Anne C. Lind

Cutis laxa: A review

Cutis laxa is a rare disorder of elastic tissue resulting in loose, redundant, hypoelastic skin. Both acquired and inherited forms exist, some of which have significant systemic manifestations. Here, we review the various forms of cutis laxa, with focus on the inherited forms. Recent molecular studies have provided many new insights into the causes of cutis laxa and revealed greater genetic heterogeneity than previously appreciated.

Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas?

Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-Go phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context. Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages. Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. The largest proportion of Ki-67–positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well. The prototypical malignant melanocytic tumor representing the vertical growth phase—nodular melanoma—demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P =.008, χ2) and p53 reactivity (P <.000001, χ2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P <.00001, χ2). Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.

State of the art in myeloid sarcoma

Introduction:  Myeloid sarcomas are extramedullary lesions composed of myeloid lineage blasts that typically form tumorous masses and may precede, follow, or occur in the absence of systemic acute myeloid leukemia. They most commonly involve the skin and soft tissues, lymph nodes, and gastrointestinal tract and are particularly challenging to diagnose in patients without an antecedent history of acute myeloid leukemia.

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.

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.

The pathological distinction between "deep penetrating" dermatofibroma and dermatofibrosarcoma protuberans.

In selected cases, the clinicopathological distinction between deep penetrating dermatofibroma (DPDF), which involves the subcutis, and dermatofibrosarcoma protuberans (DFSPs) may be challenging. In most instances, attention to the cytological constituency of the lesions and the overall architecture is sufficient to make this separation. DPDF is typified by cellular heterogeneity, including giant cells and lipidized histiocytes; when it extends into the hypodermis, it does so either using the interlobular subcuticular fibrous septa as scaffolds or in the form of broad pushing fronts of tumor. In contrast, DFSP is a cytologically monotypical tumor, which entraps subcutaneous adipocytes diffusely or grows in stratified horizontal plates in the hypodermis. In the minority of cases where conventional morphological analysis of optimal biopsy specimens is diagnostically indeterminate, immunostaining for CD34 and factor XIIIa (FXIIIa) is helpful; it is also often necessary when a poorly-representative sample of the lesion has been obtained by the clinician. Characteristically, DF is diffusely FXIIIa-reactive and CD34-negative, whereas DFSP manifests the converse of those findings. Other markers such as Ki-M1p, mutant p53 protein, and metallothionein may also provide adjuvant diagnostic information in this context, as may the observation of abnormalities in chromosomes 17 and 22 by direct karyotypic analysis.

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.

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.

Histopathology of acneiform eruptions in patients treated with epidermal growth factor receptor inhibitors.

Epidermal growth factor receptor inhibitors (EGFRIs) are anticancer agents that have been approved for use in a variety of solid tumors. EGFR‐inhibiting agents produce a variety of cutaneous adverse events: most commonly a follicular papulopustular (acneiform) eruption on the face, scalp, chest and upper back.