Trigeminal trophic syndrome: A systematic review.

OBJECTIVES: To systematically report and document Trigeminal Trophic Syndrome (TTS), characterize its clinical presentation, diagnostic tests performed, outline management strategies, outcomes; and highlight the role of otolaryngologists in the tissue diagnosis of this rare syndrome. DATA SOURCES: PubMed/Medline, Scopus, and Cochrane databases. REVIEW METHODS: PubMed/Medline, Scopus, and Cochrane databases were systematically reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all cases of TTS published with an English translation from inception to December 2020. RESULTS: A total of 142 articles describing 214 patients with TTS were included in the analysis. There was a female predominance (62.9 %) and a median age of 57 (range 1-93) years at presentation. A trigeminal neurological insult was identified in 200 (93.5 %) cases. The most common triggers for TTS were treatment for trigeminal neuralgia (35.7 %) and cerebrovascular accident (21.6 %). Self-inflicted trauma occurred in 137 (64 %) patients. Biopsy was done in 123 (57.5 %) patients. Patient education, barrier devices, and medications to address parasthesias were the most common treatment strategies. The majority of patients (72.5 %) received multimodal therapy. Surgery was performed in 35 (22.7 %) patients. Treatment outcomes were discussed in 120 (56.1 %) patients. CONCLUSIONS: TTS is a rare condition with poorly understood pathophysiology. It should be suspected in a patient with non-healing facial ulceration and altered sensation within the trigeminal nerve distribution. Biopsy of the ulcer is important to confirm the diagnosis and exclude malignancy. Treatment options include conservative and pharmacologic measures, and less frequently surgery.

Incipient Intracholecystic Papillary Neoplasm of the Gallbladder Without Dysplasia.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a rare tumor described as a mucosal exophytic neoplastic lesion that projects into the gallbladder lumen. In regards to the size, lesions that did not make the arbitrary 1cm cutoff are described as "incipient" ICPN. Not much is known about these incipient ICPNs, as they are often excluded in ICPN studies, given the attempted adherence to the traditional 1cm cutoff. We present the youngest reported case of incipient, non-mucinous gastric-pylorus type ICPN who underwent cholecystectomy. Resection with negative margin for ICPN appears to be sufficient treatment and post resection imaging surveillance could be of value but further studies are required.

Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of TH 1 T-cells.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. METHODS: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. RESULTS: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. CONCLUSIONS: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.

Solitary Vulvar Syringoma With Deep Extension; Potential for Misdiagnosis as the Microcystic Adnexal Carcinoma (MAC).

ABSTRACT: A 43-year-old woman presented with a palpable, pruritic, minimally painful right vulvar lesion. Physical examination revealed approximately 2.0-cm tender nodule at 70' clock in the right labia majora. Histological sections of the excision specimen showed an unremarkable epidermis with large, well-circumscribed dermal proliferation with extension to the reticular dermis. Within this proliferation are small solid and ductal structures relatively evenly distributed in the sclerotic stroma. The epithelial elements consisted of monomorphous cuboidal cells and assumed round, oval, curvilinear, or have other peculiar geometric shapes, including "comma-like" or "tadpole"-like configurations. The tumor cells were positive for CEA, EMA, and estrogen receptor and negative for progesterone receptor. The clinical presentation and the deep extension of the tumor were similar to the microcystic adnexal carcinoma. Although a syringoma generally presents with multiple lesions and usually involves the superficial dermis, a syringoma with deep extension was favored based on the lack of follicular differentiation, atypia, mitoses, and perineural invasion. Microcystic adnexal carcinoma and syringoma have a morphologic overlap and are misdiagnosed in 30% of the cases. Thus, it is exceptionally important for pathologists to be aware of and be able to distinguish these entities. To the best of our knowledge, this is the first case of a solitary, painful vulvar syringoma with deep extension.

Primary Cutaneous Ewing Sarcoma of the Scalp With Metastasis to the Lung: An Unusual Manifestation During Pregnancy.

ABSTRACT: A 32-year-old G2P1L1 (5 months pregnant) woman presented with a 3-month history of a slow-growing cystic lesion on her scalp vertex. Similar lesions in the exact location were excised twice in the past with a diagnosis of trichilemmal carcinoma (TC). A biopsy of the scalp lesion showed morphology and immunoprofile consistent with previously diagnosed TC. Staging PET/CT demonstrated a 4.7 cm right upper lobe lung, and a subsequent lung biopsy showed a small, round blue-cell tumor with necrosis, morphologically identical to the prior biopsies from the scalp. Considering the unusual clinical course of TC, a lung biopsy was sent for next-generation sequencing that showed EWSR1-FLI1 (type1) fusion. Additionally, CD99 immunostaining revealed uniform cytoplasmic and membranous staining in the tumor cells. The previous scalp excision specimen was also sent for mutation analysis, which showed EWSR1-FLI1 fusion. In conjunction with clinical history and histological and molecular findings, a definitive diagnosis of primary cutaneous Ewing sarcoma (PCES) with local recurrence and metastasis to the lung was made. We present a case of PCES, which was previously misdiagnosed and treated as TC. This case emphasizes the importance of CD99 in the initial screening of cutaneous small round blue-cell tumors to avoid misdiagnosis from other morphological overlaps. Also, despite its rarity, PCES should be included in the differential diagnosis of small, round, blue cell tumors at cutaneous sites. Our case also exemplifies common biases in medical decision-making, including premature closure and anchoring bias which can result in misdiagnosis or diagnostic delay and associated delay in appropriate management.

Isolated leukemia cutis as extramedullary relapse of acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. In rare instances, AML can recur with prominent extramedullary manifestations (i.e., leukemia cutis or myeloid sarcoma), either simultaneously or preceding marrow involvement, or as a sole site of primary disease relapse.

Histopathologic features of inverse psoriasis.

BACKGROUND: Inverse psoriasis represents a less commonly described form of psoriasis in intertriginous areas. The pathologic findings of inverse psoriasis are typically grouped in with those of plaque psoriasis, as the histopathologic features specific to inverse psoriasis have not received significant investigation. METHODS: A single institution, retrospective cohort study was performed to review biopsy slides for psoriasis occurring in typical intertriginous areas. Patient's charts were reviewed and only those where the clinical diagnosis of inverse psoriasis was also favored were included. RESULTS: Twelve patients met inclusion criteria: 58% male and 42% female, 18 to 86 years of age. Classic features of psoriasis such as hypogranulosis, confluent parakeratosis, and thinning of the suprapapillary plate were seen in 100%. Regular psoriasiform acanthosis and dilated tortuous dermal vessels were seen in 92%. Neutrophils were present in the scale in 83% and in the dermis in 100%. Features considered atypical for psoriasis included spongiosis in 83%, eosinophils in 67%, and focal serum in the scale in 42%. CONCLUSIONS: While inverse psoriasis commonly exhibits features considered to be classic for psoriasis, it is not unusual for inverse psoriasis to show features considered atypical for plaque psoriasis such as dermal eosinophils, epidermal spongiosis, and focal serum in the scale.

A Case of Primary Myelofibrosis With Transformation to Leukemia Cutis.

ABSTRACT: We report an extraordinary case of primary myelofibrosis with transformation to leukemia cutis. A 64-year-old Caucasian man with a history of JAK2-positive primary myelofibrosis presented with erythematous papulonodules on his right lower extremity. A punch biopsy revealed a normal epidermis with an underlying diffuse dermal infiltrate composed of medium-to-large-sized myeloid cells and leukocytes. Neoplastic cells were immunoreactive for LCA, CD34, CD61, CD117, and CD68 and negative for lysozyme, CD20, CD3, myeloperoxidase, and TdT. These findings were consistent with a diagnosis of leukemia cutis. A concurrent bone marrow biopsy demonstrated a markedly fibrotic, hypercellular marrow without a significant increase in blasts. With no morphologic evidence of bone marrow involvement by acute myeloid leukemia, our case suggests that the patient's primary myelofibrosis transformed to leukemia cutis. Our patient died 2 months after the onset of his skin nodules. Our case demonstrates that leukemia cutis should be included in the differential diagnosis for cutaneous nodular lesions in patients with a history of an advanced-stage hematological malignancy.

Chronic myeloid leukemia-leukemia cutis mimicking a neutrophilic panniculitis-like leukemia cutis: Report of a rare case.

While drug-induced panniculitis is not uncommon in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor therapy, it is rare for CML to initially present as a leukemic panniculitis. We present the case of a 45-year-old male with no relevant prior medical history presenting with 6 months of migratory nodules, 2 months of drenching night sweats, and a 20 pound weight loss. Physical examination showed firm subcutaneous nodules with overlying ecchymoses present on the right lateral thigh and left lower back. Biopsy of a nodule from the right thigh showed a subcutaneous lobular panniculitis involved by a dense infiltrate of neutrophils and granulocyte precursors. Fluorescent in-situ hybridization (FISH) was positive for t(9;22)(q34;q11.2)BCR-ABL1 fusion. A concurrent hemogram revealed a white blood cell count elevation of 600,000 K/µL. Bone marrow biopsy examination showed marked myeloid expansion with an increase in granulocyte precursors and Philadelphia chromosome positivity by FISH, consistent with bone marrow involvement by CML. Herein, we describe this unusual and rare case of CML initially presenting as a neutrophilic panniculitis-like leukemia cutis. Arriving at this challenging diagnosis may be easily missed without clinical and laboratory correlation, which would certainly lead to the patient's not receiving life-saving treatment.

Multifocal Langerhans Cell Histiocytosis: A Unique Presentation of Eosinophilic Granuloma with Intracranial Extension, Massive Lymphadenopathy, and Epstein-Barr Viral Infection in an Adolescent Female.

We report the case of an otherwise healthy 17-year-old female who presented for surgical removal of an enlarging "atypical cyst" on her scalp. During subtotal excision, only friable serosanguinous translucent ribbons of tissue were found. A histopathologic diagnosis of Langerhans cell histiocytosis (LCH) was rendered and imaging studies revealed extradural invasion of the tumor. Within weeks, the patient also developed progressive lymphadenopathy with grossly elevated levels of Epstein-Barr virus viral capsid antigen antibody levels. This report aims to highlight a unique presentation of LCH with discussion of workup, management, and avoidance of potential surgical complications.

The Role of IL-13, IL-15 and Granulysin in the Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are Severe Cutaneous Adverse Reactions (SCARS) characterized by fever and mucocutaneous lesions leading to necrosis and sloughing of the epidermis. Conjunctival lesions are reported in 85% of patients. The pathogenesis of SJS/TEN/SCARS is not completely understood. It is hypothesized that IL-13, IL-15 and Granulysin expressed in plasma and skin may play a role. We measured the circulating levels of these cytokines in the plasma using ELISA and their expression in the skin using immunofluorescence microscopy. A total of 12 SJS/TEN skin biopsy samples (8 SJS, 2 SJS/TEN overlap and 2 TEN) were analyzed. Biopsy samples from patients with Lichen Planus (an inflammatory condition of the skin and mucous membranes) served as controls. Studies were also performed in human corneal epithelial cells where expression of these cytokines were measured following a challenge with TNF-α (0, 1, 10 and 100 ng/ml). The intensity of immunofluorescence was measured Using Imaris® software. The results showed significantly increased expression of these cytokines in the skin biopsy samples as measured by the average intensities of IL-13 (6.1 x 133.0 ± 4.231 x 10^8), and Granulysin (4.2 x 123.0 ± 4.231 x 10^8) compared to Lichen planus control (3.0 x 123.0 ±1.62 x 10^5). Increased expression of IL-13 and IL-15 were noted in cell culture studies and in the plasma samples when compared to Normal Human Plasma as controls. It is concluded that IL-13, IL-15 and Granulysin play a role in the pathogenesis of SJS/TEN.

Pembrolizumab-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in a Patient With Metastatic Cervical Squamous Cell Carcinoma: A Case Report.

We present a rare case of a pembrolizumab-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). A 55-year-old woman with a history of metastatic cervical squamous cell carcinoma presented with a widespread mucocutaneous rash. Seventeen days after receiving her first cycle of pembrolizumab, she presented with fever, difficulty breathing, watery eyes, and painful oral ulcers. Physical examination revealed widespread erythematous papules and papulovesicles involving the trunk, upper extremity, and lower extremity and hemorrhagic plaques on the lower lip and buccal mucosa. Biopsy confirmed a diagnosis of SJS/TEN. This case highlights the importance of awareness of SJS/TEN as a possible adverse reaction for patients receiving pembrolizumab, a medication increasingly being used to treat metastatic or unresectable malignancies.

The Conundrum of Diagnosing Cutaneous Composite Lymphoma in the Molecular Age.

INTRODUCTION: Cutaneous composite lymphoma (CCL) is extremely rare. When 2 potentially distinct lymphoid lesions occur at one skin site, distinguishing between one neoplastic clone and a secondary reactionary lymphoid response versus a second neoplasm is difficult. In this study, we describe a unique case of CCL along with a review of reported cases in literature to identify clues and discuss issues that are relevant to the diagnosis of CCL. DESIGN: Review of a CCL case from our institution and a systematic review of reported cases of CCL in the literature. RESULTS: A total of 18 studies describing 22 cases and a case report from our institution are included. The mean age at diagnosis was 68 years. Most cases herein presented with multiple skin lesions (67%) and reported a history of immune suppression (76%). Nineteen cases (83%) had a combination of T-cell and B-cell neoplasms, whereas the remaining cases had 2 distinct B-cell clones. Clonal differentiation was confirmed based on morphology and immunohistochemistry in all cases, and by polymerase chain reaction studies in 19 cases. Complete remission was achieved in only one quarter of reported cases. CONCLUSION: Diagnosing CCL can be challenging because accurate differentiation of 2 or more clonal populations at 1 site is tedious. A stepwise approach and integration of clinical, morphologic, immunohistochemistry, and molecular data along with an understanding of the prognosis of the lymphomas in question is essential for an accurate diagnosis and necessary because of therapeutic and prognostic implications.

Clonal highlights: Clonal seborrheic keratoses often demonstrates p16 expression.

BACKGROUND: At times, distinguishing Bowen disease (BD) and benign seborrheic keratosis (SK) is histologically challenging, especially when SK shows clonal features (clonal seborrheic keratosis [CSK]). While p16 is often reported as positive in BD and negative in SK, p16 expression in CSK is rarely studied. Here we investigate p16 immunohistochemistry in CSK, SK, and BD. METHODS: p16 immunohistochemistry with pattern of expression was noted for 14 CSK, 12 SK, and 18 BD. The degree of inflammation among lesions with respect to p16 expression was also noted. RESULTS: When examining p16 staining in clonal nests of CSK, 57% showed diffuse or patchy/diffuse positivity, 21% showed patchy positivity, and 21% showed clusters of single positive cells. 67% of BD showed diffuse positivity, 11% showed patchy/diffuse positivity, 17% showed patchy positivity, and 6% were negative. 25% of SK showed focal areas of patchy to full thickness positivity, 25% showed moderate number of positive single cells with or without patchy staining, and 50% showed negative/scattered single cell positivity. CONCLUSION: Our findings support that p16 positivity limited to clonal nests in CSK is normal. p16 positivity in clonal nests of CSK in isolation without concurrent atypical histologic features should not be used to support a diagnosis of BD.

Is melanocyte density our last hope? Comparison of histologic features of photodamaged skin and melanoma in situ after staged surgical excision with concurrent scouting biopsies.

Differentiating melanocytic hyperplasia (MH) on photodamaged skin from junctional lentiginous melanocytic proliferations (JLMP), early evolving melanoma in situ (MIS), or the periphery of a lesion of MIS on staged excision can be challenging. Although previous cross-sectional studies have elucidated important criteria for distinguishing MH on photodamaged skin from more concerning lesions, this study highlights a technique to treat JLMP and MIS with staged mapped excision and baseline scouting biopsies of adjacent nonlesional photodamaged skin to assist in determination of surgical margin clearance. Additionally, we compare the lesional and photodamaged control biopsies from the same patient to evaluate relevant histologic criteria that may be used to distinguish MH in photodamaged skin from JLMP/MIS, while minimizing confounding factors. There was a statistically significant difference (P ≤ 0.05) found for melanocyte density, irregular melanocyte distribution, melanocyte clustering, follicular infundibulum involvement, and nesting. However, criteria such as nesting, epithelioid cells and melanocyte clustering were seen in both photodamaged skin and MIS. These findings underscore the fact that histologic features of photodamaged skin can overlap with the histopathological features of MIS. Of all of the criteria evaluated, melanocytic density was the most objective histologic criterion and did not show overlap between the sun-damaged and JLMP/MIS groups.

Gene expression profiling of lichenoid dermatitis immune-related adverse event from immune checkpoint inhibitors reveals increased CD14+ and CD16+ monocytes driving an innate immune response.

BACKGROUND: Cancer patients receiving antibodies abrogating immune checkpoint pathways may develop a diverse array of immune-related adverse events (irAEs), of which lichenoid dermatitis (LD) is the most common. The mechanism driving the emergence of these irAEs remain understudied, underscoring a critical need to determine the unique gene expression profiles and immune composition in LD-irAE. METHODS: LD-irAE (n = 3) and benign lichenoid keratosis (BLK) control (n = 3) were profiled with NanoString nCounter PanCancer Immune Profiling Panel interrogating the mRNA levels of 770 genes. Immunohistochemical (IHC) studies (n = 14 samples) for CD14, CD16, T-Bet, Gata-3, and FoxP3 were further evaluated using Aperio digital image analysis. RESULTS: The LD-irAE showed downregulation of 93 mRNA transcripts (P < 0.05) and upregulation of 74 mRNA transcripts (P < 0.04) including toll-like receptor (TLR) 2 and TLR4 (P < 0.05). CD14+ and CD16+ monocytes quantified by IHC (H-score) were higher in LD-irAE than in the BLK control (P < 0.05). The immune composition of LD-irAE exhibited higher numbers of T-Bet+ (Th1) cells compared with Gata-3+ (Th2) cells (P = 0.016) and lower numbers of FoxP3 (T regulatory) cells (P = 0.008). CONCLUSIONS: LD-irAE exhibited activation of CD14/TLR innate immune response with increased CD14+ and CD16+ monocytes compared with BLK control. CD14/TLR signaling may drive the development of LD-irAE.

Perianal extramammary Paget disease treated with topical imiquimod and oral cimetidine.

Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma. The current mainstay of treatment is wide local excision. We present the case of a 56-year-old woman with perianal EMPD that recurred 4 years after initial treatment with wide local excision with Mohs micrographic surgery tissue processing of marginal tissue. Upon recurrence with anal canal involvement, the patient was treated with a 16-week combination course of topical imiquimod and oral cimetidine. There is growing evidence to support both the use of topical imiquimod for the treatment of EMPD as well as the antioncogenic effects of oral cimetidine. We present this case of primary perianal EMPD to highlight an alternative treatment regimen for poor surgical candidates.

Cutaneous Cytomegalovirus Infection in an Immunocompetent Patient: Innocent Bystander or Culprit?

We present a rare case of cutaneous cytomegalovirus (CMV) infection in a nonimmunocompromised patient. A 74-year-old woman with a history of diabetes presented with an ulcer on the right lateral tibia that occurred at the site of a nerve core biopsy. Subsequent biopsy of the ulcer edge showed granulation tissue with neutrophilic inflammation. The patient underwent extensive antibiotic treatment for possible infection with weekly wound care. However, the ulceration persisted and enlarged. A repeat biopsy 1 year later showed superficial and deep mixed inflammation with an associated vasculitis. On close examination, endothelial and eccrine ducts cells showed characteristic CMV viral cytopathic changes with positivity on CMV immunohistochemical stain. Although the patient was started on valganciclovir, the ulceration did not resolve with treatment and slightly enlarged. Treatment modalities included dapsone, prednisone, weekly wound care, wound vacuum, and eventually a skin graft of the ulcer site. This case highlights the presence of CMV infection in a cutaneous ulceration in a relatively immunocompetent patient, and the lack of response to treatment raises the question whether CMV was causative, partially contributory, or simply an innocent bystander.