Psoriasis vulvae.

OBJECTIVE: Case presentation, differential dia-gnostic, possible therapeutic procedure and a brief literature report. CASE REPORT: An 84-year-old woman was repeatedly examined for chronic extended dermatologic lesion on lower abdomen, external genitals, perianal region, groin and adjacent inner thighs. CONCLUSION: Neither colposcopy with dermatovenerologic consultation, nor histopathological examination led to a precise conclusion. Only a special dermatopathologic expertise showed a dia-gnosis of inverse psoriasis with suggested therapy.

Tumor lesions of penis and scrotum according to WHO classification 2022.

Similarly to testicular tumors, key changes on penile and scrotal neoplasia were incorporated into WHO classification 2016. Therein, penile squamous cell carcinomas were divided into two groups based on the pathogenesis, namely HPV-associated and HPV-independent. This remains unchanged in WHO classification 2022. For those carcinomas where HPV status can not be determined, a category of squamous cell carcinoma NOS was added. Variants of squamous cell carcinoma, namely basaloid, papillary-basaloid, warty, warty-basaloid, clear cell and lymphoepithelioma-like carcinomas are not recognized as distinctive variants of HPV-associated group anymore. Similarly, squamous cell carcinoma, usual type, pseudohyperplastic, pseudoglandular, verrucous carcinoma, carcinoma cunniculatum, papillary, adenosquamous, sarcomatoid and mixed carcinoma are no more not recognized as distinctive variants of HPV-independent carcinomas. Instead, these variants are now called subtypes. Some previously distinct subtypes now belong to the morphological spectrum of other subtypes. Basaloid-papillary subtype belongs to basaloid squamous cell carcinoma and carcinoma cunniculatum is currently recognized as morphological variation of verrucous carcinoma. Pseudohyperplastic and mixed subtypes were removed from the classification. Adenosquamous carcinoma is currently termed adenosquamous and mucoepidermoid carcinoma and represents distinct entity. Precursor lesions of squamous cell carcinoma underwent substantial modifications in the WHO classification 2016 as well, and remain unchanged in WHO classification 2022. Terminology for HPV - induced lesions have been unified to low grade squamous intraepithelial lesions (LSIL) and high grade squamous intraepithelial lesions (HSIL). This classification applies to the whole anogenital area, including penis, anus, perianal region, vulva, vagina and uterine cervix. LSIL is further divided to condyloma accuminatum and (penile) intraepithelial neoplasia grade 1 (PeIN1), HSIL is divided to PeIN2 and PeIN3. Penile HPV-independent precursor lesions are named differrentiated penile intraepitelial neoplasia (dPeIN) and are identical to analogous lesions on vulva.

Stewart-Treves syndrome: Case report and literature review.

Lymphangiosarcoma, or Stewart-Treves Syndrome (STS), is a very rare skin angiosarcoma with poor prognosis, which usually affects the upper limbs of patients who underwent breast cancer surgery, including axillary dissection followed by radiotherapy (RT). Cutaneous lymphangiosarcomas, which account for approximately 5% of all angiosarcomas, usually originate in the limb with chronic lymphedema. Lymphatic blockade is involved in the onset of STS. RT contributes indirectly to an increased risk of developing STS by causing axillary-node sclerosis and resulting in a lymphatic blockade and lymphedema. Chronic lymphedema causes local immunodeficiency, which indirectly leads to oncogenesis. Currently, axillary nodes are no longer routinely irradiated after axillary dissection, which is associated with a reduction in the incidence of chronic lymphedema from 40% to 4%. The use of sentinel lymph node biopsy technique is also widespread and the associated risk of lymphedema is further reduced. Thus, the incidence of STS decreased significantly with improved surgical and radiation techniques. The overall prognosis of STS patients is very poor. Only early radical surgical removal, including amputation or disarticulation of the affected limb, or wide excision at an early stage offers the greatest chance of long-term survival. Only a few case reports and series with a small number of patients with lymphangiosarcoma can be found in the literature. We present a case report of the first diagnosed STS at our department in an effort to highlight the need of the consideration of developing lymphangiosarcoma in patients with chronic lymphedema.

Acquired elastotic hemangioma-like changes and eccrine sweat duct squamous metaplasia in lichen simplex chronicus/prurigo nodularis-like lesions of the knee and elbow.

BACKGROUND: The so-called acquired elastotic hemangioma (AEH) represents a peculiar vascular lesion affecting the sun-damaged skin of the extensor surface of the forearms or the lateral aspect of the neck of middle-aged or elderly women. METHODS: This is a clinicopathological and immunohistochemical study of a series of 6 lesions located on the knee or elbow showing epithelial features of lichen simplex chronicus (LSC)/prurigo nodularis (PN) with a marked subepidermal vascular proliferation closely resembling AEH. RESULTS: Microscopically, all cases of cutaneous lesions showed epithelial features of LSC/PN, that is compact hyperkeratosis with focal parakeratosis, irregular acanthosis, prominent hypergranulosis. Moreover, a marked subepidermal vascular proliferation arranged in a horizontal band closely resembling AEH was detected in these lesions. Another common histopathological finding was eccrine duct squamous metaplasia and/or hyperplasia. CONCLUSIONS: While AEH represents a distinctive clinicopathological variant of hemangioma characteristically appearing on sun-exposed areas of middle-aged or elderly patients, the herein described lesions seem to be non-neoplastic epithelial, vascular and eccrine sweat duct reactive changes which are likely to be associated with chronic pressure or repeated mechanical stimulation with a marked predilection for the knee and elbow.

Study of Selected BRCA1, BRCA2, and PIK3CA Mutations in Benign and Malignant Lesions of Anogenital Mammary-Like Glands.

Anogenital mammary-like glands (AGMLGs) are nowadays considered a normal component of the anogenital area. Lesions involving AGMLGs are histopathologically very similar to their mammary counterparts, but the information on molecular biological mechanisms in these vulvar/perianal tumors is scarce. Mutations in the PI3K-AKT cascade have been found in hidradenoma papilliferum. The authors studied selected BRCA1, BRCA2, and PIK3CA mutations in series of benign and malignant neoplasms thought to be associated with AGMLGs, including 9 cases of primary extramammary Paget disease, 3 different cases of mammary-type carcinoma (adenoid cystic like, tubulolobular, and invasive ductal like), and 5 cases of hidradenoma papilliferum. No BRCA mutation was detected, whereas 3 neoplasms yielded PIK3CA mutation, including extramammary Paget disease, mammary-type invasive ductal carcinoma, and tubulolobular carcinoma. Our study expands the spectrum of lesions of AGMLGs harboring mutations in genes encoding the PI3K-AKT cascade. Further studies of the whole BRCA1 and BRCA2 genes using a larger cohort are needed to clarify their role in the pathogenesis of AGMLG lesions.

Anogenital Mammary-Like Glands: A Study of Their Normal Histology With Emphasis on Glandular Depth, Presence of Columnar Epithelial Cells, and Distribution of Elastic Fibers.

The normal histology of anogenital mammary-like glands (AGMLG) has been studied previously, but some aspects, including glandular depth, presence of columnar epithelium resembling columnar cell change/hyperplasia as defined in mammary pathology, and distribution of elastic fibers, have not been previously investigated. To address these issues, we studied 148 AGMLG identified in 133 paraffin blocks sampled from 64 vulvar wide excision or vulvectomy specimens (64 patients, various indications for surgery). The depth of AGMLG ranged from 0.64 to 3.9 mm. Epithelial columnar cell change was noted in 33.1% of all AGMLG, whereas columnar cell hyperplasia was detected in 10.1%. Occasionally, combinations of cuboidal epithelium and columnar cell change were seen within 1 histological section. Of 22 specimens stained for elastic fibers, in only 6 (27.3%) cases were elastic fibers found around glands. Periductal elastic fibers were demonstrated around 3 of the only 5 ducts, which were available for analysis in slides stained for elastic fibers. The depth of AGMLG should be taken into account when planning topical and surgical therapies for lesions derived or evolving from AGMLG. Alterations identical to columnar cell change may represent a normal variation of AGMLG.

Squared-Off Nuclei and "Appliqué" Pattern as a Histopathological Clue to Periocular Sebaceous Carcinoma: A Clinicopathological Study of 50 Neoplasms From 46 Patients.

The histopathological diagnosis of periocular sebaceous carcinoma can be difficult in poorly differentiated cases showing few mature sebocytes. The authors examined 50 periocular sebaceous carcinomas from 46 patients to determine the frequency of 2 features seen in this neoplasm, namely cells with squared-off nuclei and so-called "appliqué" pattern (peritumoral subnecrosis of peripherally located neoplastic cells). Neoplastic cells with squared-off nuclei were found in varying numbers in both the intraepithelial and dermal (invasive) components in all neoplasms, whereas the appliqué pattern was observed in a third of the cases. It is concluded that these features, taken together, may serve as a clue for the diagnosis of periocular sebaceous carcinoma.

Differentiated squamous intraepithelial lesion (dSIL)-like changes in the epidermis overlying anogenital melanocytic nevi: A diagnostic pitfall.

BACKGROUND: Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemically analogous in the whole anogenital region. dSIL is a premalignant lesion frequently misinterpreted histopathologically as a benign dermatosis. The authors describe a peculiar change in the basal cell layer of the epidermis/epithelium overlying anogenital melanocytic nevi that may histopathologically imitate dSIL. The aim of this study is to familiarize the pathologists with this pitfall to avoid its possible overdiagnosis as dysplasia. Further, we tried to explore the biological characteristics of the dSIL-like changes and to focus on the differential diagnostic aspects. DESIGN: Seventy cases of anogenital nevi were retrieved from our registry. All cases were stained with hematoxylin and eosin (H&E) and reviewed. Cases in which the epidermis overlying nevi featured atypical appearing basal keratinocytes in otherwise fully differentiated epithelium, variable degrees of acanthosis and parakeratosis were selected for additional investigation. RESULTS: Thirty cases meeting the above described criteria were identified. The patients were 8 males and 22 females, with age at the time of diagnosis ranging from 4 to 68years. Follow-up data were available for 28 patients (range 0.5-19years, mean 5.1), and to date, no signs of epithelial malignancy have been recorded. Immunohistochemically (IHC), the epidermis overlying nevi showed insignificant positivity for p53 in all tested cases. Melanocytic markers (S-100 protein, SOX10, Melan A) and cytokeratin AE1/3 labeled melanocytes and keratinocytes, respectively, enabling their distinction, especially in nevi featuring a junctional component. CONCLUSIONS: Differentiated squamous intraepithelial lesion-like changes seem to occur relatively often in the epidermis overlying anogenital melanocytic nevi. Since morphologically they are virtually identical to the "true" dSIL, their distinction largely depends on p53 expression in basal keratinocytes with normal p53 expression in dSIL-like changes and diffuse nuclear/p53-null immunostaining in the "true" dSIL serving as an essential differential diagnostic tool. dSIL-like alterations seem to have no malignant potential, as to date, none of the patients included in this study have shown any signs of epithelial malignancy.

Desmoplastic melanoma: an updated immunohistochemical analysis of 40 cases with a proposal for an additional panel of stains for diagnosis.

Desmoplastic melanoma (DM) is histologically characterized by a proliferation of spindle melanocytes dispersed in a collagenous stroma that can be mistaken for a variety of neoplasms. The purpose of this study was to analyze 40 cases of DM with a comprehensive panel of immunohistochemical markers (KBA.62, p16, Ezrin, WT-1, MITF-1, SOX-10, CD117, SOX-2, nestin, PNL2, p75, MART-1, gp100 and S100p) to obtain a more complete understanding of the potential use of these antibodies in the diagnosis of DM. We found that all cases of DM expressed p16, WT-1, SOX-10, nestin and S100p and 95% of cases expressed p75. There was variable expression with Ezrin, SOX-2, KBA.62, MART-1 and HMB-45. Most DMs did not express MITF-1, PNL2 and CD117. Conditions that may enter in the histologic differential diagnosis of DM, including dermal scars, fibromatosis and dermatofibromas were also studied. Nearly all control cases also stained positive for p16 but were negative for WT1, SOX10, nestin, p75 and S-100p, as well as for most of the other markers tested. We conclude that a panel of S-100p, WT1, SOX10, p75 and nestin may constitute the optimal panel with the most sensitive and specific combination of immunostain available for the diagnosis of DM.

Hybrid Epithelioid Schwannoma/Perineurioma.

We report a case of a 58-year-old who woman presented with a solitary slowly growing subcutaneous nodule covered by normally appearing skin on her left groin. Microscopically, the lesion was well circumscribed but unencapsulated, and showed biphasic cellular differentiation. One cell population was presented by small rounded (epithelioid) cells arranged singly, in small aggregates or short cords, whereas the second one was composed of cells with slender nuclei and delicate elongated bipolar cytoplasmic processes. On immunohistochemistry, the epithelioid component showed positive reaction for S-100 protein and negative for epithelial membrane antigen (EMA), thus compatible with schwannian differentiation and resembling epithelioid schwannoma. The other component showed a reverse immunophenotype being S-100 protein negative and EMA positive, thus corresponding to perineuriomatous differentiation. The clinicopathologic and immunohistochemical features of the lesion were compatible with hybrid epithelioid schwannoma/perineurioma, a rare morphological variant of peripheral nerve sheath tumors.

Aggressive Extraocular Sebaceous Carcinoma of the Scalp Involving the Brain in a Patient With Muir-Torre Syndrome.

This article reports an unusual case of aggressive extraocular sebaceous carcinoma located on the scalp with subsequent usurpation of the bone and penetrating through the bone and meninges to the brain in a 56-year-old man affected by Muir-Torre syndrome. Microscopically, the sebaceous neoplasm was located in the middle to deep dermis without any connection to the epidermis and showed a multinodular growth with neoplastic nodules with a central comedo-type necrosis separated from each other by fibrovascular stroma. The nodules were composed of varying proportions of mature sebaceous cells and atypical basaloid cells with high degree of atypia, including high nuclear/cytoplasmic ratio, nuclear pleomorphism, macronucleoli, atypical mitoses, and necrosis. The neoplasm was totally removed. Histopathological examinations of the recurrent lesion showed identical morphological features and, in addition, signs of the tumors growing through the periosteum were noted. In the final excision specimen, both the dura mater and the brain tissue were infiltrated by the sebaceous carcinoma. The diagnosis of Muir-Torre syndrome was confirmed by molecular genetic investigation that revealed an identical germline mutation in MSH2 gene in several family members, some of whom had colorectal tumors.

Bilateral Gigantomastia, Multiple Synchronous Nodular Pseudoangiomatous Stromal Hyperplasia Involving Breast and Bilateral Axillary Accessory Breast Tissue, and Perianal Mammary-Type Hamartoma of Anogenital Mammary-Like Glands: A Case Report.

Mammary-type fibroepithelial lesions involving ectopic breast and anogenital region are rare and usually coexist with normal orthotopic breast. We present what we believe to be a unique case of synchronous bilateral gestational gigantomastia resembling fibrous mastopathy, synchronous rapidly growing pregnancy-associated nodular pseudoangiomatous stromal hyperplasia involving right breast and bilateral axillary ectopic breast tissue, and metachronous perianal mammary-type hamartoma involving anogenital mammary-like glands occurring in a 34-year-old patient with facioscapulohumeral muscular dystrophy. Also, we review the literature concerning these lesions.

Human Papillomavirus Infection and p16 Expression in Extragenital/Extraungual Bowen Disease in Immunocompromised Patients.

An increased rate of second nonmelanoma skin cancers is found in immunocompromised patients. Epidemiological and molecular data implicate ultraviolet radiation as the major risk factor. In addition, there is increasing evidence supporting the role of human papillomavirus (HPV) in the pathogenesis of premalignant and malignant skin lesions in both immunocompetent and immunocompromised patients. In a retrospective cross-sectional study, the authors examined the expression of p16 by immunohistochemistry and the presence of mucosal (α-genus) and cutaneous/epidermodysplasia verruciformis (ß-genus) HPV DNA by polymerase chain reaction in 29 biopsy specimens of extragenital/extraungual Bowen disease (BD) from 24 Eastern European white immunocompromised patients. Furthermore, the author evaluated the association between the expression of p16 protein and the presence of HPV DNA. Among 25 specimens from 21 patients evaluable by polymerase chain reaction, HPV DNA was detected in 10 (40%) BD lesions from 9 patients. Beta-HPV predominated over alpha-HPV types. Among 29 immunohistochemically evaluable BD specimens, 22 lesions (∼76%) from 20 patients were scored as p16 positive. HPV DNA-positive and HPV DNA-negative lesions displayed the same proportion of p16 positivity (80%) and no correlation was found between the HPV DNA presence and the p16 expression status. Our pilot study demonstrated that ß-HPV infections predominate in BD cases diagnosed among immunocompromised patients, although high- and low-risk mucosal (alpha) HPV genotypes may be detected in a minority of cases. In contrast to anogenital HPV-associated lesions, positive p16 expression is not a reliable marker of high-risk α-HPV infection in BD cases, as it can be also detected in ß-HPV infected and HPV-negative cases.

Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome.

A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma. In some sebaceous lesions, squamous metaplasia, intratumoral heterogeneity, mucinous changes, and peritumoral lymphocytes as sometimes seen in sebaceous lesions in Muir-Torre syndrome were noted. Mutation analysis of the peripheral blood revealed a germline mutation c.692G>A,p.(Arg231His) in exon 9 and c.1145G>A, p.(Gly382Asp) in exon 13 of the MUTYH gene. A KRAS mutation G12C (c.34G>T, p.Gly12Cys) was detected in 1 sebaceous adenoma and a NRAS mutation Q61K (c.181C>A, p.Gln61Lys) was found in 2 other sebaceous adenomas. No germline mutations in MLH1, MSH2, MSH6 and PMS2 genes, no microsatellite instability, no aberrant methylation of MLH1 promoter, and no somatic mutations in MSH2 and MSH6 were found. An identical MUTYH germline mutation was found in the patient's daughter. Despite striking clinicopathological similarities with Muir-Torre syndrome, the molecular biologic testing confirmed the final diagnosis of MUTYH-associated polyposis.

Syringocystadenocarcinoma Papilliferum In Situ-Like Changes in Extramammary Paget Disease: A Report of 11 Cases.

The authors report 11 cases of extramammary Paget disease (EMPD), all of which also demonstrated a combination of histological changes highly reminiscent of syringocystadenocarcinoma papilliferum in situ. In addition to the classical features of EMPD, characterized by the intraepidermal spread of individually dispersed neoplastic cells with ample cytoplasm, many of which contained mucin, there were areas of acanthosis with the substitution of spinous layer keratinocytes by neoplastic cells, whereas the native basal cell layer was intact. In addition to acanthosis (and sometimes papillomatosis), the dermal papillae showed a prominent infiltrate of plasma cells, completing the resemblance to syringocystadenocarcinoma papilliferum in situ; this similarity was further enhanced in 2 cases, which showed conspicuous gland formation. One additional case showed multifocal dermal proliferations compatible with eccrine syringofibroadenoma (syringofibroadenomatous hyperplasia). The changes described herein seem to be relatively rare in EMPD, and they can represent a diagnostic pitfall, as evidenced by 2 cases that were originally misinterpreted as syringocystadenocarcinoma papilliferum in situ. Clinically, these microscopic changes sometimes corresponded to nodular lesions, which were specifically noted to have a papillated erosive surface.

Hidradenoma Papilliferum: A Clinicopathologic Study of 264 Tumors From 261 Patients, With Emphasis on Mammary-Type Alterations.

Hidradenoma papilliferum (HP), also known as papillary hidradenoma, is the most common benign lesion of the female anogenital area derived from anogenital mammary-like glands (AGMLG). HP can be viewed conceptually as the cutaneous counterpart of mammary intraductal papilloma. The authors have studied 264 cases of HP, detailing various changes in the tumor and adjacent AGMLG, with emphasis on mammary-type alterations. In many HP, the authors noticed changes typical for benign breast lesions, such as sclerosing adenosis-like changes, usual, and atypical ductal hyperplasia. Almost in a third of cases, remnants of AGMLG adjacent to the lesion were evident, manifesting columnar changes reminiscent of those seen in breast lesions. This study shows that the histopathological changes in HP run a broad spectrum comparable with that in the mammary counterpart and benign breast disease.

Depth and Patterns of Adnexal Involvement in Primary Extramammary (Anogenital) Paget Disease: A Study of 178 Lesions From 146 Patients.

Extramammary Paget disease (EMPD) is a rare neoplasm usually presenting in the anogenital area, most commonly in the vulva. Adnexal involvement in primary EMPD is a very common feature and serves as a pathway for carcinoma to spread into deeper tissue. The depth of carcinomatous spread along the appendages and the patterns of adnexal involvement were studied in 178 lesions from 146 patients with primary EMPD. Hair follicles and eccrine ducts were the adnexa most commonly affected by carcinoma cells. The maximal depth of involvement was 3.6 mm in this series. When planning topical therapy or developing novel local treatment modalities for EMPD, this potential for significant deep spread along adnexa should be taken into account.

Cutaneous hidradenoma: a study of 21 neoplasms revealing neither correlation between the cellular composition and CRTC1-MAML2 fusions nor presence of CRTC3-MAML2 fusions.

Twenty-one hidradenomas from 20 patients (13 female, 7 male) ranging in age from 18 to 87years (mean, 57.75years; median, 60years) were studied for CRTC1-MAML2 and CRTC3-MAML2 fusions to find out whether there is a correlation between the particular cell type (polyhedral eosinophilic, clear, mucinous, epidermoid, and oncocytic) and presence the above alterations. CRTC1-MAML2 fusions were detected in 10 of the 21 neoplasms (47.6%). Fluorescence in situ hybridization for MAML2 break apart was analyzable in 13 specimens and in all these specimens was positive, including 4 tumors with no demonstrable CRTC1-MAML2 fusion. In none of the cases was a CRTC3-MAML2 fusion detected. No obvious correlation between the cellular composition and presence of t(11,19) translocation was found.

Verrucous localized lymphedema of genital areas: clinicopathologic report of 18 cases of this rare entity.

BACKGROUND: Localized lymphedema is a nonneoplastic condition associated with obesity and predominantly involving the legs. This condition has distinctive clinical and histologic features and only rarely has been mentioned in the dermatologic literature. OBJECTIVE: We sought to evaluate the clinical and histopathologic features. METHODS: The clinicopathologic features in patients with localized lymphedema of the genital region were studied. RESULTS: We identified 18 patients with localized lymphedema clinically presenting as large polypoid or verrucous lesions. The patients were 5 men and 13 women with a mean age of 46.5 years. Twelve patients were obese at diagnosis. Thirteen patients presented with tumors involving the vulva, 4 patients with tumors in the penis and scrotum, and 1 patient with scrotal and pubic lesions. Histologically, all cases showed marked dermal edema along with dilated lymphatic spaces, fibroplasia, and verrucous epidermal changes (papillomatous and hyperplastic epidermis). LIMITATIONS: Only 18 cases were included in our study. CONCLUSIONS: This condition is an uncommon and recently described entity that could potentially be clinically and histologically misdiagnosed as a neoplasm; thus, it needs to be included in the differential diagnosis of polypoid and verrucous skin tumors with extensive dermal edema and fibroplasia.

Fibrolipomatous hamartoma of the nerve: a clinicopathologic report of 13 cases.

BACKGROUND: Fibrolipomatous hamartoma of the nerve is a rare benign infiltrating condition of peripheral nerves with prominent cutaneous findings that has not being well described in the dermatologic and dermatopathologic literature. OBJECTIVE: We sought to evaluate the clinical and histopathological features of this rare condition. METHODS: We reviewed the clinicopathologic features of 13 cases to delineate their clinical presentation and histopathologic spectrum. RESULTS: All patients presented with unilateral lesions on the thenar areas, fingers, or both. In 7 cases the lesions presented congenitally and in 6 cases the lesions presented sporadically. Histologically, we found 2 patterns that have only been rarely mentioned before including cases with intraneural perineurioma-like features and cases with marked nerve hyperplasia. LIMITATIONS: Only 13 cases were included in our study. CONCLUSIONS: This condition is an uncommon entity. The diagnosis of this disorder can be highly suspected on its macroscopic features. Predilection of the median nerve and the frequent association with macrodactyly are characteristic clinical findings.