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Competing Interests: Conflicts of interest None disclosed.

Background: The modified Rodnan skin score (mRSS), used to measure dermal thickness in patients with systemic sclerosis (SSc), is agnostic to inflammation and vasculopathy. Previously, we demonstrated the potential of neural network-based digital pathology applied to stained skin biopsies from SSc patients as a quantitative outcome. We leveraged deep learning and histologic analyses of clinical trial biopsies to decipher SSc skin features 'seen' by artificial intelligence (AI)., Methods: Adults with diffuse cutaneous SSc (disease duration ≤ 6 years) enrolled in an open-label trial evaluating belumosudil underwent serial mRSS assessment and dorsal arm biopsies at week 0, 24 and 52/end of trial. Two blinded dermatopathologists independently scored stained sections [Masson's trichrome, hematoxylin and eosin (H&E), CD3, CD34, CD8, α smooth muscle actin (αSMA)] for 16 published SSc dermal pathological parameters. We applied our previously published deep learning model to generate QIF signatures/biopsy and generated Fibrosis Scores. Associations between Fibrosis Score and mRSS (Spearman correlation); and between Fibrosis Score mRSS versus histologic parameters [odds ratios (OR)] were determined., Results: Only ten patients were enrolled because the sponsor terminated the trial early. Median, interquartile range (IQR) for mRSS change (0-52 weeks) for the five participants with paired biopsies was - 2.5 (-11-7.5), and for the ten participants was - 2 (-9-7.5). The correlation between Fibrosis Score and mRSS was R = 0.3; p = 0.674. Per 1-unit mRSS change (0-52W), histologic parameters with the greatest associated changes were (OR, p-value): telangiectasia (2.01, 0.001), perivascular CD3+ (1.03, 0.015), and % of CD8 + among CD3+ (1.08, 0.031). Likewise, per 1-unit Fibrosis Score change, parameters with greatest changes were (OR, p-value): hyalinized collagen (1.1, < 0.001), subcutaneous (SC) fat loss (1.47, < 0.001), thickened intima (1.21, 0.005), and eccrine entrapment (1.14, 0.046)., Conclusions: Belumosudil was associated with a non-clinically meaningful improvement in mRSS. Fibrosis Score changes correlated with histologic feature changes ( e.g ., hyalinized collagen, SC fat loss) that were distinct from those associated with mRSS changes ( e.g ., telangiectasia, perivascular CD3+, and % of CD8 + among CD3+). These data suggest that AI applied to SSc biopsies may be useful for quantifying pathologic features of SSc beyond skin thickness., Competing Interests: Competing Interests MH has received consultancy fees from AbbVie and has received research grant support from Boehringer Ingelheim for an investigator-initiated research project. She is a Scientific Advisory Board Member for the Scleroderma Foundation. She has participated in clinical trials. EJB has received research grants from Kadmon, Boehringer Ingelheim and aTyr. EV has received consulting fees from Boehringer Ingelheim, GSK, Abbvie, BMS, and GLG, has received support from Boehringer Ingelheim, Horizon, Prometheus, Kadmon, and GSK, and serves on the advisory board for Cabaletta and Boehringer Ingelheim. FPW reports research support from AHRQ (R01HS027626), Amgen, and Whoop. FPW reports consulting for Hekaheart, Aura Care, and WndrHlth.

Caterpillar envenomation is a worldwide problem, with manifestations ranging from dermatitis to iridocyclitis and a fatal hemorrhagic diathesis. This article focuses on the diagnosis and management of dermatoses related to caterpillars.

Background: Skin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability. In order to develop a new histopathological outcome measure for SSc, we applied a computer vision technology called a deep neural network (DNN) to stained sections of SSc skin. We tested the hypotheses that DNN analysis could reliably assess mRSS and discriminate SSc from normal skin., Methods: We analyzed biopsies from two independent (primary and secondary) cohorts. One investigator performed mRSS assessments and forearm biopsies, and trichrome-stained biopsy sections were photomicrographed. We used the AlexNet DNN to generate a numerical signature of 4096 quantitative image features (QIFs) for 100 randomly selected dermal image patches/biopsy. In the primary cohort, we used principal components analysis (PCA) to summarize the QIFs into a Biopsy Score for comparison with mRSS. In the secondary cohort, using QIF signatures as the input, we fit a logistic regression model to discriminate between SSc vs. control biopsy, and a linear regression model to estimate mRSS, yielding Diagnostic Scores and Fibrosis Scores, respectively. We determined the correlation between Fibrosis Scores and the published Scleroderma Skin Severity Score (4S) and between Fibrosis Scores and longitudinal changes in mRSS on a per patient basis., Results: In the primary cohort (n = 6, 26 SSc biopsies), Biopsy Scores significantly correlated with mRSS (R = 0.55, p = 0.01). In the secondary cohort (n = 60 SSc and 16 controls, 164 biopsies; divided into 70% training and 30% test sets), the Diagnostic Score was significantly associated with SSc-status (misclassification rate = 1.9% [training], 6.6% [test]), and the Fibrosis Score significantly correlated with mRSS (R = 0.70 [training], 0.55 [test]). The DNN-derived Fibrosis Score significantly correlated with 4S (R = 0.69, p = 3 × 10 - 17 )., Conclusions: DNN analysis of SSc biopsies is an unbiased, quantitative, and reproducible outcome that is associated with validated SSc outcomes.

Background: Lyme disease (LD) is one of the most common tick-borne diseases caused by several Borrelia species of spirochetes. Ixodes scapularis is responsible for the transmission of LD in the northeastern United States. The rate of infection varies with the duration of tick attachment to the host; however, this information may be unknown. In skin biopsies, it is often difficult to identify spirochetes. Testing of ticks is not routinely performed. Treatment is established by clinical presentation., Objective: To test paraffin-embedded I. scapularis ticks for Borrelia by different methods., Materials/methods: We examined 20 paraffin-embedded ticks by silver stain, immunohistochemical (IHC) and direct immunofluorescent (DIF) methods and compared the percentage of positivity with DIF results from the Connecticut Agricultural Experiment Station., Results: The results were similar by DIF, which proved to be the most sensitive method, followed by the silver stain and IHC., Conclusion: We found that the identification of spirochetes in paraffin-embedded ticks was less difficult than in tissue with a comparable turnaround time to that of a routine biopsy. Timely identification of Borrelia in ticks may influence the clinical management of the patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms., Methods: We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases., Results: All 10 cases were negative with both CK5/6 and p63., Conclusion: Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The emergence of an association between gadolinium-based contrast agents (GBCA) and the rare condition nephrogenic systemic fibrosis (NSF) led to a warning in 2006 from the Food and Drug Administration (FDA) restricting the use of the GBCAs to patients with an estimated glomerular filtration rate of >30 mL/min/1.73m(2) . We discuss our experience with a post-FDA restriction presentation of NSF and subsequent patient death in which the prolonged lead-time of ∼5.5 years led to challenges in ensuring a secure diagnosis of NSF and establishing risk exposures. Accurate contemporary records of contrast administration and clinical factors alongside clinical and pathological expertise ensured that we were able to confidently diagnose NSF, despite the length of lead time and confounding factors., (© 2014 Wiley Periodicals, Inc.)

Objective: To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts., Methods: The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration., Results: The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA., Conclusion: Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA., Advances in Knowledge: This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

Background: Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function., Objective: The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources., Materials and Methods: We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting., Results: We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources., Conclusion: Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

Nephrogenic systemic fibrosis is a chronic, progressive condition that develops in some patients with renal impairment after exposure to gadolinium-based contrast agents used in magnetic resonance imaging. Thickening of the skin is typical, usually affecting the extremities. Visceral organs can also be affected. The diagnosis of the disease requires careful clinicopathological correlation. Treatment aims at restoring renal function, which is associated with delayed progression and, eventually, remission of skin changes. Reduction and prevention of nephrogenic systemic fibrosis cases are based on limiting the use of gadolinium-based contrast agents in patients with kidney disorders (especially in patients with advanced renal failure at stages 4 and 5), and restricting their use to situations in which they are essential to diagnosis/follow-up. Other than limiting exposure to gadolinium based contrast agents, no effective preventive methods have been reported. Due to increased awareness about the disease among radiologists and nephrologists, the incidence of nephrogenic systemic fibrosis is declining.

We present the case of a 60-year-old male with known stage IA mycosis fungoides (MF) who developed a suspicious tumor within a pre-existing lymphomatous plaque of the right forearm. Microscopy revealed an unusual mixed fibrohistiocytic proliferation as well as atypical intraepidermal and dermal lymphocytes. There was no evidence of large-cell transformation. Histopathological, immunohistochemical and clinical clues suggest this lesion might not have represented a dermatofibroma, but rather a hitherto unreported dermatofibroma-like process arising within a lesion of MF. The potential impact of this atypical lesion on the prognosis and clinical management of this patient highlights the importance of recognizing unusual clinical presentations of more common, benign lesions within this patient population., (Copyright © 2011 John Wiley & Sons A/S.)

Nephrogenic systemic fibrosis (NSF) is a rare fibrosing disorder described among patients with renal disease. Currently, no standard therapy exists, although therapeutic modalities have included plasmapheresis, extracorporeal photopheresis, sodium thiosulphate, imatinib and renal transplantation. We describe a patient with NSF who was physically debilitated and underwent renal transplantation. After transplantation, the patient's lesions improved clinically, and the patient was ambulatory. Despite developing worsening renal function, her lesions remained unchanged. We conclude that renal transplantation improves symptoms of NSF, and believe that in patients with NSF, careful consideration should be made for early renal transplantation.

Gadolinium-containing magnetic resonance imaging (MRI) contrast agents such as Omniscan are associated with nephrogenic systemic fibrosis (NSF). To determine if Omniscan can affect the differentiation of monocytes into fibroblast-like cells called fibrocytes that are found in the fibrotic lesions of NSF, peripheral blood mononuclear cells (PBMCs) from NSF patients, hemodialysis patients without NSF, and healthy, renally sufficient controls were exposed to Omniscan in a standardized in vitro fibrocyte differentiation protocol. When added to PBMCs, the gadolinium-containing MRI contrast agent Omniscan generally had little effect on fibrocyte differentiation. However, 10(-8) to 10(-3) mg/mL Omniscan reduced the ability of the fibrocyte differentiation inhibitor serum amyloid P (SAP) to decrease fibrocyte differentiation in PBMCs from 15 of 17 healthy controls and one of three NSF patients. Omniscan reduced the ability of SAP to decrease fibrocyte differentiation from purified monocytes, indicating that the Omniscan effect does not require the presence of other cells (such as T cells) in the PBMCs. Omniscan also reduced the ability of a different fibrocyte differentiation inhibitor, interleukin-12, to decrease fibrocyte differentiation. These data suggest that Omniscan interferes with the regulatory action of signals that inhibit the differentiation of monocytes to fibrocytes. J. Magn. Reson. Imaging 2009;30:1284-1288. (c) 2009 Wiley-Liss, Inc.

Nephrogenic systemic fibrosis (NSF) is a relative newcomer to the world of medicine. NSF was introduced just over 10 years ago as nephrogenic fibrosing dermopathy, but with further investigation, its systemic nature was determined. The strict adherence to a definition requiring both clinical and pathological concordance has allowed for careful separation of this entity from other fibrosing disorders, leading eventually to the realization that gadolinium-based contrast agents were closely associated with its onset. As planned prospective studies get underway, it is of paramount importance that researchers and clinicians realize that NSF remains a very challenging diagnosis, and that both clinical and histopathological criteria must be employed to reach the most accurate diagnosis possible.

Nephrogenic systemic fibrosis (NSF) is a progressive, debilitating, and emotionally distressing disease that can affect patients with renal dysfunction. Prevention, early recognition and early treatment are essential to limiting its impact. The most significant risk factors for developing NSF are chronic or significant acute kidney disease (usually necessitating dialysis) and the administration of gadolinium-containing contrast agents (GCCA). Early symptoms include swelling, redness, pruritus, and pain in the limbs, sometimes with muscle weakness. Early signs are edema, erythema, and occasionally palpable warmth of the involved extremities; there may be florid scleral telangiectasia resembling conjunctivitis. We must redouble our efforts to avoid the administration of GCCA to patients with renal insufficiency. The most effective treatment for NSF to date is maximization of renal function via medical therapy or transplantation. There are data to support a beneficial effect from extracorporeal photopheresis, and all patients can gain from physical therapy.

In 1997, a new fibrosing skin disorder became apparent among patients with renal disease. Nephrogenic systemic fibrosis, as this disorder has come to be known, has recently been tied to the administration of contrast agents containing gadolinium. This overview examines the discovery and elucidation of the major research accomplishments to date. It was presented as the keynote address at the First Annual Scientific Symposium on Nephrogenic Systemic Fibrosis and MRI Contrast, conducted at Yale University on May 4, 2007.

Objective: Metastatic cutaneous neoplasms may be difficult to differentiate from primary cutaneous neoplasms. Herein, we report an unusual case of metastatic cutaneous carcinoid tumor mimicking an adnexal poroid neoplasm., Methods: A 53-year-old male man presented with a neoplasm on the vertex of the scalp, clinically resembling a pigmented basal cell carcinoma., Results: A shave biopsy was suggestive of an apocrine poroma, however, a metastatic carcinoma could not be excluded. After acquiring additional clinical information and the complete excision of the neoplasm, further immunohistochemical stains supported the diagnosis a metastatic carcinoid tumor., Conclusion: To our knowledge, this is the first case of metastatic carcinoid tumor reported that has mimicked a poroid neoplasm.

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare fibrotic condition that presents in patients with a history of renal disease. The aetiology is unknown, but it has recently been proposed that gadolinium, a paramagnetic contrast agent, may be a trigger of this disease. We report three patients with NSF with a history of use of gadolinium in magnetic resonance angiography a few weeks before the onset of symptoms. In the future, gadolinium should probably be avoided as much as possible in renal insufficiency patients until its role in the development of NSF is clarified.

Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P < or = 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised.

Background: Nephrogenic systemic fibrosis (NSF) is a disease of unknown etiology that affects a subset of patients with renal insufficiency. Recent publications suggested an association between exposure to gadolinium-containing contrast agents and subsequent development of NSF. We sought to detect gadolinium within the skin and soft tissue of patients with NSF who were exposed to gadolinium-based contrast., Methods: Paraffin-embedded skin and soft tissue from NSF patients exposed to gadolinium, and from negative controls, was provided by the NSF Registry (New Haven, Conn). The tissue was searched for metals using a field emission scanning electron microscope that was equipped with energy dispersive spectroscopy. The presence of gadolinium and other metals was verified through identification of unique and requisite X-ray emission spectra., Results: Gadolinium was detected in 4 of 13 tissue specimens from 7 patients with documented NSF who were exposed to gadolinium-based radiographic contrast. No gadolinium was detected in a paraffin-embedded specimen from a negative control. Based upon the known exposure history of patients with detectable gadolinium, a tissue residence time of 4 to 11 months was observed., Limitations: As this was a pilot investigation, only a single control specimen and a single histological section from each block of tissue were utilized., Conclusion: In this pilot investigation, gadolinium was detected in the tissue of a number of patients with NSF. Although neither dispositive of a pathophysiologic mechanism, nor proof of causation, the detection of gadolinium within tissue of NSF patients is supportive of an epidemiologic association between exposure to gadolinium-containing contrast material and development of disease.

NSF is a new and emerging disease. Significant investigative work to date has led to an unexpected suspect-gadolinium-containing contrast agents. Considerable additional work is now underway to formulate specific recommendations about the use of these agents in the population of patients who have renal disease. Goals on the immediate research horizon include (1) the identification of risk factors and conditions that must be met to permit the development of NSF in patients who have renal disease, (2) the characteristics of contrast agents that make them more or less likely to induce NSF, and (3) the development of prophylactic or treatment strategies that can reduce the overall development and severity of NSF. The investigative process has already yielded new insight into the functions (and malfunctions) of the CF in the setting of NSF. As the CF is being increasingly implicated in other organ-specific and systemic fibrosing disorders, we can expect to see significant developments in the studies of allied disorders as well.

Fibrocytes are cells that circulate in the peripheral blood and produce connective tissue proteins such as vimentin and collagens I and III. Fibrocytes are associated with skin lesions, pulmonary fibrosis, and tumors and they contribute to the remodeling response by secreting matrix metalloproteinases. Fibrocytes can further differentiate, and they are a likely source of the contractile myofibroblast that appears in many fibrotic lesions. There is evidence in the skin for a prominent role for fibrocytes in the development of hypertrophic scars and keloids. In asthma or in experimental models of pulmonary fibrosis, fibrocytes have been shown to infiltrate areas of inflammation and tissue damage. Fibrocytes constitute part of the stromal response to tumor invasion, and there is evidence that these cells may be a prognosticator of malignant potential. IL-1, TGF-beta, chemokines, and serum amyloid P modulate the appearance and function of fibrocytes. Fibrocytes themselves produce inflammatory cytokines, growth factors, and chemokines. The intercellular signals that modulate fibrocyte trafficking, proliferation, and differentiation are only partially defined, but a better understanding of these signals enable new therapies to prevent pathologic fibrosis or to improve the tissue repair response.

Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an emerging systemic fibrosing disorder that develops in the setting of renal insufficiency. Since its recognition in 1997, several case reports of NSF have been published in the rheumatology literature, reflecting the increasing incidence and recognition of this disorder in the United States and abroad. As rheumatology professionals are commonly the first to encounter newly developing cases, it is imperative that they recognize the symptoms and comorbidities of NSF and initiate work-up and treatment. To date, the precise causes of NSF have not been established; however, several promising lines of inquiry have led to a new model of the disorder. This model speculates that circulating fibrocytes of bone marrow origin are aberrantly recruited to the skin and other systemic sites by a process likely triggered or exacerbated by endothelial damage.

Alopecia typically is divided into cicatricial (scarring) and noncicatricial (nonscarring) forms. "Scarring" alopecia implies that follicular epithelium has been replaced by connective tissue and is therefore an irreversible process. In contrast, nonscarring alopecia is potentially reversible as follicular epithelia remain intact. Classification of cicatricial alopecia can be confusing and controversial as most disorders demonstrate overlapping clinical and histologic features. Herein, we present an overview of the histologic assessment of cicatricial alopecia, including an algorithmic approach to the evaluation of biopsy specimens from patients with scarring alopecia.

Background: Antibodies to CD56 label natural killer (NK) cell lymphomas and neuroendocrine tumors such as Merkel cell carcinoma (MCC). In MCC altered by crush artifact or obscured by lymphocytes, the histologic features coupled with CD56 positivity can lead to an erroneous impression of NK-cell lymphoma., Methods: Eighteen cases of MCC were stained for CD56, CK20, MNF116, and pankeratin. The results were compared to histologic features and CD56 staining pattern of three NK-cell lymphomas., Results: Three of 18 cases of MCC histologically resembled lymphoma, and CD56 positivity with CD3 and CD20 negativity initially raised the possibility of NK-cell lymphoma. Two additional cases were obscured by dense inflammation, again suggesting the diagnosis of lymphoma. Seventeen of 18 MCC labeled for CD56 and an equal number stained for CK20. All MCC tested were positive for CAM5.2 (14/14) and MNF116 (17/17). Antibodies to pankeratin labeled only one of 18 MCC. Staining for CD56 was stronger in MCC than NK-cell lymphomas., Conclusions: CD56 is a sensitive marker for MCC as well as for NK-cell lymphoma, but is not specific. Importantly, CD56 positivity in crushed or inflamed biopsies of MCC may lead to an erroneous impression of NK lymphoma. Awareness of this potential pitfall will prevent misdiagnosis. McNiff JM, Cowper SE, Lazova R, Subtil A, Glusac EJ. CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: Magic bullet, diagnostic pitfall, or both?

Background: Digital fibromas are common benign acral tumors typically reported as angiofibromas (AFs) or acquired digital fibrokeratomas (ADFs). Cellular variants are not well recognized., Methods: We collected 14 acral fibrocytic lesions showing a spindle cell morphology from our files, and evaluated CD34, Factor XIIIa, epithelial membrane antigen (EMA), and S100 protein staining of these lesions. We compared the histologic and immunohistochemical features of these cellular fibromas with five digital AFs, five ADFs, and five digital dermatofibromas., Results: The 14 cellular digital fibromas showed intersecting fascicles of thin delicate bland spindle cells in the superficial reticular dermis with a fibrotic-to-slight myxoid stroma. The spindle cells in all cases stained strongly for CD34, and only scattered stromal cells stained for Factor XIIIa. Five tested cases were negative for EMA and S100 protein. The digital AFs, fibrokeratomas, and dermatofibromas stained predominately for Factor XIIIa, with no or minimal staining for CD34., Conclusions: These findings suggest that a subset of digital fibromas is characterized by a dense cellular proliferation of CD34-positive spindle cells. Awareness of this variant of digital fibroma and its staining pattern is critical in preventing misdiagnosis as dermatofibrosarcoma protuberans, particularly in superficial biopsies.