Proliferative activity in melanocytic nevi from patients grouped by age with clinical follow-up.

Any mitotic activity in a melanocytic nevus is a source of concern about the biologic potential of that lesion, especially in an adult. Previously diagnosed benign melanocytic nevi in individuals from six different age groups were re-examined; mitotic figures were counted in routine hematoxylin and eosin-stained sections; Ki-67 nuclear positivity was assessed by immunohistochemistry. Mitoses were seen in 0-14.3% of nevi in all groups of patients >1 year of age; 55.6% (5/9 cases) of nevi in patients <1-year old had mitoses identified histologically. Ki-67-positive melanocytes were seen in all cases of those lesions in infants (less than 1-year old) and only in a minority of lesions from the other age groups. The maximum and mean numbers of Ki-67-positive melanocytes per square millimeter were highest in patients <1-year old (16.7 and 5.6, respectively), and decreased in all other groups. Follow-up data were available in the majority of the patients. There were no examples of malignant melanoma in the various age groups. We conclude that proliferative activity in benign melanocytic nevi decreases with age, however, proliferative activity can be seen at any age and its significance must be judged in the context of other histopathologic features.

Histopathologic characteristics of therapy-associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma.

BACKGROUND: Activating mutations in BRAF have been observed in up to 60% of melanomas, indicating a pivotal role for kinase deregulation in tumor progression. Vemurafenib is a specific inhibitor of BRAF for treatment of melanomas with activating BRAF V600E mutations and has been a major advancement in melanoma treatment. Treatment with vemurafenib, and to a lesser extent, sorafenib, a relatively non-specific inhibitor of BRAF, has been associated with cutaneous squamous cell carcinoma (SCC). METHODS: Clinical and microscopic characteristics of cutaneous neoplasms were evaluated following vemurafenib administration. RESULTS: Twenty-four of 47 (51%) patients receiving vemurafenib at our institution developed 146 total cutaneous neoplasms, with 75% developing multiple lesions. The median number of lesions in affected patients was three. Body distribution included head/neck (29%), chest/back (21%), upper (23%) and lower extremities (27%). Lesions were biopsied and pathologically showed multiple types of epidermal tumors including, but not limited to, verrucous keratoses with/without partial thickness dysplasia, actinic keratoses and well-differentiated and invasive SCCs with/without keratoacanthomatous features. CONCLUSIONS: We describe the histopathologic findings of skin lesions potentially associated with vemurafenib. Additional investigation is necessary to further elucidate cutaneous neoplasms associated with vemurafenib; however, frequent dermatologic evaluation is warranted in all patients receiving BRAF inhibitors.

Growth-associated protein 43 in differentiating peripheral nerve sheath tumors from other non-neural spindle cell neoplasms.

The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n=18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n=13/21; 62%). GAP43 is also positive in neurofibromas (n=17/18; 94%), schwannomas (n=11/12; 92%) and desmoplastic melanomas (n=7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n=20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n=14/16; 88%) and clear-cell sarcomas (n=8/8), and only focally positive in monophasic synovial sarcomas (n=3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.

Lipid synthesis and processing proteins ABHD5, PGRMC1 and squalene synthase can serve as novel immunohistochemical markers for sebaceous neoplasms and differentiate sebaceous carcinoma from sebaceoma and basal cell carcinoma with clear cell features.

BACKGROUND: Sebaceous carcinoma represents a rare and potentially fatal adnexal malignancy. Poorly-differentiated sebaceous carcinoma consisting of infiltrative basaloid tumor cells with inapparent lipid vesicles can mimic basal cell carcinoma (BCC). Conversely, other epithelial tumors can exhibit clear cell histopathology and mimic sebaceous carcinoma. At the present time, immunohistochemical markers unique for sebaceous carcinoma are limited. METHODS: We evaluated the expression of three lipid synthesis/processing protein markers alpha/beta hydrolase domain-containing protein 5 (ABHD5), progesterone receptor membrane component-1 (PGRMC1) and squalene synthase (SQS) in sebaceous carcinoma and investigated their utility in differentiating sebaceous tumors from BCC with clear cell features. Immunohistochemistry was performed on 23 sebaceous carcinomas, 14 sebaceomas and 14 BCCs with clear cell features. RESULTS: In sebaceous carcinomas, ABHD5 showed dispersed, cytoplasmic punctate and/or vesicular staining (n = 19/23, 83%), while PGRMC1 and SQS each showed vesicular and membranous staining in tumor cells (n = 22/23, 96%). In all sebaceomas, these markers highlighted tightly clustered lipid vesicles in sebocytes. All BCCs with clear cell features were negative for these three markers. CONCLUSION: ABHD5, PGRMC1 and SQS are novel markers for sebaceous carcinoma and can reliably distinguish sebaceous neoplasms from non-sebaceous tumors, specifically BCC with clear cell features.

Diagnostic utility of neural stem and progenitor cell markers nestin and SOX2 in distinguishing nodal melanocytic nevi from metastatic melanomas.

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3+) nestin, 4 showed rare cells with strong (3+) nestin, and one showed diffuse but faint (1+) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (<1+) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n=22/23; 96%), but not in nodal melanocytic nevi (n=15/17; 88%; P<0.0001). SOX2 was also expressed in metastatic melanomas (n=13/23; 57%) but not in the majority of nodal melanocytic nevi (n=13/16; 81%; P=0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging.

Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

Differentiating neurotized melanocytic nevi from neurofibromas using Melan-A (MART-1) immunohistochemical stain.

CONTEXT: Neurotized melanocytic nevi and neurofibromas are common, benign cutaneous neoplasms. Usually they are histologically distinct from each other; however, neurotized melanocytic nevi and neurofibromas can be clinically and histologically similar. OBJECTIVE: To determine whether Melan-A (MART-1) immunohistochemical stain is sufficient to differentiate neurotized melanocytic nevi from neurofibromas. DESIGN: Forty-nine consecutive specimens of melanocytic nevi with neurotization and 49 specimens of neurofibromas were selected. We used antibodies against Melan-A, S100, and neurofilament protein. RESULTS: All of the melanocytic nevi showed Melan-A staining within the neurotized areas, with most of the areas staining strongly positive, whereas all the neurofibromas were completely absent of Melan-A stain. All of the nevi, including the neurotized areas, stained strongly and diffusely for S100, whereas all the neurofibromas showed a distinctive, sharp, wavy pattern of S100 staining. Neurofilament protein showed scattered staining of both melanocytic nevi and neurofibromas. CONCLUSIONS: Our data indicate that Melan-A immunohistochemical staining is helpful in differentiating neurotized melanocytic nevi from neurofibromas when distinction on histomorphology alone is difficult.

Sebaceous neoplasms with mismatch repair protein expressions and the frequency of co-existing visceral tumors.

BACKGROUND: Visceral malignancy has been associated with sebaceous neoplasms in patients with Muir-Torre syndrome. However, no large studies have been done to evaluate the frequency of visceral tumors in patients with sebaceous neoplasms and mismatch repair (MMR) protein expression of the sebaceous tumors. OBJECTIVE: We sought to determine the frequency of visceral tumors in patients with sebaceous neoplasms, MMR protein expression of the sebaceous tumors, and the related surveillance practices of physicians. METHODS: We identified 85 patients with sebaceous neoplasms. Relevant clinical information was obtained via chart review and database searches. MMR protein expression was examined by immunohistochemistry. RESULTS: Nineteen of the 85 patients had a total of 22 visceral malignancies, of which 41% were genitourinary in origin. Ten of the 17 patients (59%) with visceral malignancy had loss of MMR expression in their sebaceous neoplasms or somatic MMR mutation. Thirty patients had other findings such as colonic adenomas and polyps. Of the 23 patients who had a family history of visceral malignancy, 9 had a personal history of visceral malignancy. LIMITATIONS: Only one sebaceous tumor from each patient (except one) was tested for MMR, which might reduce the sensitivity. CONCLUSION: Our findings demonstrate an increased frequency of internal malignancy in patients with sebaceous neoplasms compared with the general population, and highlight the heterogeneous nature of the visceral tumors. A majority of the sebaceous tumors show loss of MMR expression. The study reminds us to strive toward a consistent and comprehensive approach to screening for internal malignancy when a patient is given a diagnosis of a sebaceous neoplasm.

Nevoid hyperkeratosis of the areola misinterpreted as mycosis fungoides.

Nevoid hyperkeratosis of the nipple and areola is a benign condition with fewer than 70 cases reported in the literature. We report a case of unilateral nevoid hyperkeratosis of the areola with intraepidermal lymphocytes that resembled Pautrier's microabscesses on histological examination. This is the third report of mycosis fungoides-like changes in nevoid hyperkeratosis of the nipple and areola. In addition, this is the first case to present immunohistochemical and T-cell gene rearrangement studies of the intraepidermal lymphocytes. This case highlights a potential histopathological pitfall in the diagnosis of nevoid hyperkeratosis of the nipple and areola.

Use of classic and novel immunohistochemical markers in the diagnosis of cutaneous myeloid sarcoma.

Cutaneous myeloid sarcoma is often challenging to diagnose based solely upon histopathological features. Although immunohistochemistry can aid in its diagnosis, specific markers have not been clearly identified. We evaluated the utility of immunohistochemical markers in 57 cutaneous myeloid sarcoma cases. In addition to classical markers (CD117, CD163, CD34, myeloperoxidase and lysozyme), we used CD33 and CD14, recently described markers in paraffin-embedded tissue samples, and Kruppel-like factor 4 (KLF-4), a novel monocytic marker. Our results show that lysozyme was expressed in 91%, CD33 in 60%, myeloperoxidase in 54%, CD34 in 39% and CD117 in 36% of cases. An antibody panel that included lysozyme, CD117 and CD33 identified all cases. The monocytic markers CD14, KLF-4 and CD163 were expressed in 60, 58 and 40% of all cases, respectively. CD14 and KLF-4 expression was significantly more common in cases with monocytic differentiation. CD14 is the single most sensitive and specific marker for monocytic differentiation (79 and 80%). Although KLF-4 in isolation is relatively insensitive (50 and 87%), it enhances sensitivity in detecting monocytic cutaneous myeloid sarcoma when combined with CD14. Our results indicate that in addition to classical immunohistochemical markers, targeted use of newer antibodies, including CD33, CD14 and KLF-4 is useful in the diagnosis of cutaneous myeloid sarcoma and in the detection of monocytic differentiation.

Cutaneous collagenous vasculopathy: report of the first pediatric case.

We describe a 16-year-old girl who presented with a 3-year history of telangiectatic patches on the extremities and trunk. Skin biopsies demonstrated dilated vessels with thickened walls containing hyaline material in the papillary dermis, resembling those seen in systemic amyloidosis, porphyrias, or lipoid proteinosis. A diagnosis of cutaneous collagenous vasculopathy was made. To our knowledge, cutaneous collagenous vasculopathy has previously only been described in adults aged 50 and older.

The microcephaly-capillary malformation syndrome.

We report on three children from two families with a new pattern recognition malformation syndrome consisting of severe congenital microcephaly (MIC), intractable epilepsy including infantile spasms, and generalized capillary malformations that was first reported recently in this journal [Carter et al. (2011); Am J Med Genet A 155: 301-306]. Two of our reported patients are an affected brother and sister, suggesting this is an autosomal recessive severe congenital MIC syndrome.

Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway.

Alterations in the microenvironment collaborate with cell autonomous mutations during the transformation process. Indeed, cancer-associated fibroblasts and senescent fibroblasts stimulate tumorigenesis in xenograft models. Because senescent fibroblasts accumulate with age, these findings suggest that they contribute to age-related increases in tumorigenesis. Previously we showed that senescence-associated stromal-derived osteopontin contributes to preneoplastic cell growth in vitro and in xenografts, suggesting that it impacts neoplastic progression. Analysis of fibroblasts within premalignant and malignant skin lesions ranging from solar/actinic keratosis to squamous cell carcinoma revealed they express osteopontin. Given the stromal expression of osteopontin, we investigated how osteopontin impacts preneoplastic cell growth. We show that osteopontin promotes preneoplastic keratinocyte cellular proliferation and cell survival through the CD44 cell receptor and activation of the MAPK pathway. These data suggest that stromal-derived osteopontin impacts tumorigenesis by stimulating preneoplastic cell proliferation thus allowing expansion of initiated cells in early lesions.

Melanoma: from patient presentation to pathology report.

Melanoma is an increasingly common and potentially fatal malignancy of the skin and some mucous membranes. Early detection and diagnosis based on patient or primary care physician awareness can potentially reduce both related morbidity and mortality. This article will detail a basic clinical approach to pigmented skin lesions followed by a discussion of pathologic analysis and staging.

Acral angiokeratomas in a patient with Turner syndrome.

Several types of vascular anomalies have been described in patients with Turner syndrome, including cutaneous lymphatic malformations, vascular anomalies of the heart and aorta, acral venous malformations, and intestinal vascular anomalies. Angiokeratomas have rarely been reported in patients with Turner syndrome. Here, we describe a 14-year-old girl with Turner syndrome who presented with a 2-year history of tender bluish-black keratotic acral papules. Biopsy showed acral skin with focal epidermal acanthosis that was centered on a dilated superficial vessel, consistent with an angiokeratoma. Lysosomal enzyme assays were normal, and she did not demonstrate any other features of a lysosomal storage disorder.