils, and histiocytes. Although these shave biopsies included up to superficial reticular dermis, angiocentriticy, vascular damage, or granulomas were not identified. Immunophenotyping revealed that the tumor cells were positive for CD3 (Fig. 1D), CD2 (Fig. 1E), CD8 (Fig. 1F), TCR βF1 (Fig. 1G), CD45R0 (Fig. 1H), and TIA-1 (Fig. 1I) and negative for CD4 (Fig. 1J), CD30 (Fig. 1K), CD56, CD7, and CD20. There are numerous CD4+ cells in the dermis. These cells may represent a combination of normal reactive CD4+ T cells and dermal histiocytes/dermal dendritic cells expressing CD4. However, we cannot exclude the possibility of CD4+ LyP cells also. In the context of the epidermotropic component was clearly CD8+ and CD4−, we favor that the neoplasm has a CD8+ phenotype rather than CD8+/CD4+ phenotype.FIGURE 1: Lymphomatoid papulosis type D. A–C, A skin shave biopsy from the abdominal lesion showed an ulcer and necrosis with massive epidermotropic lymphoid infiltrate (A), with atypical pleomorphic medium to large lymphoma cells (B, C). Frequent eosinophils and histocytes were admixed (C). D–K, Immunohistochemical studies revealed that the tumor cells were positive for CD3 (D), CD2 (E), CD8 (F), TCRβF1 (G), CD45R0 (H), and TIA-1 (I) and negative for CD4 (J) [only epidermal Langerhans cells positive; inset, for comparison with CD8 from the same area] and CD30 (K). [Original magnifications: (A, D) ×2; (B, H, I, J, K) ×200; (C) ×400; (E, F, G) ×100].Combining the morphologic and clinical findings (recurrent, self-healing eruption of papules with a waxing and waning course), a diagnosis of CD30− LyP type D was made. However, the histological and immunophenotypic findings raised 2 main following differential diagnoses: primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and CD8+ mycosis fungoides with large cell transformation. The former is characterized by a rapid onset of patches/papules/tumors in elderly adults, frequently exhibiting necrosis and ulcers. The clinical course is aggressive with a median survival of 32 months and rapid extracutaneous dissemination.3 Histologically, however, this lymphoma is nearly identical to our case including extensive necrosis, massive epidermotropism, positivity for CD8 and cytotoxic markers, and negativity for CD30.3 In mycosis fungoides with large cell transformation, the clinical course and striking epidermotropism seen in our case would be unusual.5 This case demonstrates the importance of considering LyP type D in the differential diagnosis even in elderly adults with massively epidermotropic CD8+ cytotoxic T cells and CD30 negativity. An accurate clinicopathologic correlation is crucial to avoid overdiagnosis that might lead to overtreatment for this low-grade cutaneous lymphoma.
<div>Abstract<p>Anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E–binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing <i>mTOR</i> gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G<sub>1</sub>-S-phase regulators, including the cyclin-dependent kinase inhibitors p21<sup>waf1</sup> and p27<sup>kip1</sup>. Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL. (Cancer Res 2006; 66(13): 6589-97)</p></div>
