Brian Poligone

A Distinct Entity in the Spectrum of the Cd30+ Cutaneous Lymphoproliferative Diseases: Oligolesional Nodules With Pseudoepitheliomatous Hyperplasia Followed by Spontaneous Resolution

Pseudoepitheliomatous hyperplasia (PEH) in biopsies of CD30+ anaplastic large-cell lymphoma (ALCL) is present infrequently and is of unknown prognostic value and significance. Our goal was to review the clinicopathologic features of cases of ALCL with PEH, study their course, and review the literature on the subject. Biopsy specimens of all cases of CD30+ lymphoproliferative disorders (59) were retrieved from the files of Yale Dermatopathology Laboratory over a 17-year period and reviewed. We identified 4 cases of ALCL (7%) exhibiting prominent PEH. All 4 patients presented with 1 or 2 nodules. In 2 patients, the lesions spontaneously regressed within a few months after initial diagnosis. One patient chose to have an excision in which only a small number of CD30+ cells were present. We were unable to obtain follow-up for the fourth patient. In the spectrum of CD30+ lymphoproliferative disorders, cases of ALCL with PEH are infrequent. In addition to the 4 cases described here, in our review of the literature we found 35 cases of ALCL with PEH. Most of these patients present with 1 or a few lesions. In the majority of these cases, the lesions started showing evidence of clinical spontaneous regression and even complete resolution within a few months of initial diagnosis. The clinicopathologic correlation between ALCL and PEH has not been emphasized. Because most of these cases follow a relatively benign clinical course, we recommend a more conservative approach in the clinical management of these patients.

A Role for NF-κB Activity in Skin Hyperplasia and the Development of Keratoacanthomata in Mice

Background Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin. Methods A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity. Results The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata. Conclusion Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced.

Primary Cutaneous T-Cell Lymphoma Localized to the Lower Leg A Distinct, Locally Aggressive Cutaneous T-Cell Lymphoma

BACKGROUND Distinct categories of skin lymphoma with preferential site localization and unique clinical behavior, including leg-type primary cutaneous diffuse large B-cell lymphoma, have recently been described. Although these entities are rare, they exhibit reproducible clinicopathologic features, and their recognition may allow more appropriate treatment protocols. OBSERVATIONS We describe the distinctive clinicopathologic features that were observed in 3 patients with an unusual variant of primary cutaneous T-cell lymphoma. All cases originated on the legs of elderly patients and exhibited a locally aggressive clinical behavior with relatively rapid relapses after radiotherapy and resistance to other therapies. Histologically, dense dermal-centered infiltrates of atypical, variably sized mature helper T cells were identified. One patient died of progressive disease. CONCLUSIONS Rare cases of primary cutaneous lymphomas do not necessarily fit current criteria for a standard diagnostic category but may represent unique clinicopathologic entities, such as primary cutaneous T-cell lymphoma localized to the lower leg. It is important to be able to identify these unusual lymphoma variants for prognosis and adequate treatment. The aggressive nature of lymphomas preferentially localized on the lower extremities may not be restricted to B-cell or cytotoxic neoplasms.

Bazex syndrome (acrokeratosis paraneoplastica)

In March, 2006, a 62-year-old black man presented to his primary care physician with a 4-day history of bilateral auricular pruritus associated with pain. He had temporary improvement with topical triamcinolone and oral cefalexin. After 2 months of gradual worsening with involvement of the distal fi ngers and toes he was referred to us in May, 2006, for dermatological evaluation. Other than one upper respiratory infection he denied fevers, chills, or other systemic complaints. He had no dysphagia, odynophagia, change in appetite, weight loss, nausea, vomiting, altered bowel habits, haematochezia, or melaena. Medical history showed hypertension, a non-ischaemic cardiomyopathy (with an ejection fraction of 35%), and, 6 years previously, pulmonary tuberculosis, for which he had received appropriate antibiotic therapy. Current medications were aspirin, furosemide, metoprolol, lisinopril, and a salbutamol/ipratropium inhaler. He had a history of alcohol misuse and was currently drinking over half a litre of vodka per day. He had smoked 10 cigarettes a day for 50 years. On examination, there were hyperpigmented, erythematous plaques with silvery scales on the helices of both ears, and the dorsal surfaces of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints of the hands and feet which had only minor improvement with topical corticosteroids (fi gure A and B). Nail thickening with ridging was present. No oral or ocular lesions were noted. There was no heliotrope erythema, periungal telangiectasia, or poikyloderma. Cardiovascular, respiratory, and abdominal examinations were normal. No lymphadenopathy was detected. Bazex syndrome (acrokeratosis paraneoplastica) was suspected and chest radiography and upper gastrointestinal evaluation was requested. Skin biopsy showed acanthosis, psoriasiform epi dermal hyperplasia, hyperkeratosis, focal parakeratosis, exocytosis, spongiosis, and spongiotic vesicles. There were superfi cial perivascular lymphocytic infi ltrates and necrotic keratinocytes at the dermoepidermal junction. Barium swallow showed a broad based ulceration in the distal oesophagus, and follow-up CT scan and endoscopy showed invasive squamous cell carcinoma of the oesophagus (stage III). The patient was started on localised radiation therapy with adjuvant 5-fl uorouracil and cisplatin. When seen for his second course of chemotherapy in June, 2006, a striking resolution of the hyperkeratosis on his hands and feet was noted. His ears had returned to normal with no more pruritus. The association of acral hyperkeratosis and malignancy was fi rst described by Bazex in 1965. Bazex syndrome generally aff ects men over the age of 40 years and has universally been associated with malignancy in over 125 case reports. The most common sites of involvement are the ears (79%), nails (75%), nose (63%), fi ngers (61%), hands (57%), and feet (50%). The presenting symptoms in this patient, pruritus and pain, are not usually associated with Bazex syndrome, although pruritus can occur in up to 18% of cases. A wide range of histological fi ndings has been described in Bazex syndrome, including acanthosis, psoriasiform epidermal hyperplasia, hyperkeratosis, parakeratosis, and perivascular lymphocytic infi ltrate. Less common but more specifi c fi ndings include dyskeratotic keratinocytes and vacuolar degeneration of the basal epidermal layer. More than half of acrokeratosis paraneoplastica associated malignancies are found in the upper aerodigestive tract (upper parts of the respiratory and gastrointestinal tracts). Regional lymphadenopathy is often present. In nearly two-thirds of cases, cutaneous lesions precede the symptoms or diagnosis of malignancy. Thus, suspicion of Bazex syndrome should include a skin biopsy followed by a complete evaluation of the upper aerodigestive tract. If this is negative, a search for the other malignancies reported with Bazex syndrome would have to include screening for colon cancer, lymphoma, bladder, prostate, uterine, vulvar, and neuroendocrine tumours.

Cutaneous T cell Lymphoma: an Update on Pathogenesis and Systemic Therapy

Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas (CTCL). Treatment of CTCL is limited and can be approached by skin-directed therapy or systemic therapy. Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e.g., pralatrexate, doxorubicin, bendamustine, and forodesine), as well as multi-agent chemotherapy regimens.

Romidepsin: evidence for its potential use to manage previously treated cutaneous T cell lymphoma

Introduction: Cutaneous T cell lymphoma (CTCL) encompasses a heterogeneous group of neoplasms of skin-homing T cells, which includes mycosis fungoides, the most common form, and Sézary syndrome, the leukemia equivalent of mycosis fungoides. Histone deacetylase inhibitors are currently under investigation for their therapeutic value in a variety of conditions. Through multiple mechanisms, they induce apoptosis or inhibition of tumor cell growth. Some studies have also shown histone deacetylase inhibitors to have synergistic activity with existing therapeutic agents in selected conditions. Romidepsin is a histone deacetylase inhibitor with a promising efficacy and safety profile that may represent a valuable treatment alternative for patients with treatment-resistant mycosis fungoides and Sézary syndrome. Aims: To review emerging evidence regarding the use of romidepsin in the management of treatment-resistant CTCL. Evidence review: There is evidence that romidepsin can induce significant and durable responses in patients with refractory CTCL. In two independent Phase II trials including a total of 167 patients with CTCL, there was an overall response rate of 34% with a partial response of 28% and complete response rate of 6%. The most frequent toxicities reported from the Phase II trials were nausea, vomiting, fatigue, anorexia, and dysgeusia. Clinical potential: Romidepsin may be an effective therapeutic option for patients with CTCL who have had treatment failure with multiple standard treatment modalities.

PKK Suppresses Tumor Growth and Is Decreased in Squamous Cell Carcinoma of the Skin

Non-melanoma skin cancer (NMSC) represents the most common cancer in the United States. Squamous cell carcinoma (SCC) of the skin is a sub-type of NMSC that shows a greater potential for invasion and metastasis. The current study identifies the Protein Kinase C-associated Kinase (PKK), which is also known as the Receptor-Interacting Protein Kinase 4 (RIPK4), as a suppressor of tumor growth in SCC of the skin. We show that expression of PKK is decreased in human SCC of the skin compared to normal skin. Further, suppression of PKK in human keratinocytes leads to increased cell proliferation. Use of RNA interference to reduce PKK expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression. Consistent with the results obtained from cell culture, there is a dramatic increased tumorigenesis after PKK knockdown in a xenotransplant model and in soft agar assays. The loss of tumor suppression involves the NF-κB and p63 pathways. NF-κB is inhibited through inhibition of IKK function and there is increased nuclear TP63 activity after PKK knockdown. This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments.

Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells

Cutaneous T-cell Lymphoma (CTCL) is a rare non-Hodgkins lymphoma that can affect the skin, blood, and lymph nodes, and can metastasize at late stages. Novel therapies that target all affected disease compartments and provide longer lasting responses while being safe are needed. One potential therapeutic target is NF-λB, a regulator of immune responses and an important participant in carcinogenesis and cancer progression. As a transcription factor, NF-λB targets genes that promote cell proliferation and survival. Constitutive or aberrant activation of NF-λB is encountered in many types of cancer, including CTCL. Recently, while analyzing gene-expression profiles of a variety of small molecule compounds that target NF-λB, we discovered the tetracycline family of antibiotics, including doxycycline, to be potent inhibitors of the NF-λB pathway. Doxycycline is well-tolerated, safe, and inexpensive; and is commonly used as an antibiotic and anti-inflammatory for the treatment a multitude of medical conditions. In our current study, we show that doxycycline induces apoptosis in a dose dependent manner in multiple different cell lines from patients with the two most common subtypes of CTCL, Mycosis Fungoides (MF) and Sézary Syndrome (SS). Similar results were found using primary CD4+ T cells from a patient with SS. Doxycycline inhibits TNF induced NF-λB activation and reduces expression of NF-λB dependent anti-apoptotic proteins, such as BCL2α. Furthermore, we have identified that doxycycline induces apoptosis through reactive oxygen species.

Innovative Therapy of Cutaneous T-Cell Lymphoma: Beyond Psoralen and Ultraviolet Light and Nitrogen Mustard

Cutaneous T-cell lymphoma is a malignancy of skin-homing T cells. This unique population of lymphocytes requires alternative therapies to those used in nodal lymphomas. Although phototherapy and nitrogen mustard have been standard treatments for decades, newer therapies have been arriving with increased frequency. Moreover, some therapies, currently used to treat other diseases, have been used with good effect. These innovative therapies are discussed, with review of current data and examples of how these therapies may be used today.

A critical role for the protein kinase PKK in the maintenance of recirculating mature B cells and the development of B1 cells.

Protein kinase C associated kinase (PKK) regulates NF-κB activation and is required for the survival of certain lymphoma cells. Mice lacking PKK die soon after birth, and previous studies suggest that the role of PKK in B cell development might be context dependent. We have generated a mouse strain harboring conditional null alleles for PKK and a Cre-recombinase transgene under the control of the endogenous CD19 promoter. In the present study, we show that knockout of PKK in B cells results in the reduction of long-lived recirculating mature B cell population in lymph nodes and bone marrow as well as a decrease in peritoneal B1 cells, while PKK deficiency has no apparent effect on early B cell development in bone marrow or the development of follicular and marginal zone B cells in the spleen. In addition, we demonstrate that PKK-deficient B cells display defective proliferation and survival responses to stimulation of B cell receptor (BCR), which may underlie the reduction of recirculating mature B cells in PKK mutant mice. Consistently, BCR-mediated NF-κB activation, known to be required for the survival of activated but not resting B cells, is attenuated in PKK-deficient B cells. Thus, our results reveal a critical role of PKK in the maintenance of recirculating mature B cells as well as the development of B1 cells in mice.