Karolyn A. Wanat

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

BACKGROUND Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy. OBJECTIVE We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib. METHODS We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients. RESULTS Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort. LIMITATIONS This study was limited by the small number of cases, all from a single institution. CONCLUSION Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

Consensus Guidelines for the Management of Plaque Psoriasis

The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.

Viral-Associated Trichodysplasia: Characterization of a Novel Polyomavirus Infection With Therapeutic Insights

BACKGROUND Viral-associated trichodysplasia of immunosuppression is a rare cutaneous eruption that is characterized by follicularly based shiny papules and alopecia with characteristic histopathologic findings of abnormally anagen follicules with excessive inner root sheath differentiation. Prior reports have described the histopathologic characteristics on vertical sections; however, to our knowledge, immunohistochemical analysis of polyomavirus proteins has not been previously performed. OBSERVATIONS We discuss the thorough diagnostic evaluation and therapy of an unusual case of viral-associated trichodysplasia due to a newly described human polyomavirus that occurred in a patient with posttreatment chronic lymphocytic leukemia and an abnormal white blood cell count. Unique to our study is the immunohistochemical staining for the polyomavirus middle T antigen, which demonstrated positive staining of cellular inclusions within keratinocytes that compose the inner root sheath. Further evaluation with scanning electron microscopy and polymerase chain reaction analysis of viral DNA confirmed the presence of the virus. Treatment with topical cidofovir resulted in dramatic clinical improvement and hair regrowth. CONCLUSIONS Several tools, including immunohistochemical staining for the polyomavirus middle T antigen, can be used to identify the pathogenic virus associated with viral-associated trichodysplasia. This case highlights the utility of multiple diagnostic modalities and a robust response to a topical therapeutic agent, cidofovir.

Seasonal variation of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with trimethoprim-sulfamethoxazole

BACKGROUND Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe cutaneous adverse reactions to medications and infections. OBJECTIVE We sought to determine whether a seasonal variation to SJS and TEN exists and to define the characteristics in our tertiary referral hospital. METHODS A retrospective chart review of 50 patients from 1995 through 2007 was performed and statistically analyzed. RESULTS The most common medication implicated as a cause of SJS/TEN was trimethoprim-sulfamethoxazole (TMX) (26%). A seasonal trend, favoring springtime, was observed for the total number of cases of SJS and TEN (P = .34). There was a significant increase in cases due to TMX (53%) occurring in spring compared to other seasons (P = .002). These patients were significantly younger (37.8 +/- 13.7) than other patients with SJS and TEN (53.7 +/- 16.4) (P = .003). Their overall mortality (1 death) and average SCORTEN value (1.62 +/- 1.6) was also significantly lower (P = .04 and 0.03, respectively). Based on outpatient pharmacy records, there was no increase in TMX prescriptions filled during the spring. LIMITATIONS The study was limited by reliance on chart data, the use of inpatient records, and number of patients. CONCLUSIONS A seasonal variation in SJS and TEN caused by TMX affecting younger patients may exist.

Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early stage cervical cancer

OBJECTIVE Heritable polymorphisms modulate metastatic efficiency in Cancer Single nucleotide polymorphisms (SNPs) in MMP9 (rs17576) and SIPA1 (rs746429, rs931127) have been associated with nodal metastases in multiple cancers. We investigated the association of these SNPs with nodal metastases in early-stage cervical cancer. METHODS Consecutive patients with stage IB cervical cancer who underwent a pelvic lymph node (LN) dissection were included. Cases (>1 positive LN, n=101) were compared with controls (negative LN pathology, n=273). Genotyping was performed on genomic DNA in the 3 SNPs using a TaqMan assay and correlated with clinical variables. RESULTS The G allele at SIPA1 rs931127 was associated with an increased risk of nodal disease (OR 1.9, P=0.03) and approached significance at SIPA 1 rs746429 (OR 2.2, P=0.09) and MMP9 rs17576 (OR 1.5, 0.08). In patients with stage Ib1 lesions (n=304), the G allele at both SIPA1 SNPs was associated with LN metastases (rs746429 OR 10.1, P=0.01; rs931127 OR 2.4, P=0.01). In patients with no lymph vascular space invasion, SIPA1 SNPs were again associated with LN metastases, and all patients with nodal disease had at least one G allele at SIPA1 rs746429. CONCLUSIONS In this case-control study, SNPs in SIPA1 varied statistically in cervical cancer patients with and without nodal metastases and in MMP9 after controlling for stage and lymphvascular space invasion. Further work is needed to characterize inherited polymorphisms that provide a permissive background for the metastatic cascade.

Pigmented Onychomatricoma: A Rare Pigmented Nail Unit Tumor Presenting as Longitudinal Melanonychia That Has Potential for Misdiagnosis as Melanoma

Pigmented onychomatricoma is a rare nail unit tumor that can clinically mimic nail unit melanoma. We report the case of a 63-year-old male with new-onset longitudinal melanonychia involving his right second toe. An excisional biopsy was performed and demonstrated pigmented onychomatricoma. We present this case to alert clinicians of this rare nail unit tumor and the importance of clinicopathologic correlation to avoid misdiagnosis.

Ipilimumab-associated Sweet syndrome in a melanoma patient

the buttocks, axillae, and groins and evolved in crops. Besides these nodules, physical examination revealed bridged scars, but no interconnecting tracts. Histologic examination of a skin biopsy and cultures ruled out Crohn disease and an opportunistic infection, respectively. The diagnosis was HS grade II according to the Hurley classification. A 6-month course of oxacillin (2 g/day), followed by a combination of rifampicin (600 mg/day) with clindamycin (600 mg/day) for 9 months were ineffective (Fig 1). In February 2012, Cs was replaced with tacrolimus (2 mg/day) based on the hypothesis of a deleterious effect of Cs on pilosebaceous apparatus and of a potential efficacy of tacrolimus as suggested in another report. In November 2012, all inflammatory lesions had disappeared (Fig 2). To our knowledge, this patient is the first case of HS appearing in the setting of organ transplantation. Although a fortuitous association cannot be excluded, considering the patient’s age, the clinical scenario speaks in favor of an iatrogenic origin of HS. Indeed, rare cases of iatrogenic HS have been reported. Even if several Cs-responsive cases of HS exist, Cs is known to induce hyperplasia of the pilosebaceous apparatus. Isotretinoin may also have played an aggravating role. This patient is similar to one suffering from HS for more than 20 years, in whom treatment with Cs had been ineffective. He was cured at the age of 40 years, a few months after kidney transplantation, while receiving tacrolimus and mycophenolate mofetil as immunosuppressive treatment. We recently observed another case of HS that appeared within 2 years after transplantation, for which we suggested a switch from Cs to tacrolimus. Although tacrolimus and Cs exert very similar immunosuppressive effects, the former proved more effective than the latter against HS in these cases. This may be due to the fact that tacrolimus exerts fewer effects on the pilosebaceous apparatus. This observation suggests that patients in whom HS develops while on Cs should be switched to tacrolimus.

Sarcoidosis and Psoriasis: A Case Series and Review of the Literature Exploring Co-Incidence vs Coincidence

IMPORTANCE Sarcoidosis is a chronic multisystem disorder characterized by the formation of noncaseating epithelioid cell granulomas affecting multiple organ systems. The role of the type 1 helper T (T(H)1) cell in sarcoidal granuloma formation has been well documented, and the T(H)17 pathway in sarcoidosis is just now being investigated. T(H)17 cells are also known to involved in the pathogenesis of psoriasis, and the coexistence of sarcoidosis and psoriasis is mechanistically plausible based on potential shared underlying immunologic pathways. OBSERVATIONS We report a case series of 7 patients with sarcoidosis and psoriasis vulgaris. All patients had psoriasis ranging from limited disease to involvement of 30% of their body surface area and had evidence of pulmonary sarcoidosis. Three of these patients also had cutaneous sarcoidosis, and 1 of these patients had evidence of both psoriasis and sarcoidosis in the same cutaneous specimen. CONCLUSIONS AND RELEVANCE We report a case series of concomitant sarcoidosis and psoriasis, suggesting that common pathogenesis involving the T(H)1 and T(H)17 pathways may be responsible for this disease association. Although additional data are needed to clarify this association, this observation may lead to important understanding of the pathophysiologic and therapeutic management in these disorders.

A Practical Approach to Cutaneous Sarcoidosis

Sarcoidosis is a chronic inflammatory disorder that has the potential to affect multiple organs, including the skin. Its cutaneous manifestations are varied and can provide clues to underlying systemic manifestations. Unfortunately, they also can be disfiguring. Therapy is usually directed at the organ system most severely affected, which often may help cutaneous disease. However, cutaneous disease may be recalcitrant to treatment directed at extracutaneous disease, or it may be severe enough to require targeted therapy. This article focuses on the dermatologist’s role in recognizing and diagnosing cutaneous sarcoidosis, evaluating patients for systemic disease involvement, and treating the skin manifestations of sarcoidosis.

Hypopigmented onychocytic matricoma as a clinical mimic of onychomatricoma: clinical, intraoperative and histopathologic correlations.

Onychocytic matricoma is a newly described matrical tumor of the nail unit that clinically presents with localized thickening of the nail plate and melanonychia and represents a benign acanthoma of onychocytes. Onychocytic matricoma can be classified according to its histopathologic type (acanthotic, papillomatous or keratogenous with retarded maturation) and pigmentation (pigmented, melanocytic or non‐pigmented). However, there are no published reports of non‐pigmented onychocytic matricoma. We report a case of hypopigmented onychocytic matricoma that presented with a thickened nail plate, xanthonychia and histopathologic features of acanthosis, prekeratogenous zone and keratogenous zone cells forming pseudosquamous eddies, and minimal pigmentation with Fontana staining. We also provide detailed clinical, intraoperative and histopathologic correlations of this rare tumor. Both clinicians and dermatopathologists should be aware that onychocytic matricoma can present with xanthonychia, thickening of the nail plate and mimic an onychomatricoma.