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. METHODS: We conducted a search of the English language medical literature for recent studies of interest to individuals involved in the diagnosis of myeloid sarcoma. RESULTS: The differential diagnosis includes non-Hodgkin lymphoma, blastic plasmacytoid dendritic cell neoplasm, histiocytic sarcoma, melanoma, carcinoma, and (in children) small round blue cell tumors. The sensitivity and specificity of immunohistochemical markers must be considered when evaluating a suspected case of myeloid sarcoma. A high percentage of tested cases have cytogenetic abnormalities. CONCLUSION: A minimal panel of immunohistochemical markers should include anti-CD43 or anti-lysozyme as a lack of immunoreactivity for either of these sensitive markers would be inconsistent with a diagnosis of myeloid sarcoma. Use of more specific markers of myeloid disease, such as CD33, myeloperoxidase, CD34 and CD117 is necessary to establish the diagnosis. Other antibodies may be added depending on the differential diagnosis. Identification of acute myeloid leukemia-associated genetic lesions may be helpful in arriving at the correct diagnosis.

CRTC1 rearrangements in the absence of t(11;19) in primary cutaneous mucoepidermoid carcinoma.

BACKGROUND: Mucoepidermoid carcinoma (MEC) of the skin is an uncommon neoplasm with a remarkable resemblance to MEC of the salivary glands. The latter has been shown to harbour an oncogenic translocation resulting in a fusion gene consisting of exon 1 of CRTC1/MECT1/TORC1 at 19p and exons 2-5 of MAML2 at 11q. OBJECTIVES: While t(11;19) and rearrangements of the involved loci have been demonstrated in MEC of the salivary gland and other sites, it remains to be determined if morphological similarities in cutaneous MEC are reflected at the molecular level. METHODS: Cases of cutaneous MEC were defined by three histopathological features: (i) cystic dermal nodule with (ii) overlying intact epidermis and (iii) presence of three cell types (squamoid, intermediate, mucinous), and characterized by reverse transcription-polymerase chain reaction (RT-PCR), interphase fluorescent in situ hybridization (FISH) and immunohistochemistry. RESULTS: Eight primary cutaneous MECs were analysed. All informative cases showed CRTC1 rearrangements; none of the cases had MAML2 rearrangements or the presence of t(11;19) by RT-PCR. One case of primary MEC of the breast showed amplification of MAML2 in the absence of CRTC1 or t(11;19). Two MECs metastatic to the skin, histologically identical to primary cutaneous MEC, were included, one of which harboured the CRTC1-MAML2 fusion gene by RT-PCR, verified by interphase FISH and sequencing. CONCLUSIONS: MEC of the skin harbours CRTC1 rearrangements, a molecular finding that reflects morphological similarities between glandular and cutaneous MEC. The absence of oncogenic t(11;19) or MAML2 aberrations in our series, which is the largest reported, may explain the innocuous clinical behaviour of this uncommon adnexal tumour.

Trichofolliculoma of the vulva associated with vulvar intraepithelial neoplasia: report of three cases and review of the literature.

Trichofolliculoma is an uncommon, benign cutaneous adnexal neoplasm most commonly occurring on the head and neck. Trichofolliculoma of the vulva has not been previously reported. The juxtaposition of a trichofolliculoma in an excisional biopsy specimen performed for vulvar intraepithelial neoplasia (VIN III) created a diagnostic dilemma and prompted a review of our files from 1989 to 2000 for additional cases. A search for benign hair follicle tumors of the vulva identified two additional trichofolliculomas. All three vulvar trichofolliculomas were associated with VIN III. During this same period, 628 cases of vulvar intraepithelial neoplasia II and III were identified. The appearance of trichofolliculoma at this previously unreported site may present diagnostic difficulty.

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-G(o) 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, chi2) and p53 reactivity (P < .000001, chi2). 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, chi2). 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.

Surgical treatment of pseudosyndactyly of the hand in epidermolysis bullosa: histological analysis of an acellular allograft dermal matrix.

Recessive dystrophic epidermolysis bullosa is an inherited mechanobullous disorder of skin and mucous membranes. The most striking clinical characteristic of the disease is the formation of blisters following trivial trauma. Repeated cycles of blistering and scarring result in gradual encasement of the hand in an epidermal "cocoon." The authors treated an 11-year-old boy with recessive dystrophic epidermolysis bullosa who presented with hand contractures and interdigital pseudosyndactyly. Treatment included release of contractures and application of a biosynthetic dermal analog. This report is a histological analysis of the dermal matrix 1 year after initial placement of the allograft. Fibroblasts repopulating the dermal allograft had a normal synthetic phenotype and lacked the myofibroblastic features seen in the ungrafted control biopsy. Collagen and elastin in the repopulated dermal allograft had normal dermal orientation and maturity in contrast to the sparse, immature collagen and lack of elastin compared with the dermis of an ungrafted control region. Results of this histological study indicate that treatment of recessive dystrophic epidermolysis bullosa with an acellular human dermal allograft may restore some features of normal dermal architecture. Although the initial results are encouraging, longer follow-up is required before definitive conclusions can be made.

Angiomatosis with angiokeratoma-like features in children: a light microscopic and immunophenotypic examination of four cases.

We have identified three patients with an initial clinical or biopsy diagnosis of angiokeratoma, all of whom were found to have a more extensive vascular lesion within the surgical excision. A fourth patient with identical histologic findings had no specified clinical diagnosis and his first procedure was excisional. The patients ranged in age from 7 to 16 years, and the lesions were located on the buttock, thigh, calf, and foot. Macroscopic appearances included mildly keratotic pink-red or blue-grey macules (three cases) and pink macules with focal ulceration (one case). In three of the four cases, a shave biopsy diagnosis of angiokeratoma had been made, and the extensive and deeply infiltrative nature of the vascular proliferation was recognized only at subsequent resection, at which point angiomatosis was diagnosed. In the fourth case. excisional biopsy was attempted at presentation, and the superficial morphology was angiokeratoma-like, but the vascular proliferation was present in the deep subcutaneous fat. CD31 and CD34 reactivity was present in the superficial and deep vessels in all cases, and lesional vessels were rimmed by a bland population of smooth muscle actin positive pericytes, findings that differentiate these cases from angiokeratoma, which has previously been reported to be CD34 negative. We conclude that the dilated vascular spaces that typify angiokeratoma may also be seen overlying a deep vasoformative process that is not amenable to resection, and suggest that caution should be exercised in evaluating small biopsies with angiokeratoma-like appearance.

Postoperative/posttraumatic spindle cell nodule of the skin: the dermal analogue of nodular fasciitis.

Spindle cell proliferations of the skin are diverse, both morphologically and mechanistically. The authors have encountered four examples of a distinctive reactive/reparative cutaneous spindle cell lesion that shows homology with ones seen in the genitourinary tract and oral cavity and that is known as "postoperative/posttraumatic spindle cell nodule" (PSCN). These occurred in the skin of the face and scalp (2 cases), arm (1 case), and vulvar skin (one case), and were clearly related historically to prior episodes of trauma. The proliferations were characterized by variably-apposed and cytologically-bland spindle cells with numerous mitotic figures, set in a highly vascular stroma containing extravasated erythrocytes and inflammatory cells. All lesions were immunoreactive for vimentin, actin, and desmin, with no labeling for keratin. Postoperative/posttraumatic spindle cell nodule of the skin is a significant pseudoneoplastic lesion that is related (and perhaps identical pathogenetically) to nodular fasciitis; as such, it may be mistaken for a sarcoma or a spindle cell carcinoma. Careful attention to clinicopathologic and histologic details should result in its accurate recognition.

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.

Lymphoepithelioma-like carcinoma of the skin with apparent origin in the epidermis--a pattern or an entity? A case report.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is prototypically represented by "undifferentiated" nasopharyngeal carcinoma, but it has also been described in many other anatomic locations, including the skin. In the last of these sites, primary LELC has been assumed in the past to show dermal adnexal differentiation. METHODS: The authors present a case wherein LELC of the skin (LELCS) instead appeared to be a morphologic manifestation of squamous carcinoma of the skin surface, as supported by the results of immunohistology and in situ hybridization. RESULTS: Like other examples of LELCS, it showed no evidence of integration of the Epstein-Barr viral genome, and its behavior was indolent. CONCLUSIONS: The heterogeneous nature of LELC as seen in different body sites is reviewed in this report, resulting in the conclusion that this tumor probably represents a morphologic pattern rather than a distinct clinicopathologic entity.

Deep granuloma annulare (pseudorheumatoid nodule) in children: clinicopathologic study of 35 cases.

Deep granuloma annulare (DGA) is one of several lesions of skin and superficial soft tissues whose histologic character is a palisading granuloma with a small central focus of necrosis or necrobiosis. Unlike the other palisading necrobiotic lesions, DGA has a predilection for children in the first 5 to 6 years of life. A painless subcutaneous nodule(s) in the lower anterior tibial region or foot and the scalp, typically in the occiput, was the most common presenting feature in this study of 35 cases. Additional or recurrent lesions were reported in approximately 70% of cases with clinical follow-up. All lesions showed the presence of necrobiosis; however, one of the characteristic features was the multinodular character of the predominantly mononuclear cellular aggregates. The presence of vascular spaces at the periphery of the nodular profiles served as a clue to the diagnosis of DGA. The palisading arrangement of the mononuclear cells was evident only in those foci with central necrobiosis. A histiocytic disorder or fibrohistiocytic process was a common consideration in the differential diagnosis, especially in those cases with less apparent foci of necrosis. Palisading histiocytes with prominent eosinophilic cytoplasm and some nuclear atypism were problematic with regard to possible epithelioid sarcoma. Our study failed to identify any underlying or predisposing factors in the development of DGA. Despite the fact that DGA is a well-documented lesion in children, it occurs sufficiently infrequently that it is often not considered clinically when it presents as a subcutaneous mass or masses in a child. Its recognition by the pathologist is especially important as the occurrence of additional lesions in a high proportion of children can be anticipated without undue concern.

Prospective peer review in surgical pathology.

Quality assurance (QA) in surgical pathology has focused primarily on retrospective audits of randomly selected cases. The authors describe an effective method of prospective audit for a selected class of surgical specimens--diagnostic biopsies--and document the benefits, additional staff time required and impact on turnaround time. Additionally, these results were compared with a retrospective review. During a 6-month period, all diagnostic surgical pathology biopsies (n = 2,694, 55% of all cases) were reviewed by a second pathologist before release of the final report. Errors detected were subdivided into four categories: (1) major: errors in diagnosis that could directly affect patient care; (2) diagnostic discrepancies: errors in diagnosis that should not affect patient care; (3) minor: correct diagnosis rendered, but report correction required to add supportive information; (4) clerical: typographical and grammatical errors. Thirty-two major errors were found, involving 1.2% of cases reviewed. This manner of review caused an increase in overall turnaround time from 1.62 days to 1.79 days, and an increase in turnaround time for diagnostic biopsies from 1.44 days to 1.50 days. Time spent in performing prospective peer review averaged 4 hours per day. For comparison, results were included from a retrospective review performed on 480 of the 5,556 cases accessioned in a 6-month period before the institution of prospective quality assurance. This retrospective review revealed eight major errors (1.7%). In conclusion, the prospective peer review of diagnostic biopsies yields sufficient benefits in increased accuracy of diagnostic reports to justify the slight increase in additional work by pathologists.