Ixazomib-induced cutaneous necrotizing vasculitis.

Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

Risk stratification in extramammary Paget disease.

Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best-understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki-67, cyclin D1, Mucin 5AC and E-cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research.

Tetraspanin CD151 plays a key role in skin squamous cell carcinoma.

Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared with other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3 (signal transducers and activators of transcription), a regulator of cell proliferation and apoptosis. CD151 also supports protein kinase C (PKC)α-α6ß4 integrin association and PKC-dependent ß4 S1424 phosphorylation, while regulating α6ß4 distribution. CD151-PKCα effects on integrin ß4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including 7,12-dimethylbenz[α]anthracene (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting epidermal growth factor receptor, PKC, Jak2/Tyk2 and STAT3. Hence, CD151 'co-targeting' may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151/laminin-binding integrin complexes.

My approach to atypical melanocytic lesions.

Histological assessment of melanocytic naevi constitutes a substantial proportion of a dermatopathologist's daily workload. Although they may be excised for cosmetic reasons, most lesions encountered are clinically atypical and are biopsied or excised to exclude melanoma. Although dysplastic naevi are most often encountered, cytological atypia may be a feature of several other melanocytic lesions, including genital type naevi, acral naevi, recurrent naevi, and neonatal or childhood naevi. With greater emphasis being given to cosmetic results, and because of an ever increasing workload, several "quicker and less traumatising" techniques have been introduced in the treatment and diagnosis of atypical naevi including punch, shave, and scoop shave biopsies. A major limitation to all of these alternatives is that often only part of the lesion is available for histological assessment and therefore all too frequently the pathologist's report includes a recommendation for complete excision so that the residual lesion can be studied. Complete or large excision of all clinically atypical naevi permits histological assessment of the entire lesion, and in most cases spares the patient the need for further surgical intervention.

Cytologic findings in granular cell tumors, with emphasis on the diagnosis of malignant granular cell tumor by fine-needle aspiration biopsy.

BACKGROUND: Granular cell tumors (GCTs) are uncommon tumors of putative schwannian derivation that are rarely malignant. Although recent studies have addressed a histologic correlation with malignant behavior, similar studies have not been done on cytologic material. METHODS: The authors evaluated 3 malignant GCTs and 17 benign GCTs (comprising 17 fine-needle aspiration biopsy samples and 3 samples from direct scrapes) for the following cytologic features: hyperchromasia; coarse chromatin; nuclear-to-cytoplasmic (N/C) ratio; nuclear pleomorphism; and vesicular nuclei with enlarged nucleoli, mitoses, necrosis, and spindle cell morphology. RESULTS: Hyperchromasia, coarse chromatin, increased N/C ratio, nuclear pleomorphism, and vesicular nuclei with enlarged nucleoli and spindle cell morphology were associated the most closely with malignancy when they were present throughout the cytologic sample. All were diffusely present in three of three malignant tumors, except vesicular nuclei and spindle cell morphology, which were present diffusely in two tumors and focally in one tumor. By contrast, although one to five of these features were present focally in 8 of 17 benign GCTs, none was present diffusely in any benign GCTs, with one exception, which had a combination of focal nuclear pleomorphism and hyperchromasia together with diffuse vesicular nuclei, large nucleoli, and coarse chromatin. The N/C ratio in this tumor was not increased, and there were no spindle cells or mitoses. Mitoses were present in 2 of 3 malignant GCTs and absent from all 17 benign GCTs. Necrosis was not seen in any tumors. CONCLUSIONS: Malignant GCTs have characteristic cytologic features that differ from those of benign GCTs. However, morphologic heterogeneity precludes definitive classification of some tumors by cytologic features alone.

Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature.

Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus. Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses. Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm. We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.

Microphthalmia transcription factor: not a sensitive or specific marker for the diagnosis of desmoplastic melanoma and spindle cell (non-desmoplastic) melanoma.

Microphthalmia transcription factor (Mitf), a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, Mitf expression was shown to be both a sensitive and specific marker of epithelioid melanoma. Because loss of specific melanocytic markers in melanomas with spindle cell morphology is more common compared with those tumors with epithelioid morphology, we investigated the sensitivity of D5, an anti-Mitf antibody, for diagnosis in this diagnostically problematic subset of melanomas. Twenty of 21 (95%) spindle cell and desmoplastic melanomas examined were reactive for S-100 protein. Only 4 of 21 (19%) spindle cell and desmoplastic melanomas were reactive for HMB-45. Six of 21 tumors (29%) were reactive for D5, including one case that was non-reactive for S-100 and HMB-45. Melan-A reactivity was seen in 2 of 13 cases (15%) studied. Eight of 24 (33%) non-melanocytic spindle cell tumors were reactive for D5, including 4 of 6 dermatofibromas, 1 of 6 schwannomas, 1 of 2 leiomyomas, and 2 of 6 leiomyosarcomas. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study show it is not a sensitive or specific marker of spindle cell and desmoplastic melanomas. Nevertheless, we believe that diffuse positive staining for D5 when taken in clinical, histologic and immunohistochemical context may be diagnostically useful in selected cases of melanoma.

Papanicolaou smear sensitivity for the detection of adenocarcinoma of the cervix: a study of 49 cases.

BACKGROUND: Papanicolaou smear sensitivity for cervical adenocarcinoma (CVCA) is not well established. Also uncertain are the relative contributions to falsely negative diagnoses of sampling, screening, and interpretive errors. METHODS: Papanicolaou smears were identified from all patients at our institutions with biopsy-proven cervical adenocarcinoma from 1988-1998. All available negative and unsatisfactory smears were reviewed. RESULTS: Of 49 patients with CVCA, 66 smears initially diagnosed as negative and 4 smears initially diagnosed as unsatisfactory from 30 patients were identified. Thirty-two negative smears and 4 unsatisfactory smears from 19 patients were available for review. The retrospective diagnoses in the cases initially called negative were: unsatisfactory in 2, negative in 15, and atypical glandular cells consistent with either adenocarcinoma in situ (AIS) or CVCA in 15. Three of four smears initially called unsatisfactory had neoplastic glandular cells identified retrospectively. The 18 falsely negative or falsely unsatisfactory smears were from 13 patients obtained up to 5 years before biopsy diagnosis. These smears contained neoplastic cells likely to have been mistaken for lower segment endometrial cells (LUS) or endocervical cells with tubal metaplasia (TM) in 11, reactive endocervical cells in 6, and both in 1. In 16 of the 18 smears, the abnormal cells were abundant, although preservation was suboptimal in 6. CONCLUSIONS: Sensitivity of a single Papanicolaou smear for CVCA was between 45% and 76% depending on the classification of negative slides that were not available for review, comparable to previously reported sensitivity for AIS. The diagnostic false-negative or false-unsatisfactory rate in reviewed smears was 50% (18 of 36). Diminished sensitivity is due to the under recognition of glandular neoplasia resembling LUS, TM, or reactive endocervical cells. Cancer (Cancer Cytopathol)

Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called 'malignant blue nevus'.

The term "malignant blue nevus" refers to a rare and heterogeneous group of melanomas that arise in several clinical settings. This includes melanomas arising in association with a common or cellular blue nevus and those arising de novo and resembling cellular blue nevi. We reviewed the clinicopathologic features of 10 cases of malignant blue nevi. Six cases proved to be de novo melanoma mimicking cellular blue nevus, but lacking a clear-cut benign component. Two melanomas arose in association with a common blue nevus, and two with a cellular blue nevus. The patients' (5 males, 5 females) ages ranged from 11 to 77 years (average age, 48.1 years). The head and neck was the most common location (6 of 10 patients), with five scalp tumors. Four tumors were located on the trunk; none was located on the extremities. Tumor size ranged from 0.5 to 2.2 cm (average size, 1.1cm). Most lesions had been present for many years before surgical removal. Pigmented dendritic cells were observed in 9 of 10 cases. The malignant and benign components were easily distinguished in the four cases that arose in association with a common or cellular blue nevus. Abrupt transition between a benign blue nevus and melanoma was readily recognized at scanning magnification as distinctive nodules of epithelioid to spindled cells with a sheet-like growth pattern. In all cases, malignancy was evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli. All 7 patients with follow-up information experienced recurrence (3 patients) or metastasis (4 patients). Three patients died of disease. Malignant blue nevus is a heterogeneous group of melanomas that are highly aggressive and often lethal, with a propensity for metastasis to the lymph nodes and lungs.

Clear cell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation.

Microphthalmia transcription factor, a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master regulator in modulating extracellular signals. Recently, microphthalmia transcription factor expression was shown to be both a sensitive and specific marker of epithelioid melanoma. We investigated the sensitivity of D5, an anti-microphthalmia transcription factor antibody, for diagnosis of clear cell sarcoma (also known as malignant melanoma of soft parts). Immunoreactivity in a nuclear pattern for D5 was present in 8 of 12 (75%) tumors. D5 staining was strong in three tumors, moderate in two, and weak in three. S-100 protein expression was seen in all 12 cases that had clear cell sarcoma examined. HMB-45 staining was seen in 11 of 12 (92%) tumors. Focal Melan-A positivity was seen in 3 of 7 (43%) tumors. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study expand the spectrum of tumors showing immunoreactivity for D5. D5 immunoreactivity in clear cell sarcoma provides further evidence for melanocytic differentiation in this unusual tumor.

Metastatic, sarcomatoid, and PSA- and PAP-negative prostatic carcinoma: diagnosis by fine-needle aspiration.

Fine-needle aspiration of prostatic carcinoma usually yields an acinar carcinoma that is immunoreactive for prostatic-specific antigen (PSA) and prostatic acid phosphatase (PAP). We report on two FNAs of metastatic sarcomatoid prostatic carcinoma that were PSA- and PAP-negative. Our methods included a review of the medical records and pathology results. Both cases presented with elevated serum PSA levels and prostate needle biopsies with Gleason score 8 and 9 tumors, respectively. Both cases developed retroperitoneal/pelvic lymphadenopathy, and fine-needle aspirations were performed. These showed high-grade, sarcomatoid tumors with marked anisonucleosis. Immunocytochemical staining for PSA and PAP was negative in both cases. Clinical and radiologic evaluation failed to reveal any other potential primary sites. Metastatic, sarcomatoid, PSA- and PAP-negative prostatic carcinoma is a rare diagnosis of exclusion that should be considered in the characteristic clinical setting.

Immunohistochemical distinction of epithelioid histiocytic proliferations from epithelioid melanocytic nevi.

Histiocytic tumors can be confused with melanocytic nevi and malignant melanoma and vice versa. To explore the use of immunohistochemistry for this diagnostic problem, we examined the expression of S-100 protein, gp100 (the antigen recognized by HMB-45), tyrosinase (T311), Melan-A (A103), Factor XIIIa (FXIIIa), and CD68 in 10 juvenile xanthogranulomas (JXGs), five epithelioid histiocytomas (EHs), and 15 melanocytic nevi composed of large epithelioid cells. All epithelioid melanocytic nevi were immunoreactive for Melan-A, tyrosinase, and S-100 protein in most melanocytes. Four nevi were completely negative with HMB-45. Nine nevi had only a minor HMB-45-positive component in the superficial dermis. Two nevi were diffusely HMB-45-positive. Melanocytes in all nevi were completely negative for FXIIIa. Thirteen nevi were completely negative for CD68. Two nevi contained rare cells with weak staining for CD68. All 15 histiocytic proliferations were completely negative for Melan-A, tyrosinase, and gp100. They lacked expression of S-100 protein or had at most 10% immunopositive cells. In JXGs, most cells were strongly reactive for CD68, although only a few were positive for FXIIIa. In EHs, 40% to 60% of cells were immunoreactive for FXIIIa, and only 20% to 30% were positive for CD68. Our results demonstrate that Melan-A and tyrosinase are sensitive and specific markers to distinguish epithelioid melanocytic nevi from epithelioid histiocytic tumors.

Adenoid basal carcinomas of the cervix: a unique morphological evolution with cell cycle correlates.

Adenoid basal carcinoma (ABC) is a rare cervical carcinoma of postmenopausal women composed of small basal-type (basaloid) cells with focal endocervical ("adenoid") differentiation. ABCs are associated with high-grade squamous intraepithelial lesions (HSIL) and contain integrated human papillomavirus type 16 DNA. However, ABCs have a favorable prognosis and do not metastasize. Five (5) ABCs were analyzed histologically for a marker distinguishing basal/ squamous from columnar (adenoid) differentiation (p63) and cell cycle activity (Ki-67), and compared with 20 cervical (CC) carcinomas. In contrast to other CCs, ABCs contained 4 distinct components, including (1) a classic HSIL; (2) a limited invasive component with squamoid maturation, often with a discrete layer of peripheral basal cells; (3) outgrowth of small basal cells from either HSIL or squamoid areas; (4) focal endocervical (adenoid) differentiation. ABCs showed distinct differences in cell cycle activity relative to CCs. Ki-67 positivity was high in associated HSILs but remained high and concentrated in the suprabasal cells of the invasive squamoid component of ABC. Moreover, proliferative index was variable to sharply reduced in areas of basaloid and adenoid differentiation, in contrast to conventional CCs. ABC is a unique neoplasm, not only by its transition through multiple phenotypes during invasion, but also by a proliferative index that is high in more mature neoplastic cells during the infiltrative process and reduced with progressive basal differentiation. The precise mechanism underlying this unique process of tumor evolution is unclear. However, the postmenopausal status of these patients suggests that host factors related to aging may influence tumor evolution and morphology after HPV 16 infection.

Malignant eccrine spiradenoma (spiradenocarcinoma): a clinicopathologic study of 12 cases.

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.

Epidermal growth factor, estrogen, and progesterone receptor expression in primary sweat gland carcinomas and primary and metastatic mammary carcinomas.

The distinction between primary sweat gland carcinomas and metastatic breast carcinoma to the skin is sometimes difficult. In an effort to improve this discrimination, we compared the immunohistochemical staining pattern of 42 primary sweat gland carcinomas (SGCs) with 30 metastases from breast carcinoma (BC) to the skin, 125 primary BCs, and 30 noncutaneous metastases from BCs. The antibodies used were against the receptors for epidermal growth factor (EGF-R), estrogen receptor (ER), and progesterone receptor (PR). The frequencies of positive staining were as follows for EGF-R: 34 (81%) of 42 SGCs, 5 (17%) of 30 BCs metastatic to skin, 28 (22%) of 125 primary BCs, and 6 (20%) of 30 noncutaneous BC metastases. For ER, the frequencies were 9 (21%) of 42 SGCs and 10 (33%) of 30 BCs metastatic to skin. The frequencies for PR were 8 (19%) of 42 SGCs and 8 (27%) of 30 BCs metastatic to skin. These results suggest that expression of EGF-R may be diagnostically helpful, because it is strongly associated with SGCs when compared with metastatic BCs (P < .0001). This association is also present when ductal eccrine and apocrine types of SGC, which are the histologic subtypes of SGC most difficult to distinguish from metastatic BC, are separately analyzed (P < .001). The frequencies of expression of ER and PR in SGCs and BCs metastatic to skin were not significantly different.

Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes.

Renal cell carcinomas in children and young adults are rare, and the pathologic features of these tumors have not been well described. We reviewed 24 renal cell carcinomas in children and young adults ages 6 to 29 years, 14 of whom were younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the tumor met histologic criteria for papillary renal cell carcinoma, with at least 50% papillary architecture. Four of the remaining five cases were typical clear cell tumors in patients known to have von Hippel Lindau syndrome, and one case was of chromophobe type. In the papillary tumors, calcifications, high nuclear grade, extracapsular extension (American Joint Commission on Cancer stage T3), and lymph node metastases were common. Among these papillary tumors, four distinct histologic patterns could be identified. Collecting duct-like tumors (two cases) involved the large collecting ducts, were multifocal and predominantly papillary, and had focal tubular and solid areas. These tumors were reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but negative for Ulex europeaus and high molecular weight keratin 34BE12. Voluminous cell tumors (four cases) were composed of cells with extremely voluminous clear cytoplasm and, although predominantly papillary, had areas that also resembled clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were otherwise negative for all other keratins, EMA, and U. europeaus. One of these tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled papillary tumors of adults. These tumors were reactive for EMA and keratins, including CK7, and all but one were negative for U. europeaus and keratin 34BE12. This last case had trisomies of chromosomes 7, 16, 17, and 20. The final neuroendocrinelike case was multifocal, organoid, and composed of nests of small cells in a neuroendocrinelike pattern. Three of 13 patients were alive with disease at last follow-up, and three additional patients died of disease, all within 2 years. Progression was highly associated with lymph node involvement at the time of resection. We conclude that the clinicopathologic features of renal cell carcinomas in children and young adults differ from those arising in older adults. These tumors are characteristically high-grade, high-stage, papillary tumors with numerous calcifications, and several subtypes can be identified based on histologic, immunohistochemical, and cytogenetic features. Some subtypes appear to be unique to this age group.