ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars.

The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.

Eccrine spiradenoma of eyelid - a rare tumor at an unusual location with literature review.

Eccrine spiradenoma is a rare sweat gland tumor and usually presents as a solitary, painful nodule. A solitary spiradenoma involving the eyelid is quite rare. A 39-year-old Indian female presented with a gradually increasing, painless, nodular upper eyelid mass for the past 4 years. On examination, a non-tender approximately 4 × 3 mm cystic mass was noted, which was not adherent to underlying structures. The mass was excised in toto, and the histopathological examination was suggestive of eccrine spiradenoma with a low Ki-67 index. The patient was doing well without any signs of recurrence at 2 months of follow-up.

Distant metastasis from morphologically low-grade spiradenocarcinoma: A report of two cases.

Malignant tumors arising from benign eccrine spiradenomas are rare. They are divided by morphology into low-grade and high-grade spiradenocarcinomas, with prognosis and metastatic potential closely linked to their histopathologic features. Tumors with low-grade morphology are known for their indolent behavior, with only two reported instances of metastatic spread. We report herein two further low-grade metastatic spiradenocarcinomas resulting in distant metastasis. Both tumors showed a background of a benign spiradenoma and subtle histopathologic signs of malignant transformation, characterized by loss of the dual-cell population, up to moderate cytological atypia and increased mitotic activity. Both patients developed metastases to the lungs years after the initial presentation, and one showed additional lymph nodal disease. We show that even the morphologically low-grade tumors may rarely show more aggressive behavior. Although often challenging, recognition of the morphologically low-grade malignant spiradenocarcinoma and long-term follow-up of the patients are important to detect metastatic disease.

Direct intracranial invasion of eccrine spiradenocarcinoma of the scalp: a case report and literature review.

BACKGROUND: Eccrine spiradenocarcinoma (SC), also known as malignant eccrine spiradenoma, is a rare malignant cutaneous adnexal neoplasm arising from long-standing benign eccrine spiradenoma. Malignant skin tumors rarely show direct intracranial invasion. However, once the intracranial structure is infiltrated, curative excision with sufficient margins can become extremely difficult, particularly when the venous sinuses are involved. No effective adjuvant therapies have yet been established. Here, we report an extremely rare case of scalp eccrine SC with direct intracranial invasion, which does not appear to have been reported previously. CASE PRESENTATION: An 81-year-old woman presented with a large swelling on the parietal scalp 12 years after resection of spiradenoma from the same site. The tumor showed intracranial invasion with involvement of the superior sagittal sinus and repeated recurrences after four surgeries with preservation of the sinus. The histopathological diagnosis was eccrine SC. Adjuvant high-precision external beam radiotherapy (EBRT) proved effective after the third surgery, achieving remission of the residual tumor. The patient died 7 years after the first surgery for SC. CONCLUSIONS: Scalp SC with direct intracranial invasion is extremely rare. Radical resection with tumor-free margins is the mainstay of treatment, but the involvement of venous sinuses makes this unfeasible. High-precision EBRT in combination with maximal resection preserving the venous sinuses could be a treatment option for local tumor control.

Metaplastic spiradenocarcinoma: Report of two cases with sarcomatous differentiation.

Spiradenocarcinoma (SC) is a very rare malignant skin adnexal tumor with sweat gland differentiation that develops from a pre-existing spiradenoma, cylindroma, or hybrid tumor called spiradenocylindroma, or arises de novo. We present two exceptionally rare SC cases showing sarcomatous differentiation; we also discuss the clinicopathologic features of SC, as well as its differential diagnoses and available therapeutic modalities. Given the aggressive behavior of SC, rapid diagnosis and complete removal of the tumor with tumor-free margins is mandatory. Owing to the marked morphological heterogeneity of individual SC cases, dermatopathologists must be familiar with the different possible histopathologic manifestations of this neoplasm.

Eccrine spiradenoma: a rare adnexal tumour with atypical presentation: A case report.

First described in 1934, eccrine spiradenoma (ES) is a rare, benign adnexal tumour arising from eccrine sweat glands. It commonly presents as a slow-growing nodule on the upper trunk, and head and neck region, mostly in the age bracket of 15-35 years, with no gender preference. While no established guidelines exist for optimal management of malignant ES, some therapies have been studied. The diagnosis of this entity is extremely important as it can harbour a malignant component with disastrous outcomes which may be missed due to its strong resemblance to benign lesions, such as a papilloma. Here, we present the case of a 35-year-old lady who presented with a papilloma-like growth on the upper medial aspect of the thigh which was diagnosed as eccrine spiradenoma upon excision.

Ultrasonographic Features of Eccrine Spiradenoma.

The purpose of this series was to evaluate the features of eccrine spiradenoma on ultrasonography (US). We reviewed the clinical data of 8 patients with eccrine spiradenoma who underwent preoperative US at 4 different medical institutions from 2004 to 2016 and analyzed the US features in terms of the tumor location, size, shape, margin, echo texture, echogenicity, posterior acoustic enhancement, calcification, septum, and color Doppler flow. There were 7 female patients and 1 male patient. The mean patient age was 45.6 years (range, 28-60 years). Most of the tumors were located primarily in the subcutaneous fat layer. The mean size of the tumors was 14.3 mm. The masses had a lobular appearance in 7 patients and had a tractlike structure in 3 patients. In 6 patients, the masses had a heterogeneous echo texture. Six cases showed hypoechogenicity with more hypoechoic foci in the masses, and 2 cases showed hypoechogenicity only. Color Doppler flow was evaluated in 7 patients; the blood flow was central and peripheral in 4 patients and only peripheral in 3 patients. All cases showed posterior acoustic enhancement and had well-defined margins. Calcification and septa were not seen in any cases. Eccrine spiradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, a lobulated appearance, occasionally with a tractlike structure, a heterogeneous echo texture, a hypoechoic appearance with internal hypoechoic foci and posterior acoustic enhancement, and shows blood flow in the peripheral portion, with or without blood flow in the central portion.

[Malignant transformation of an eccrine spiradenoma]. / Transformation maligne d'un spiradénome eccrine.

INTRODUCTION: Malignant eccrine spiradenoma is a rare and aggressive tumor, developed on the epithelium of eccrine sweat glands. Typically, it occurs after malignant transformation of benign eccrine spiradenoma, but sometimes it happens de novo. OBSERVATION: We report a case of malignant eccrine spiradenoma in a 62-year-old woman. The patient presented a rapid increase in size of a long-standing tumoral lesion of her forearm. There was no secondary lesion on the chest, abdomen or pelvis at the CT-scanner. Cutaneous biopsy of the lesion was performed and showed a carcinoma with no contact with epidermis. On this biopsy, we could not affirm if the tumor was a metastatic process or a primary tumor of the skin. Histologic examination of the surgical removal of the tumor showed an undifferentiated carcinoma with adjacent nodules of eccrine spiradenoma. Immunohistochemical assessment of Ki67 expression showed a weak expression (5%) in the benign spiradenoma nodules and a high rate expression (80%) in the malignant neoplasm. The final diagnosis was an undifferentiated carcinoma arising from preexisting benign spiradenoma. DISCUSSION: Malignant eccrine spiradenoma is not frequent and is rarely described in the international literature that may lead to diagnostic difficulties.

Distinctive immunostaining of claudin-4 in spiradenomas.

The intercellular bridges are essential structures in maintaining the histologic organization of the epithelium, while providing a very efficient way to exchange molecules between cells and transduction of the cell-to-cell and matrix-to-cell signals. Derangement in those important structures' physical integrity and/or function, which can be assessed by the presence or absence of several intercellular bridge proteins including claudin-4, E-cadherin, and ß-catenin, was found to be related to several phenomena in the path to the neoplastic transformation. However, these proteins have not been studied in the wide variety of the skin neoplasms, in detail. Herein, we immunohistochemically assessed the expression patterns of these 3 intercellular bridge proteins on a total of 86 epidermal and eccrine adnexal tumors including basal cell carcinoma, squamous cell carcinoma, poroma, spiradenoma, syringoma, and hidradenoma. We observed a selective and distinct claudin-4 expression in the ductal-type cells of all cases of spiradenomas. Similarly, in the poromas, syringomas, and hidradenomas, claudin-4 was only positive in the luminal cells of microcystic structures, although not as conspicuous as in the spiradenomas. On the other hand, E-cadherin and ß-catenin were positive in almost all types of the tumors, in a way which was not contributory to differentiate from each other. In conclusion, we think that claudin-4 can be helpful at least in making a reliable differential diagnosis of spiradenoma when overlapping morphologic features do not allow to further subclassification in the overwhelming variety of the adnexal tumors.

Spiradenoma and cylindroma originate from the hair follicle bulge and not from the eccrine sweat gland: an immunohistochemical study with CD200 and other stem cell markers.

BACKGROUND: Spiradenoma and cylindroma have historically been described as sweat gland tumors and have often been considered to be of eccrine lineage. However, (a) associations with trichoepitheliomas in Brooke-Spiegler syndrome or with trichoepitheliomas and milia in Rasmussen syndrome, (b) neoplastic combinations with hair follicle tumors in solitary cases, and (c) anatomical considerations support a folliculosebaceous-apocrine lineage. Follicular stem cell markers may allow for further characterization of these neoplasms. METHODS: A total of 97 tumors were examined for the expression pattern of follicular stem cell markers cytokeratin 15 (CK15), cytokeratin 19 (CK19), pleckstrin homology-like domain, family A, member 1 (PHLDA1), and CD200. The tumors were comprised of 27 spiradenomas, 30 cylindromas, 16 hidradenomas, 19 poromas, 4 dermal duct tumors and 1 hidroacanthoma simplex. RESULTS: All spiradenomas and cylindromas were CD200-positive whereas the other tumors classified as eccrine in lineage were all CD200-negative. CK15 also discriminated between spiradenomas and cylindromas and the remaining neoplasms but not to the degree of CD200. PHLDA1 and CK19 were noncontributory. CONCLUSIONS: It is concluded that both spiradenoma and cylindroma are not eccrine but follicular tumors. More specifically, it is proposed that both adnexal neoplasms are derived from the hair follicle bulge and as such represent one of the least differentiated follicular tumors.

Perineural growth of benign cutaneous sweat gland tumors: a hitherto unrecognized phenomenon unassociated with malignancy.

BACKGROUND: Cutaneous intraneural reactive epithelial proliferations mimicking malignancy include epithelial sheath neuroma, re-excision perineural invasion and reactive neuroepithelial aggregates. Nevertheless, intraneural growth of benign sweat gland tumors has not been reported before. AIMS: To report a predominantly intraneural proliferation of morphologically bland sweat gland tumors, describe their clinicopathological features and correlate them with survival. RESULTS: We analyzed a spiradenoma and a hidradenoma with a prominent intraneural growth, occurring on the back of the 19-year-old woman and on the arm of the 53-year-old woman. Both lesions presented as a painful and slightly raised papule. After complete excision, an uneventful clinical course was observed during the follow-up period of 52 and 54 months. Pathologically, the most striking feature was an almost exclusive intraneural growth within the peripheral nerves of the deep dermis and subcutis. CONCLUSION: We report for the first time the predominantly intraneural growth of benign sweat gland tumors. Although their histogenesis is unknown, perineural displacement due to previous surgery or trauma, as well as development from intraneural embryological epithelial remnants remains possibilities. Long-term follow-up of our patients suggests that intraneural growth of otherwise bland sweat gland tumors does not signify malignancy. Complete excision appears to be sufficient treatment procedure.

[CO2 laser treatment of skin cylindromas in Brooke-Spiegler syndrome]. / Traitement des cylindromes cutanés par laser CO2 dans le syndrome de Brooke-Spiegler.

BACKGROUND: Multiple skin cylindromas are of autosomal dominant transmission and may be associated with spiradenoma and trichoepithelioma. This condition is known as Brooke-Spiegler syndrome. The aim of this study is to compare surgical and laser treatment for these lesions. CASE REPORTS: Five patients from a single family (two male and three female) consulted at the dermatology department for the treatment of multiple cylindromas of the scalp. The female patients presented a more severe form that had developed into "turban tumour". All patients were initially treated by surgery. Two had undergone multiple surgical excisions alone while the others had been treated with CO2 laser. One of the female patients treated with surgery had undergone complete excision of the scalp covered by total skin graft. The three patients treated with CO2 laser were completely satisfied with their therapy, which enabled a larger number of lesions to be treated at each session. They underwent one session every three months under local anaesthesia. CONCLUSION: CO2 laser constitutes an alternative to surgery in the treatment of multiple skin cylindroma. It gives excellent cosmetic result with excellent safety and a high degree of satisfaction among treated patients. It should be proposed for patients refusing surgery or where the number of lesions enables first-line use of this approach to be envisaged.

A rare sweat gland tumor in an ovarian teratoma: Spiradenocylindroma case report.

Background: Spiradenocylindroma is a benign tumor of skin adnexal origin with overlapping features of two distinct neoplasms: spiradenoma and cylindroma. This cutaneous tumor typically presents on the head and neck and extracutaneous presentations are uncommon. The presentation described below involves a spiradenocylindroma within a mature ovarian teratoma is very rare. Aim: The aim of this article is to portray the diagnostic process of this unusual spiradenocylindroma presentation. Case presentation: A 65 year-old female with a left adnexal mass underwent ultrasonography and magnetic resonance imaging (MRI) which showed a left ovarian multiseptated lesion, with mural calcifications and projections into the mass. Excisional surgery was performed and histopathological examination revealed a spiradenocylindroma. Conclusion: Spiradenocylindroma is rare, hard to identify, and often misdiagnosed. Our study described the process of diagnosis and depicts the rare presentation of this lesion arising within a mature teratoma.

Eccrine spiradenoma on the anterior forearm in a pediatric patient: A rare case report.

Spiradenoma is a rare benign adnexal tumor arising from eccrine sweat glands. It presents as a painful bluish nodular lesion which occurs rarely over the arms. This case report adds to a case where a recurrent spiradenoma occurred over the arm. The majority of reported cases involve young adults, making our pediatric case particularly unusual. Early diagnosis through excisional biopsy is crucial for optimal management and prevention of recurrence or malignant transformation. Eccrine spiradenoma is an uncommon tumor that should be kept in mind in case of a patient with a painful nodule. More genetic studies are needed for the best understanding of this rare tumor entity.

A Misdiagnosed Familiar Brooke-Spiegler Syndrome: Case Report and Review of the Literature.

Aim of the report: Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant disease characterized by the growth of cylindromas, spiradenomas, trichoepitheliomas, or their combination. These neoplasms usually begin in the second decade and progressively increase in number and size over the years. Diagnosis necessitates consideration of family history, clinical examination, histological findings, and genetic analysis. The aim of this paper is to explore the clinical overlap between Brooke-Spiegler syndrome (BSS) and neurofibromatosis type 1 (NF1). We aim to highlight the challenges associated with their differential diagnosis and emphasize the lack of standardized diagnostic criteria and treatment approaches. Case presentation: Hereby, we introduce the case of a 28-year-old male referred for suspicion of neurofibromatosis type 1 (NF1) who initially declined the recommended surgical excision for a scalp mass. After four years, he returned with larger masses of the scalp, and underwent excision of multiple masses, revealing cylindromas, spiradenomas, and spiradenocylindromas. Family history reported similar tumors in his father, who was also diagnosed with NF1 for the presence of multiple subcutaneous lesions on the scalp. Clinical overlap led to a genetic consultation, but testing for CYLD mutations yielded no significant variations. Despite this, the strong family history and consistent findings led to a revised diagnosis of Brooke-Spiegler syndrome, correcting the initial misdiagnosis of NF1 syndrome. Conclusions: Thanks to the evolving landscape of BSS research over the past two decades, its molecular underpinnings, clinical presentation, and histopathological features are now clearer. However, a thorough family history assessment is mandatory when BSS is suspected. It is our belief that a multidisciplinary approach and cooperation between specialists are essential when dealing with BSS. By sharing this case, we hope to underscore the importance of considering BSS as a differential diagnosis, especially in cases with atypical presentations or overlapping features with other syndromes like NF1.

Lymphangiectatic Variant of Low-Grade Malignant Eccrine Spiradenoma.

Low-grade malignant eccrine spiradenoma (spiradenocarcinoma) is a rare sweat gland tumor, which usually arises from a pre-existing benign eccrine spiradenoma. This paper presents the case of a 55-year-old male who had a lesion in his right elbow for 10 years. The microscopic examination revealed a well-demarcated, multilobulated tumor in the dermis and subcutis, which presented with many blood-filled vessels and extensive hemorrhage. The tumor was composed of hyperchromatic, round to oval cells with nucleolar prominence, mild to moderate atypia, and increased mitotic index. Additionally, lymphangiectatic appearance was observed in areas with prominent stromal lymphedema. P53 and Ki-67 had high positivity. Surgical excision of the lesion was performed with adequate surgical margins, and the dissected lymph nodes in the axilla were tumor-negative. After 15 months of follow-up, there was no recurrence or distant metastasis.