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Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive monogenic autoinflammatory syndrome that is classically characterised by polyarteritis nodosa, systemic vasculitis and stroke. The spectrum of disease manifestations has broadened to encompass a range of cutaneous, vascular and haematological manifestations. We report a novel association in two sisters with heterozygous p.R169G/p.M309l mutations in ADA2 with low serum ADA2 activity who both presented similarly with clinical and histological features consistent with histiocytoid Sweet syndrome.

The distinction between nevoid melanoma and a mitotically active nevus can be challenging at the microscopic level. In this study, we performed cytogenetic testing on a cohort of 25 mitotically active melanocytic proliferations resembling common melanocytic nevus from 25 patients. Based on cytogenetic findings, the lesions were classified as "nevoid melanoma" (n = 13) or "mitotically active nevus" (n = 12). Subsequently, we compared the clinicopathological features between these 2 groups. Nevoid melanomas occurred in older patients (P = 0.007); however, there were no significant differences in gender, size, or anatomical distribution between the 2 groups. Histologically, deep/marginal mitoses (P = 0.006), lack of maturation with depth (P = 0.036), and pseudo-maturation (P = 0.006) were significantly more common in nevoid melanomas. Immunohistochemically, complete loss of p16 was an important divisive feature (P = 0.0004), seen in 70% of nevoid melanomas, and highly correlated with loss of CDKN2A gene (chromosome 9p21). Our findings suggest that such reproducible immunomorphological differences can be of value in distinguishing nevoid melanoma from mitotically active nevus. Nevoid melanomas demonstrated a spectrum of chromosomal aberrations similar to those seen in common subtypes of melanoma, which can serve as a powerful adjunct diagnostic tool in morphologically challenging lesions.

Squamoid eccrine ductal carcinoma is a poorly documented skin adnexal carcinoma showing squamous and duct differentiation. It is regarded to be of low-grade malignant potential, but limited follow-up information is available. To study their clinical behavior and histologic features, 30 squamoid eccrine ductal carcinomas were identified from departmental and referral files. Hematoxylin and eosin-stained sections were reviewed, and immunohistochemistry for carcinoembryonic antigen and epithelial membrane antigen was examined to confirm duct differentiation. Clinical follow-up was obtained from patient records and referring pathologists. The tumors presented as nodules or plaques (median size, 1.0 cm; range, 0.5 to 2.5 cm) with a predilection for the head and neck (77%). The patients were elderly (median age, 79.5 y; range, 10 to 96 y) with a male predominance. Histologically, these poorly demarcated tumors were characterized by an infiltrative growth pattern within the dermis and additional invasion of subcutis in 70%. Median tumor thickness was 4.3 mm (range, 1.5 to 18 mm). Superficially, the tumors resembled well-differentiated squamous cell carcinoma. In the deeper reaches, they were organized in cords and strands showing duct differentiation in a desmoplastic stroma. Cytologic atypia was moderate to severe. Ulceration (47%), necrosis (23%), and perineural and lymphovascular infiltration (27% and 6%, respectively) were additional features. Follow-up data (median, 29 mo; range, 7 to 99), available for 24 patients (80%), revealed a local recurrence rate of 25%. Three patients had lymph node metastasis, and 1 patient died of metastatic disease. Our study outlines the histologic characteristics of squamoid eccrine carcinoma and emphasizes its clinical behavior with risk for local recurrence and potential for more aggressive behavior with metastasis and rare disease-related mortality.

This study examines clinical and pathologic features of primary cutaneous adenoid cystic carcinoma (ACC), with emphasis on biological behavior of these tumors. A total of 27 cases of primary cutaneous ACC with detailed follow-up information were evaluated. Clinically, these were solitary, slow-growing lesions, half of which were in the head and neck area. The median age was 62 years with a male predilection. Surgical excision was the treatment of choice. Histologically, the lesions were similar to those seen in the salivary glands. Tumors were classified as grade 1 (17), grade 2 (3), and grade 3 (7). The mitotic count was generally low (mean=1.9/mm), except in 2 high-grade tumors (10 mitotic figures/mm). Sixteen cases showed perineural invasion. Immunohistochemically, cytokeratin positivity was noted in 13/13 cases, and CD117 was observed in 10/10 cases, with luminal/cytoplasmic staining for epithelial membrane antigen (14/16) and at least focal luminal expression for carcinoembryonic antigen (11/16), smooth muscle actin (10/13), and S100 staining (9/13). Eighteen cases had follow-up data (median 54 mo), 9 of which had local recurrences (50%). Three cases showed metastatic disease. No statistical difference was noted between tumor grade and local recurrence (P=0.77). Primary cutaneous ACC is a distinct entity with a more indolent behavior compared with its salivary counterpart. The cutaneous lesions tend to recur locally but have a low metastatic potential.

Lymphomatoid papulosis (LyP) is defined as a chronic recurrent skin disease characterized by waxing and waning papules and nodules with histologic features of a CD30-positive T-cell lymphoma. Three histological subtypes (A, B, and C) were already recognized, and only more recently, a further variant simulating histologically an aggressive epidermotropic CD8-positive T-cell lymphoma was described, which was named LyP type D by the authors. We report the case of a 38-year-old woman presenting with a 1-year history of recurrent self-healing papules and nodules, predominantly affecting her upper and lower limbs but also the face, including the lower lip, with no associated systemic symptoms. A biopsy from 1 lesion revealed an infiltrate of atypical lymphoid cells extending throughout the dermis with massive epidermotropism displaying a pagetoid reticulosis-like pattern and a CD8(+)CD30(+) cytotoxic T-cell phenotype. The clinicopathologic features conformed to the newly described type D variant of LyP. Diagnostic studies did not reveal any systemic involvement, and the patient remains otherwise well with no active treatment. In the present report, we discuss the need for clinicopathologic correlation to establish an accurate diagnosis and its importance for an adequate management of these patients.

Bacillary angiomatosis (BA) is an increasingly reported infection, mainly in patients with acquired immunodeficiency syndrome. Different epidemiological risk factors are associated with the transmission of the causative agents, Bartonella henselae and B. quintana. Vulval BA is described rarely. Two patients presented with a vulval mass (Patient 1) and a verrucous vulval growth (Patient 2), which were diagnosed clinically as tuberculosis and carcinoma, respectively. Patient 1 also had pulmonary tuberculosis and Kaposi sarcoma. Biopsy of the vulval lesions confirmed BA, characterized by a multilobular proliferation of blood vessels that were lined by epithelioid endothelial cells. There were prominent intervascular neutrophils, karyorrhectic debris, and clumps of paravascular argyrophilic organisms. The biopsy from Patient 1 was deep dermal/subcutaneous in location and displayed foci of confluent suppuration. There was florid pseudoepitheliomatous hyperplasia in the biopsy from Patient 2. Molecular investigations confirmed intralesional B. quintana, hitherto unreported in vulval BA, as the causative agent in both biopsies. On follow-up, Patient 2 had developed additional lesions in the vulva and thigh, but all her lesions and the vulval mass (Patient 1) responded to erythromycin treatment. Patient 1 succumbed to tuberculosis. Heightened recognition of BA underpins rapid and optimal clinicopathological diagnosis, even in uncommon locations. Identification of the causative Bartonella species is important for appropriate, interventive social management.

Sebaceous neoplasms are commonly considered in their relationship to the Muir-Torre syndrome and the now well-documented loss of DNA mismatch repair proteins leading to microsatellite instability. However, sebaceous neoplasms showing microsatellite instability comprise only a subset of this group of tumors, and thus, alternative tumorigenic mechanisms must exist. This article explores the relationship of p53, a tumor suppressor implicated in other cutaneous malignancies, and sebaceous neoplasia. We examined 94 sebaceous tumors from 92 patients. Tumors with strong nuclear p53 staining were significantly associated with the diagnosis of sebaceous carcinoma compared with benign sebaceous lesions, most notably for periocular carcinomas. Importantly, nuclear mismatch repair protein expression was intact in all lesions showing p53 alterations, suggesting that p53 dysfunction may represent a divergent pathway in the molecular pathogenesis of these tumors.

Epithelioid angiosarcomas are rare aggressive neoplasms that occur most frequently in deep soft tissues. Primary cutaneous lesions are rare, and there are discrepant findings in the literature regarding their behavior. In this study, we report a series of 13 cases of primary cutaneous epithelioid angiosarcoma and analyze their clinicopathologic features. The tumors arising in the conventional settings for cutaneous angiosarcoma (ie, in the head and neck region of elderly patients, and those occurring postradiation or associated with lymphedema) were excluded. Primary cutaneous epithelioid angiosarcoma occurred in adults (mean age, 66 y) with an equal sex distribution, and presented as solitary (n = 10) or multiple (n = 3) nodules ranging in size from 8 to 80 mm, with a predilection for the limbs (n = 10). Histopathologically, the tumors comprised infiltrative sheets of atypical epithelioid cells within the dermis with or without the involvement of the subcutis. Vascular channel formation and intracytoplasmic lumina were seen, at least focally, in most cases. Mitoses were readily identified and necrosis was seen in 40% of the cases. The tumors were immunoreactive for vascular markers, with CD31 and FLI-1 offering the highest sensitivity. Pancytokeratin was positive in two thirds of the cases, and epithelial membrane antigen was positive in one-quarter of the cases. There was rare focal expression of Melan-A (n = 2) and smooth muscle actin (n = 3). Follow-up information was available for 11 patients. Six patients died of metastatic disease after a median follow-up of 12 months (range, 3 to 36 mo), and 1 patient died of unrelated causes. These findings suggest that primary cutaneous epithelioid angiosarcoma occurring outside the conventional settings of angiosarcoma is a highly aggressive malignant tumor with mortality rates in excess of 55% after 3 years.

The clinicopathologic features of 4 AIDS patients with cutaneous colesional Kaposi sarcoma (KS) and cryptococcosis, a rare phenomenon, are described. Biopsies from 3 patients who were highly active antiretroviral therapy (HAART)-naive demonstrated predominant KS with a conspicuous spindle cell component and small aggregates of cryptococcal yeasts in 2 biopsies and predominant gelatinous cryptococcosis with attenuated KS spindle cells in 1 biopsy. One patient was HAART exposed. He had childhood pulmonary tuberculosis, was treated for disseminated cutaneous cryptococcosis 18 months earlier and presented with cutaneous lesions, odynophagia and massive cervical lymphadenopathy in the eighth week of HAART, after achieving viral suppression and a CD4 cell increase from 28 to 184 cells/μL. His skin biopsy demonstrated a dense lymphoplasmacytic infiltrate, neutrophils, and granulomas with admixed aggregates and single Cryptococcus neoformans and focal aggregation of human herpes virus 8-immunopositive spindle cells. Acid fast bacilli were not identified and mycobacterial molecular studies were negative. The features were compatible with cutaneous cryptococcal immune reconstitution inflammatory syndrome. His nodal and oropharyngeal biopsies demonstrated dense mixed, including granulomatous, inflammation with few cryptococcal yeasts and acid fast bacilli, confirmed to be Mycobacterium tuberculosis on polymerase chain reaction testing, without KS. These features were also compatible with immune reconstitution inflammatory syndrome, but the exact role of each infection in the extracutaneous sites was unconfirmed. Colesional KS and cryptococcosis served as the sentinel lesion of AIDS in 3 patients and of immune reconstitution inflammatory syndrome in 1 patient.

We performed immunohistochemical assessment of p53 expression and TP53 mutational analysis of 15 malignant neoplasms arising from preexisting benign cylindroma, spiradenoma, and spiradenocylindroma, sporadic or associated with Brooke-Spiegler syndrome. At least weak and focal p53 positivity was present in 13 of the 15 lesions. Successful PCR and sequencing were possible in 12 of the 15 cases. In one case only there were 2 p53 mutations, one being a c.673-1G>A splice-site mutation in the 3'-end of intron 6 (position--g.15289G>A, contig gb.AY838696.1) and the second being a c.743G>A (p.R248Q) mutation in exon 7 (position--15360G>A, contig gb.AY838696.1). Single nucleotide polymorphisms were detected in all 12 malignant cases analyzed. As a control group, we included 12 randomly selected sporadic cases of spiradenoma (n = 5), cylindroma (n = 4), and spiradenocylindroma (n = 3). None of the 12 benign control group cases harbored a TP53 mutation, whereas all 12 demonstrated single nucleotide polymorphisms identical to those detected in the malignant tumor group. Immunohistochemically, 1 cylindroma and 2 spiradenomas demonstrated weak and focal p53 positivity. In conclusion, we found a fairly high rate of p53 expression in malignant neoplasms arising from preexisting benign spiradenomas, cylindromas, and spiradenocylindromas. However, the mutation rate of TP53 was low. Whereas immunostaining for p53 has been suggested as an adjunct tool to differentiate benign spiradenoma, cylindroma, and spiradenocylindroma from their malignant counterparts, its utility is limited by its heterogeneous pattern of expression, especially the sometimes lack of staining in clearly malignant areas and the occurrence of focal, weak positivity in the benign residua or in unequivocally benign neoplasms.

Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.

AIDS-associated otic pneumocystosis is rare. Of 14 cases documented mainly as case reports up to now, only 1 has been reported in the surgical pathology literature. We report 6 males, mean age of 32.3 years, with external auditory canal masses and otorrhea. Two biopsies contained a predominance of granulation tissue with a mixed inflammatory cell infiltrate and elusive foci of foamy exudate. In contrast, 4 biopsies demonstrated conspicuous angiocentric mantles of stippled, foamy exudate. Fibrin was noted in intravascular, perivascular, and intervascular locations. One biopsy demonstrated bordering of the foamy exudate by a palisaded granulomatous reaction, with adjacent discrete giant cell-containing granulomas. Special stains confirmed trophozoites and cysts within the foamy exudate. Review of 2 initial "nondiagnostic" biopsies confirmed granulation tissue and necrotic debris in which Pneumocystis jiroveci was identified in focal foamy exudate. After the diagnosis of otic pneumocystosis, all patients were initiated on trimethoprim-sulfamethoxazole. One patient also had dapsone. Two patients succumbed to pulmonary tuberculosis and 2 were lost to follow-up. One patient with pneumocystis pneumonia did not return for follow-up after 6 weeks. One patient experienced complete resolution of the mass on medical therapy, and is disease free for 4 years. Heightened recognition of the characteristic foamy exudate in an unconventional location remains the gold standard in the timely diagnosis of this eminently treatable disease. In all patients, otic pneumocystosis served as the sentinel of underlying HIV infection and AIDS.

Cutaneous sebaceous neoplasia is known to exhibit a high degree of DNA mismatch repair (MMR) deficiency leading to microsatellite instability and these tumors can be markers of the Muir-Torre syndrome and internal malignancy. Other tumors, such as colonic carcinoma, show tendencies toward particular histologic features and sites of involvement correlating with MMR deficiency. There are few comprehensive studies of unselected cutaneous sebaceous neoplasms. To address this gap in knowledge, we examined 94 sebaceous neoplasms from 92 patients and 17 sebaceous hyperplasia controls using immunohistochemistry for MLH1, MSH2, and MSH6. Our results indicate that MMR deficiency is significantly associated with anatomic location (more frequently in the trunk and extremities as compared with head and neck), tumor type (more often in adenoma compared with carcinoma within the head and neck region), and architecture (keratoacanthomalike). No correlation between cystic change and MMR deficiency was noted. Cutaneous sebaceous neoplasia has tendencies toward certain tumor types and anatomic distribution based on MMR status analogous to that seen in colonic carcinomas and other tumors. These may be helpful indicators for further workup for the Muir-Torre syndrome.

Primary cutaneous apocrine carcinoma is a rare malignancy. This study of 24 examples suggests that the prognosis is not always poor and that grading criteria devised for breast carcinoma may have utility in this group of malignancies. Furthermore, steroid receptor expression should be investigated in these tumors, particularly if a tumor is unlikely to be controlled by surgery alone.

Presented here are three cutaneous sebaceous tumors (one carcinoma and two sebaceomas), each demonstrating a focal glandular pattern representing apocrine differentiation. The patients, two males and one female, each clinically presented with a small solitary nodule or tumor on the scalp. None of the patients had features of Muir-Torre syndrome. Surgical removal of the lesions was performed in all cases. None of the patients developed recurrence or metastasis after surgery (follow-up ranged from 18 to 24 months). The glandular areas represented a minor but significant component of the lesions and appeared as glands of various complexity, mostly as simple round or elongated tubular structures lined by a row of cuboidal to columnar cells with eosinophilic cytoplasm and round nuclei, with or without a distinct nucleolus. Decapitation secretion was evident but not prominent. In both sebaceomas, at least a portion of the glands had a peripheral small-cell layer that appeared similar to the basal/myoepithelial cells of normal eccrine and apocrine ducts. In some glands, the basal/myoepithelial cells seemed to have undergone hyperplasia, resulting in two or more rows of cells that even formed small islands, with an overall appearance reminiscent of basal cell hyperplasia in the prostate, arising in the basal layer of the prostatic glands. The descriptive terms seboapocrine carcinoma or seboapocrine sebaceoma are proposed for such lesions. These tumors may be viewed as rare histopathological variants of sebaceous carcinoma and sebaceoma, with a second type of differentiation along the lines of the folliculosebaceous-apocrine unit.

Tubular adenoma (TA) and syringocystadenoma papilliferum (SCAP) may show histopathological overlap, with some lesions having features of both neoplasms (SCAP + TA). TA has been recently suggested to represent a carcinoma. Four observers blindly assessed 67 cases of TA, SCAP, and their lookalikes (poroma, apocrine adenoma, apocrine carcinoma; all lesions focally featuring a pseudopapillary pattern), and classified the lesions into one of four categories: (1) TA, (2) SCAP, (3) SCAP + TA, and (4) others. Lesions were also classified as benign or malignant. In only 29 cases was there unanimous agreement among the four observers, who classified 22 lesions as TA, three as SCAP, and four cases as others. Of the 38 cases where there was interobserver diagnostic variation, in 30, the diagnosis varied between TA or SCAP or SCAP + TA; the remainder fell in the others category. Analysis of the factors leading to interobserver variability indicated that diagnostic problems occurred when there were any of the following: epidermal acanthosis, papillomatosis, connection of the neoplastic tubules to the overlying epidermis and/or follicular infundibula, and plasma cell infiltration. These features accounted for the morphological overlap between TA and SCAP. All observers agreed that the lesions were benign; the only apocrine carcinoma included was recognized as such by all observers. From the study, it was concluded that TA may arise in the deep dermis without any epidermal connection, or, in other cases, it may be more superficially located with or without an epidermal connection. It may be reasonably inferred that, possibly as a response to infection, there may be accompanying plasma cells and variable acanthosis and papillomatosis, such that the appearances are those of "pure" SCAP, or lesions may have features "intermediate" or overlapping between TA and SCAP.

Rosai-Dorfman Disease (RDD) is an idiopathic reactive proliferation of distinctive histiocytes that have abundant cytoplasm and commonly exhibit intracytoplasmic ingestion of inflammatory cells (emperipolesis). The histiocytes are immunopositive for S100 protein and are typically associated with an infiltrate of lymphocytes, plasma cells, and neutrophils. The classic clinical presentation is massive enlargement of (usually) cervical lymph nodes with a histologic appearance that mimics exaggerated sinus histiocytosis. RDD can also involve extra-nodal sites and skin involvement is common either as part of disseminated disease or as a result of primary disease. We report an exceptional case of cutaneous RDD with crystal deposition in a young male presenting with skin nodules. Skin biopsy showed classic features of cutaneous RDD with the additional feature of conspicuous rhomboidal and needle-shaped crystals within the cytoplasm of many lesional plasma cells, histiocytes, and also in an extra-cellular location. The plasma cells were polyclonal by light chain immunostaining. Crystal deposition has not been reported to date in RDD and is likely a result of the reactive plasma cell proliferation.

Pruritus is a common complaint in children who present with vulvar symptoms. Many will have inflammatory dermatoses that can be diagnosed clinically, but there are some unusual causes, which require further investigation to confirm the diagnosis.CASE REPORTWe present an unusual case of vulvar prurit

We report a case of a primary cutaneous alveolar rhabdomyosarcoma presenting on the lower limb of a 60-year old woman. The tumor was characterized by aggregates of round blue cells in an alveolar growth pattern in the dermis and subcutis, with the additional unique finding of epidermotropism. By immunohistochemistry tumor cells were positive for vimentin, muscle-specific actin, desmin, myogenin, and Myo-D1 with focal positivity for CD56, neuron-specific enolase, and S-100 protein. Staining for pan-keratin, HMB-45, melan-A, epithelial membrane antigen, chromogranin, CD99, leukocyte common antigen, and alpha-smooth muscle actin was negative. Interphase fluorescence in situ hybridization analysis from paraffin-embedded tumor demonstrated the presence of the translocation (2;13)(q35;q14) confirming the diagnosis. Further investigations revealed no tumor in the underlying deep soft tissues, and there was no evidence of metastasis in other organs. A local recurrence associated with a metastasis to a regional lymph node on the right groin was treated with an above-knee amputation and local radiotherapy to the groin area. The patient subsequently developed cutaneous metastases in the amputation stump and died 2 years after initial presentation. This case indicates that rhabdomyosarcoma may rarely present in the skin in adults and should be included in the differential diagnosis of primary cutaneous small round blue cell tumors not only in children but also in this age group.

Malignant eccrine spiradenoma is a very rare tumor. The clinicopathologic features of 12 cases are reported herein. Six patients were men, six were women, and the average patient age was 62 years. Seven tumors were located on the trunk, three on the extremities, and two in the head and neck region. All tumors were large (average size-7.5 cm). Lesions had been present from 7 months to 30 years before surgical removal. In all cases, continuity between benign eccrine spiradenoma and areas with malignant change was observed. Malignancy was evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, and hyperchromasia, loss of nested and trabecular growth patterns, and absence of a dual cell population. In most cases (8 of 12), the malignant component comprised the bulk of the lesion. Two distinctive histologic patterns were observed. Five of 12 tumors exhibited abrupt transition between a benign eccrine spiradenoma and a high-grade carcinoma component. The others lacked a clear-cut transition between benign and malignant components and were diagnostically challenging. Diagnosis in such cases was established based on the loss of two cell populations, increased nuclear to cytoplasmic ratio, hyperchromasia, and marked mitotic activity. Two tumors showed focal squamous differentiation. Five of seven patients on whom there was follow-up information were free of disease (average duration of follow-up = 3.4 years). One patient developed metastases to local lymph nodes 5 years after the primary tumor was resected. This patient had no evidence of disease 16 months after resection of her lymph node metastases.

Eight cases of a previously uncharacterized vascular neoplasm, showing varying combinations of benign, low-grade malignant, and malignant vascular components are described. Seven tumors occurred in the dermis and/or subcutis and one occurred in the oral submucosa. The patients were all adults with a median age of 39.5 years (range, 21-71 years). Five patients were men. The tumors arose predominantly in the hands and feet, and the lesions were usually of several years duration. The tumors were composed of a complex admixture of histologic components that varied from tumor to tumor, such that no two tumors looked precisely the same. This was due to variation in the proportions of each component as well as the manner in which each component was distributed throughout each lesion. The predominant histologic components were epithelioid hemangioendothelioma (HE) and retiform HE, which were each present in seven of the tumors. Areas of spindle cell HE were identified in four lesions. Angiosarcoma-like elements were identified in seven tumors. One of the tumors was associated with an arteriovenous malformation and one was associated with an area of lymphangioma circumscriptum. Of six cases with follow up (median duration, 6.5 years), three have recurred locally and, to date, only one has metastasized. We think composite HE is best regarded as a low-grade malignant vascular neoplasm, and the available data suggest that it behaves more favorably than conventional angiosarcoma. The existence of these composite lesions has led to careful reexamination of the concept of HE. The term HE, in that it is currently synonymous with a low-grade malignant vascular tumor, should be reserved for lesions that have true metastatic potential, albeit with low frequency.

The clinicopathologic features of 15 cutanous hemangiomas having a distinctive and frequently pseudomalignant morphologic appearance are presented. There were 5 male and 9 female patients, whose ages at diagnosis ranged from 11 to 58 years (median 30.5). An angiomatous/pigmented, nontargetoid, flat, or exophytic lesion of variable duration was the main presenting sign. The tumor sizes ranged from 0.4 cm to 2 cm (median 1 cm). The locations included the lower limb, particularly the thigh (8); the trunk, including the shoulder area (4); the head (1); the gingiva (1); and the tongue (1). One patient had two lesions; none had a concomitant vascular anomaly or was suspected to have HIV infection. Treatment consisted of excisional biopsy in all cases. Follow-up information on 10 patients (range 4-66 months; median 13 months) showed no recurrence. On microscopic examination, the lesion showed a biphasic pattern characterized by the presence of well-formed, dilated, vascular channels in superficial dermis and a collagen-dissecting, pseudoangiosarcomatous pattern as the lesion infiltrated deeper into the dermis. The lining endothelium consistently showed distinctive hobnail cytomorphology; although there were endoluminal stromal papillae, there was no endothelial multilayering or tufting. Cytologic atypia was minimal or absent, and there were no mitoses. In 3 cases, the morphologic features were reminiscent of retiform hemangioendothelioma. Immunohistochemistry performed in 8 cases showed variable reactivity of endothelial cells with CD31, CD34, Factor VIII-related antigen, and Ulex europaeus agglutinin-1 in all cases; smooth muscle actin-positive pericytes were observed focally around some of the abnormal vascular spaces. The above-described hemangiomatous lesions share many features with so-called targetoid hemosiderotic hemangioma (a clinically descriptive term), but show a variable, often minimal, amount of hemosiderin deposition. The histologically descriptive term hobnail hemangioma is proposed to designate these lesions. Hobnail hemangioma should be distinguished from well-differentiated angiosarcoma, patch-stage Kaposi's sarcoma, and retiform hemangioendothelioma, with which it may be confused.

A case of low-grade trichoblastic carcinosarcoma was reported in 2004. Here we present the second case of this tumor, which, in contrast to the original example, may be classified as a high-grade neoplasm. A 92-year-old man presented with an ulcerated lesion on the left ear. The tumor was excised, and the patient had no evidence of recurrence or metastasis 6 years after surgery. Microscopically, the neoplasm demonstrated a fenestrated growth pattern with a slightly myxoid matrix in the background. Two clear components were identified: the first component was clearly epithelial with formation of small round nests, lobules, delicate strands, and small cribriform structures of basaloid cells with some degree of peripheral palisading, nuclear atypia, focal nuclear crowding, and frequent mitotic figures including abnormal forms. Each epithelial aggregation was invariably surrounded by one to three rows of cells with oval to round nuclei, which appeared very similar to specific trichogenic stroma seen in anagen follicles or in trichoblastomas; however, these stromal cells manifested atypical mitoses and cellular pleomorphism. The epithelial and stromal units frequently formed structures identical to follicular papillae associated with germs or "continuous germs" contiguous with "continuous papillae." Despite the close association throughout the tumor, the epithelial and the stromal cells were sharply separated, without transition between both elements. In foci, these stromal cells lost their follicular papillae-like arrangement and proliferated in a diffuse fashion and gradually blended with highly pleomorphic mononuclear spindle-shaped cells and bizarre multinucleated cells that grew in sheets in a highly vascular stroma. Immunohistochemically, the epithelial component showed diffuse staining for cytokeratins (AE1/AE3) and was negative for vimentin and CAM5.2. The stromal cells were positive for vimentin and negative for cytokeratin markers (AE1/AE3) and desmin. We view the present case and that previously reported in 2004 as authentic carcinosarcomas, and not as metaplastic (sarcomatoid) basal cell carcinomas. This conclusion is reached after analyzing the embryological development of the hair follicle, its normal histology and the morphology of cutaneous adnexal tumors with follicular differentiation.

The accumulation of excessive amounts of melanin in melanocytic lesions can obscure cellular morphology and can further hinder immunocytochemical procedures. We have used a modification of the potassium permanganate/oxalic acid melanin-bleaching technique, involving much reduced bleaching times, in order to remove melanin granules prior to incubation with primary antibody. We have assessed a panel of antibodies applicable to the evaluation of melanocytic lesions and in addition have also assessed antibodies that may be more useful in research. The study attempts to determine which antigens may be affected by bleaching and which are not. Antigens S100, HMB 45, NKIC3, CD34, and L26 are relatively unaffected by this procedure. Factor-VIII-related antigen and vimentin and CD68 antigens produced enhanced staining. In contrast, antigens CD3, CD31, and CD45RO were abolished. In addition, smooth muscle actin and desmin antigens demonstrated considerable nonspecific background staining and were not reliable in this study. This technique demonstrates that a fairly wide range of antigens are preserved after bleaching and that distinction between melanocytes and melanophages can reliably be performed using the conventional immunocytochemical chromogen 3,3-diaminobenzidine and without the need for elaborate counterstaining.

Epithelioid hemangioendothelioma of soft tissues (EHE) represents a distinct entity with an unpredictable clinical course. We analyzed the clinicopathologic and immunohistochemical features in a series of 30 patients. Patient age range was 16-74 years (median 50); 18 of 30 patients were female. Eight tumors arose in the lower and two in the upper extremities, seven on the trunk, five each in the head/ neck and anogenital regions, two in the mediastinum, and one in the abdomen. Seventeen neoplasms were located in deep soft tissues, nine were subcutaneous or perifascial, and four were dermal; size ranged from 0.4 to 10 cm; in 11 cases the tumor was > 5 cm. Tumors with an infiltrative growth pattern were more common than entirely circumscribed lesions. The tumors were composed histologically of short strands, cords, or small clusters of epithelioid, round, to slightly spindled endothelial cells that formed at least focally, intracellular lumina and were set in a frequently myxohyaline stroma. Thirteen of 30 lesions showed angiocentric growth, which was occlusive in many cases. Immunohistochemically, all cases tested were positive for at least one endothelial marker (CD31, CD34, factor VIII, Ulex europaeus), six of 23 (26%) were positive for cytokeratin, and five of 11 (45%) were positive for alpha-smooth muscle actin. Median follow-up of 36 months (range 2-96) in 24 cases showed local recurrence in three cases and systemic metastases in five cases (21%); four patients (17%) died of tumor. Although more aggressive histologic features (striking nuclear atypia in eight cases, numerous spindled cells in 10, more than two mitoses per 10 high-power fields in nine, and small, more solid angiosarcomalike foci in four cases) tended to be related to poor clinical outcome, there was no clear correlation. Two metastasizing cases showed no histologically atypical features whatever. We suggest that EHE of soft tissue is better regarded as a fully malignant, rather than borderline, vascular neoplasm, albeit the prognosis is better than in conventional angiosarcoma.

We report 19 unusual cases of mixed tumors and myoepitheliomas arising in soft tissues. The neoplasms occurred in 12 males and seven females. The age at diagnosis ranged from 2 to 83 years (mean 35, median 30). Eight tumors arose in the upper limb, six in the lower limb, three in the trunk, and two in the head and neck region. Three cases involved both dermis and subcutis; the remainder arose in subcutaneous (13 cases) or deep subfascial soft tissue (three cases). The most common presenting complaint was a painless swelling, with duration ranging from 2 weeks to 1 year (median 2.5 months). Microscopically, the tumors were predominantly well circumscribed and lobulated. Six cases showed a focally infiltrative margin. Cardinal morphologic features included nests, cords, and ductules of epithelioid cells and/or nests of spindled cells within a hyalinized to chondromyxoid stroma. One tumor was predominantly composed of myoepithelial cells and devoid of epithelial differentiation (i.e., ductules). Cytoplasmic hyaline inclusions were noted in two cases; squamous differentiation was seen in one case. Osteoid production and/or metaplastic bone was observed in three tumors. Chondroid differentiation (usually mature) was seen in four cases. Adipocytic differentiation was seen in two tumors. Mitotic activity was variable but generally scant; atypical mitotic figures were not identified. By immunohistochemistry, 16 of 16 cases expressed pan-keratin; 16 of 17 S-100 protein; six of 14 alpha smooth muscle actin (IA4); two of 10 muscle specific actin (HHF-35); two of 10 desmin; three of 11 glial fibrillary acidic protein; and three of 16 epithelial membrane antigen. Clinical follow-up was available in 10 patients and ranged from 6 months to 20 years (mean 4.25 years, median 2 years). Two patients developed local recurrence; metastasis to lung and lymph nodes were observed in two additional patients. Both of the latter patients died. We believe that these findings expand the concept of cutaneous mixed tumors to include neoplasms composed predominantly of myoepithelial cells and to include tumors arising in deeper subcutaneous and/or subfascial tissues. The clinical behavior of such neoplasms, when arising in soft tissues, may be difficult to predict but is most often benign; however, a minority of lesions metastasize. Until larger studies with longer follow-up are available, treatment and prognostication are probably best based on criteria used in comparable salivary gland tumors.

Myxofibrosarcoma is one of the most common sarcomas in the extremities of elderly patients. We analysed the clinicopathologic features in a series of 75 patients. All patients were adults (range, 22-91 years; median, 66 years) with an approximately equal incidence in men and women. Thirty-five tumors arose in the lower and 25 in the upper extremities, nine on the trunk, two each in the retroperitoneum and the head and neck region, and one each in the pelvis and penis. Forty-eight cases (69.5%) were located in dermal or subcutaneous tissues. Distinctive histologic features included the following: a commonly nodular growth pattern; a myxoid matrix containing elongated, curvilinear capillaries; and fusiform, round or stellate tumor cells with indistinct cell margins, slightly eosinophilic cytoplasm, and hyperchromatic atypical nuclei. These lesions varied from a hypocellular, mainly myxoid, and purely spindle-cell appearance (low-grade neoplasms) to high-grade, pleomorphic (malignant fibrous histiocytoma-like) lesions with multinucleated giant cells, high mitotic activity, and areas of necrosis. Immunohistochemistry in 44 cases revealed only vimentin and occasional actin positivity. Ultrastructurally, tumor cells had a fibroblastic phenotype. DNA flow cytometry and proliferation analysis showed an association between aneuploidy and histologic grade. An average follow-up of 45 months (range, 5-300 months) in 60 cases has revealed local recurrence in 33 cases (54%). Thirteen patients developed metastases, and 13 tumor-related deaths occurred. A short interval to first local recurrence was associated with poor clinical outcome. The rate of local recurrence was independent of histologic grade, but only intermediate and high-grade neoplasms metastasized. The depth of the primary lesion did not influence the incidence of local recurrence. However, in deep-seated neoplasms, the incidence of metastases was higher and the percentage of tumor-related deaths was twice as high as in superficially located lesions, reflecting the fact that deep-seated lesions tended to be higher-grade, larger tumors. Myxofibrosarcoma tends to become progressively higher grade in recurrences, as demonstrated in five cases in our series. The poorly recognized low-grade myxofibrosarcoma is emphasized, as proper diagnosis and treatment and scrupulous follow-up are mandatory to avoid local recurrence and gradual tumor progression to a higher-grade neoplasm that may then metastasize.

A series of seven cases of a previously unrecognized potentially recurrent tumor occurring in the orbit of adult patients is reported. This lesion shows histologic appearances intermediate between, but distinct from, solitary fibrous tumor and giant cell fibroblastoma of soft tissue. Morphologically it is characterised by a richly vascularized, patternless spindle-cell proliferation containing pseudovascular spaces. Multinucleate giant cells (often of floret type) and cells with large, rounded nuclei are present both in the cellular areas and also lining the pseudovascular spaces. The stroma is variably collagenized or sometimes myxoid. Immunohistochemically, the tumor cells exhibit positivity for vimentin and CD34. Follow-up in five cases (median duration 24 months) revealed local recurrence in one patient and persistent tumor in another. The clinical and morphologic features enable distinction of this lesion from both solitary fibrous tumor and giant cell fibroblastoma, and we suggest the designation "giant cell angiofibroma of the orbit".

The unusual occurrence of a glomus tumor within a small, deep dermal nerve is reported. This phenomenon has been described previously only once in the literature. The lesion appeared as a painful cutaneous nodule in the shoulder of a 67-year-old woman. Microscopically, a typical solid, smooth muscle actin-positive glomus tumor was seen, encircled completely by neural tissue in the deep dermis. There was no extension of the tumor beyond the nerve. Immunohistochemically, the nerve fibers surrounding and within the tumor were positive for S-100 protein and neurofilament. The presence of perineurium surrounding the glomus tumor was confirmed by a layer of epithelial membrane antigen-positive cells. In view of the absence of normal glomus bodies in the nerves, an origin from a less specialized perivascular cell is proposed.

Six cases of a distinctive but poorly recognized variant of lymphangiomatosis with predominant or exclusive involvement of the soft tissues of the limb/limb girdle are described. The six patients were male and presented with slowly progressive swelling of the involved limb. The age of onset was at birth (three cases), 3 months (one case), 11 years (one case) and 12 years (one case). Five patients had involvement of the lower extremity and one of the right upper extremity. Three patients had concomitant asymptomatic bone involvement either in the affected limb (two cases) or in distant bones (one case). Only one patient had visceral involvement that was limited to the ipsilateral thorax and was associated with chylothorax. Diagnosis was confirmed in all but one patient by lymphangiography. Treatment consisted principally of surgical reduction with significant clinical improvement. No patient later developed systemic involvement and the clinical course was benign. The bone lesions did not progress in any patient. Histologically, each case was characterised by interconnecting, dilated lymphatic spaces, lined by a single, attenuated layer of endothelial cells, involving the dermis, subcutis, and occasionally, underlying fascia and skeletal muscle with characteristic and extensive "dissection" of collagen and surrounding normal adnexal structures. Despite the absence of red blood cells in the vascular spaces, interstitial hemosiderin deposition was prominent in four cases. As opposed to most cases of lymphangiomatosis, which usually have extensive visceral involvement associated with a very poor prognosis, involvement in this variant is limited almost exclusively to soft tissues of the limb and bone and is associated with good prognosis.

We report seventy-four cases of a distinctive variant of cutaneous fibrous histiocytoma, which is often mistaken histologically for sarcoma and which carries a high local recurrence rate. These tumors appeared most commonly in young or middle-aged adults, with a predominance in men (male/female ratio 1.9:1). Anatomic distribution was wide, with cases occurring mainly in the upper limb/limb girdle (34%), lower limb/limb girdle (27%), and head and neck region (20%). Most lesions had been present for only a few months, and their sizes ranged from 0.5 cm to 2.5 cm in maximum diameter. Twelve (26%) of 46 cases with follow-up (mean duration 3 years) recurred locally, in one case twice. Distinctive histologic features were a commonly fascicular growth pattern, predominance of eosinophilic spindle cells with tapering nuclei, a moderate mitotic rate (mean three per 10 high-power fields), and frequent extension into the subcutaneous fat (33% of cases). In addition, all cases showed at least focal cytologic polymorphism (inflammatory cells, foam cells, giant cells), and 58% showed associated epidermal alterations in common with usual cutaneous fibrous histiocytomas. Nine cases (12%) showed foci of central necrosis. Immunohistochemical studies (ABC method) found only vimentin and very focal smooth muscle actin positivity. Tests for CD34, desmin, S-100, keratin, and Factor XIIIa were negative in all cases. These lesions should be distinguished from dermatofibrosarcoma protuberans and leiomyosarcoma, with which many of these cases were initially confused.

Eight cases of leiomyosarcoma with osteoclast-like giant cells, arising in deep soft tissue, and that mimicked closely the "giant cell variant of malignant fibrous histiocytoma (MFH)," have been studied morphologically and immunohistochemically. The age of the patients ranged from 7 to 88 years (mean, 66.2 years; median, 74 years); five were female patients. Three lesions arose in the lower limbs, two in the buttock, and one each in the shoulder, chest wall, and the floor of the mouth. Follow-up in one case revealed a local recurrence and in two cases systemic metastases. All cases showed, at least focally, interwoven spindle cell fascicles, with the cytologic features of smooth muscle cells, as well as strong positivity for alpha-smooth-muscle actin, muscle actin, and desmin. The morphologically benign osteoclast-like giant cells expressed CD68 but failed to stain with myogenic markers. The association of leiomyosarcoma with prominent osteoclast-like giant cells is not as uncommon as generally believed, being evident in 8.7% of the deep-seated nonvisceral leiomyosarcomas that we have studied. These results provide good evidence for myogenic differentiation in at least a subset of those tumors with morphologic features currently classified as the giant cell variant of MFH. Considering that at least some other reported cases of giant cell MFH appear to be a variant of extraskeletal osteosarcoma, we would suggest that lesions with this distinctive pattern should be more carefully classified according to their apparent line of differentiation.

Fifteen cases of a distinctive type of low-grade angiosarcoma of the skin are described. Most tumors presented in the second to fourth decades of life, the youngest patient being 9 years old and the oldest 78 (mean age, 36 years). There was no sex predilection. Six tumors arose on the lower limb, four on the upper limb, three on the trunk, and one each on the penis and the scalp. One case arose in the setting of chronic lymphedema and another following radiotherapy for carcinoma of the uterine cervix. Distinctive morphologic features were the presence of long arborizing blood vessels arranged in a retiform pattern (reminiscent of normal rete testis) lined by monomorphic hobnail endothelial cells, a very prominent lymphocytic infiltrate in most cases, and the focal presence of papillae with hyaline collagenous cores, similar to those seen in malignant endovascular papillary angioendothelioma (Dabska's tumor). With a median follow-up of 7.25 years in 14 cases, retiform hemangioendothelioma has proved to be a low-grade neoplasm that recurs frequently but has a very low metastatic rate. The single regional lymph node metastasis in this series was from a case with a biphasic pattern in which only the spindle cell component was represented in the metastasis. There have been no tumor-related deaths, underlining the importance of accurate distinction from conventional angiosarcoma. This distinction is facilitated principally by the absence of dissection between individual collagen bundles and the absence of endothelial atypia or mitotic activity. The precise relationship between retiform hemangioendothelioma and Dabska's tumor is uncertain, possibly because cases of the latter may not be homogeneous.

Twelve cases of sinusoidal hemangioma, a distinctive subset of the group of lesions known as cavernous hemangioma, are described. All presented as solitary subcutaneous/deep dermal lesions in adults, predominantly females. Five arose on a limb and five on the trunk; two of the latter were situated in mammary subcutaneous tissue. Histologically they were characterized by dilated, interconnecting, thin-walled vascular channels that frequently showed a pseudopapillary pattern. These vessels had a predominantly lobular architecture but peripherally showed focally ill-defined spread into subcutaneous tissue. The lining endothelium was single-layered but showed focal pleomorphism and hyperchromasia, which, combined with the pseudopapillae and apparent infiltrative pattern in areas, raised the possibility of angiosarcoma in four cases, most notably in the breast lesions. This possibility was further suggested by the presence of pseudonecrotic central infarction in two cases. Follow-up in eight cases, however, has revealed no tendency for either local recurrence or metastasis.