Dongsi Lu

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.

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.

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

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.

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.

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

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).

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.

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.