Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Holocrine Poroma: A Distinctive Adnexal Tumor.

There are 36 cases of complex poroid tumors with folliculosebaceous and apocrine differentiation reported in the literature. The authors evaluated 111 poroid tumors including 63 typical eccrine poromas and 48 poroid tumors with folliculosebaceous elements. Folliculosebaceous poroid tumors (FSPT) had basaloid and squamous cells (100%), ducts with steatocystoma-like cuticles and holocrine secretions (89.6%), infundibular follicular structures (66.7%), and entrapped sebocytes (56.3%). No definite apocrine decapitation secretions in FSPT were found. Immunohistochemistry was strongly positive for CK903 and focally positive for CAM5.2, epithelial membrane antigen, and carcinoembryonic antigen. No loss of MLH-1, MSH-2, or MSH-6 mismatch repair proteins was found. FSPT had distinctive features that differentiate them from eccrine poromas including the frequent head and neck locations (62.5% vs. 20.6%, P < 0.01), squamous cytology (100% vs. 1.6%, P < 0.01), more prominent cytoplasmic vacuolization (score 1.4/4.0 vs. 0.3/4.0, P < 0.01), presence of infundibular follicular structures (score 1.2/4.0 vs. 0.03/4.0, P < 0.01), presence of ducts with steatocystoma-like cuticles (89.6% vs. 0.0%, P < 0.01), and less stromal hyalinization (score 1.0/4.0 vs. 2.5/4.0, P < 0.01). The authors propose that FSPT are distinctive benign tumors originating from the sebaceous gland duct and are therefore best categorized as holocrine poroma.

Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Follicular density and ratios in scarring and nonscarring alopecia.

Follicular counts from transverse sectioning of scalp biopsies have not been statistically scrutinized across disease entities in a standardized fashion. We applied uniform histological criteria and strict statistical measures to compare nonscarring and scarring alopecia. We studied 700 consecutive cases including 355 nonscarring alopecia [136 telogen effluvium, 115 alopecia areata (AA), 95 androgenetic alopecia, and 9 trichotillosis] and 345 scarring alopecia [238 central centrifugal cicatricial alopecia, 29 traction alopecia, 26 lichen planopilaris, 21 end-stage alopecia, 20 lupus erythematosus, 11 folliculitis decalvans]. We counted follicular units, anagen, catagen/telogen, and vellus-like follicles at the central follicular unit level. We calculated follicular density per square centimeter, anagen percentage, telogen percentage, anagen to telogen ratio, and terminal to vellus ratio (TVR). The following achieved statistical significance (P < 0.05): follicular density was 249.4 ± 4.6 in nonscarring alopecia versus 120.1 ± 3.8 in scarring alopecia, follicular density of telogen effluvium was 273.5 ± 7.0 (36.5 ± 12.5 above nonscarring alopecia mean), TVR of androgenetic alopecia was 1.6 ± 0.1 (3.6 ± 0.5 below nonscarring alopecia mean), TVR of AA was 3.2 ± 0.4 (1.5 ± 0.6 below nonscarring alopecia mean), anagen percentage of AA was 26.8 ± 1.8 (26.3 ± 3.0 below nonscarring alopecia mean), anagen to telogen ratio of AA was 1.6 ± 0.4 (3.9 ± 0.7 below nonscarring alopecia mean), and telogen percentage of AA was 59.0 ± 2.3 (31.0 ± 3.5 above nonscarring alopecia mean). There exists a great overlap of densities and ratios across the various disorders due to the limited nature of the punch biopsy sample, variations in scalp anatomy, disease biology and duration, patient gender, and age, etc. Our data provide a bell curve distribution that helps analyze hair counts in the clinicopathologic context.

The pathobiology of Kaposi's sarcoma: advances since the onset of the AIDS epidemic.

Since the perplexing early Kaposi's sarcoma (KS) observations at the dawn of the acquired immunodeficiency syndrome epidemic, KS has been extensively studied, revealing a complex disease. The identification and complete elucidation of the genome of its causal agent, the KS-associated herpesvirus/human herpesvirus 8, have shed important insights into the pathobiology of this disease. The purpose of this review is to describe the scientific advances and understanding of KS over the past three decades.

Follicular streamers (stelae) in scarring and non-scarring alopecia.

BACKGROUND: Follicular streamers are residual fibrovascular tracts representing the impermanent lower third of the hair follicle below the bulge region. Streamers are generally not counted in transverse alopecia samples as they may represent catagen/telogen (CT) follicles and vellus-like (VL) follicles, or be mistaken as follicular scars. DESIGN: We evaluated 22 non-scarring alopecia cases, including alopecia areata (AA) and androgenetic alopecia (AGA), and 22 scarring alopecia cases, including follicular degeneration syndrome (FDS)/central centrifugal cicatricial alopecia and other scarring alopecia (OSA) disorders. We counted terminal follicular streamers found at a deep dermal level (L2) and followed them into a mid-dermal level at the central follicular unit (FU) to determine their precise derivation. RESULTS: We found streamers in 8/9 AA, 11/13 AGA, 6/12 FDS and 3/10 OSA cases. We counted a total of 74 streamers at L2, including 61 in non-scarring alopecia cases (p < 0.001). At the more superficial FU level, 72% of streamers corresponded to CT follicles, 25% to VL follicles and 3% to follicular scars. CONCLUSIONS: Follicular streamers are found predominantly in non-scarring alopecia cases. Streamers found at deep dermal or subcutaneous levels should be followed and identified at the FU level in order to obtain accurate follicular counts and follicular ratios needed for non-scarring alopecia diagnosis.

Dermatofibrosarcoma protuberans and giant cell fibroblastoma exhibit CD99 positivity.

According to most authors, dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) represent the adult and juvenile forms, respectively, of the same disease entity, as evidenced by similar morphology, an identical chromosomal translocation, and CD34 positivity. It has been shown that DFSP and nuchal-type fibroma (NTF) (which is also CD34-positive) are related lesions, and that there might possibly be a continuum between the two. In addition, NTF exhibits CD99 positivity. It was therefore, hypothesized that both DFSP and GCF would show similar immunopositivity for CD99. Archives of pathology at several institutions were searched for DFSP and GCF tissue blocks. A total of 29 DFSP and 5 GCF were analyzed by immunohistochemistry for expression of CD99. Twenty-three of 29 DFSP (79%) and 2 of 5 GCP (40%) expressed CD99. Comparison of CD99 and CD34 showed that the non-tumoral periphery of DFSP was less probable to be CD99 positive, but this finding was not statistically significant.

Investigation of the hair follicle inner root sheath in scarring and non-scarring alopecia.

BACKGROUND: Premature desquamation of the inner root sheath (IRS) is described as a defining histologic feature of follicular degeneration syndrome/central centrifugal cicatricial alopecia (CCCA). However, IRS abnormalities have been noted in other types of alopecia. DESIGN: We evaluated the IRS in terminal hair follicles with transverse sections stained with hematoxylin-eosin and Ziehl-Neelsen stains in 22 non-scarring (7 areata and 15 androgenetic) and 21 scarring (13 CCCA, 2 lichen planopilaris, 2 lupus erythematosus, 1 folliculitis decalvans and 3 end stage) alopecia cases. In addition, we evaluated 15 normal controls with longitudinal sections to establish the level of IRS desquamation. RESULTS: The IRS was present in 99.5 +/- 0.01% (mean +/- standard error) of normal follicles at the level of the arrector pili muscle/sebaceous gland/sweat gland coil (L2) and variably present at higher levels. The IRS was present at L2 in 97.9 +/- 1.5% of alopecia areata, 87.4 +/- 5.3% of androgenetic alopecia, 59.3 +/- 7.0% of CCCA and 49.4 +/- 11.3% of other scarring alopecia follicles. CONCLUSIONS: Premature desquamation of the IRS was identified in CCCA; however, it was also noted in other scarring alopecia cases. IRS premature desquamation is a non-specific histologic feature in scarring alopecia and cannot be used alone as a defining feature of CCCA.

Displacement of dermal solar elastosis in malignant melanoma.

BACKGROUND: Ultraviolet radiation (UVR) is a major environmental causal factor for skin malignancy. In this study, we investigated the morphology of the solar elastosis (SE) band in benign and malignant melanocytic lesions. METHODS: We measured the SE band in perilesional and lesional skin of 13 melanomas (9 invasive and 4 in situ) and 11 melanocytic nevi (5 usual intradermal nevi, 4 blue nevi and 2 desmoplastic nevi) occurring in sun-exposed areas. RESULTS: The melanoma and nevus groups had similar age range, gender ratio and anatomic distribution. The mean SE thickness was 0.35 mm in melanomas and 0.29 mm in nevi (p = 0.56), indicating similar UVR exposure. There was a mean downward SE displacement (SED) of 0.43 mm in melanomas and essentially no displacement (-0.02 mm) in nevi (p < 0.005). Tumor cells and inflammatory host response were responsible for SED in melanoma. CONCLUSIONS: SED may help in the differential diagnosis of melanocytic lesions in sun-exposed areas. In melanoma, the new lesion depresses the pre-existing SE band. Conversely, the long-standing nevus co-exists with the SE band without significant displacement. Evaluation of the SE band may help to differentiate melanoma with chronic sun-induced damage as they have a distinct set of molecular alterations.

Hypomelanosis of Ito associated with precocious puberty.

Hypomelanosis of Ito has been associated with precocious puberty in two cases. This study reports a third case involving a female with hypomelanosis of Ito including severe mental retardation and seizure disorder with autonomic symptoms (gastroesophageal reflux and asthma). At age 5 she developed vaginal discharge, thelarche, and adrenarche. Soon after, she died of pneumonia stemming from her neurologic deficits. A postmortem examination revealed normal gonads and endocrine organs. The breasts and vulva were prematurely developed. Central nervous system findings included megalencephaly, neuronal eosinophilic inclusions, leptomeningeal neuroglial heterotopias, and cortical dysplasia. Both previously reported cases of hypomelanosis of Ito associated with precocious puberty had abnormal gonads and responded to cyproterone acetate therapy, indicating a peripheral mechanism of precocious puberty (gonadotrophin-independent). The current case, which was autopsied, lacks significant gonadal pathology, and has extensive neurologic involvement that suggests that a central mechanism of precocious puberty (gonadotrophin-dependent) can also be associated with hypomelanosis of Ito.

Aneurysmal bone cyst of the temporal bone associated with reversible hemifacial paralysis.

Aneurysmal bone cyst (ABC) is an uncommon lesion of the temporal bone (TB), with only 20 cases reported. Facial paralysis is a rare complication (2 cases); however, no cases have been reported with preoperative reversal of paralysis. We report a 60-year-old man with a history of remote head trauma, who presented with serious otitis media and right hemifacial paralysis, which resolved with nonsurgical therapeutic measures. Magnetic resonance imaging and computed tomography showed a destructive and expansile lesion of the TB. The lesion was surgically removed, and ABC was diagnosed histologically. The patient had an uneventful recovery and demonstrated no recurrence at 1 year of follow-up. This report presents an unusual presentation of ABC in the TB, with a review of the clinical, radiological, pathological, and therapeutic features of this entity.

Cardiofaciocutaneous syndrome (CFC) with congenital peripheral neuropathy and nonorganic malnutrition: an autopsy study.

Many phenotypic manifestations have been reported in cardiofaciocutaneous (CFC) syndrome, but none, to date, are pathognomonic or obligatory. Previous histopathological studies reported findings in skin and hair; no autopsy studies have been published. We report the clinical and autopsy findings of a 7-year-old boy with severe CFC syndrome and malnutrition of psychosocial origin. Manifestations of CFC, reported previously, included macrocephaly and macrosomia at birth; short stature; hypotonia; global developmental delays; dry, sparse thin curly hair; sparse eyebrows and eyelashes; dilated cerebral ventricles; high cranial vault; bitemporal constriction; supraorbital ridge hypoplasia; hypertelorism; ptosis; exophthalmos; depressed nasal bridge; anteverted nostrils; low-set, posteriorly-rotated, large, thick ears; decayed, dysplastic teeth; strabismus; hyperelastic skin; wrinkled palms; keratosis pilaris atrophicans faciei; ulerythema ophryogenes; hyperkeratosis; gastroesophageal reflux; and tracheobronchomalacia. Additional findings, not previously reported, include islet cell hyperplasia, lymphoid depletion, thymic atrophy and congenital hypertrophy of peripheral nerves with onion bulb formations. Although the islet cell hyperplasia, lymphoid depletion, and thymic atrophy are nonspecific findings that may be associated with either CFC or malnutrition, the onion bulb hypertrophy is specific for a demyelinating-remyelinating neuropathy. These findings implicate congenital peripheral neuropathy in the pathogenesis of the developmental delays, feeding difficulties, respiratory difficulties, ptosis and short stature in this case. Additional studies of other cases of CFC are needed.

Age-related diffuse chronic telogen effluvium- type alopecia in female squirrel monkeys (Saimiri boliviensis boliviensis).

We investigated the diffuse alopecia affecting some female squirrel monkeys (Saimiri boliviensis boliviensis) housed in a breeding facility. We randomly selected 100 female and 10 male animals and performed a complete physical exam and a hair assessment on all animals; blood tests, trichograms, hair density; and skin biopsies in representative cases; and a dominance behavioral assessment of 50 animals. Hair coat was normal in 35 female monkeys and all 10 male animals. Of the 65 females with diffuse alopecia, 17 had mild, 22 moderate, and 26 severe hair loss. The alopecia group had a mean age of 9.6 +/- 0.6 years, whereas that of the normal group was 4.7 +/- 0.6 years (P < 0.05). The parity in the alopecia group was 4.2 +/- 0.6 but 2.0 +/- 0.6 (P < 0.05) in the normal group. There were no statistically significant differences in body weight, hemoglobin, blood urea nitrogen, serum glucose, liver aspartate aminotransaminase, or free thyroxine. The trichogram demonstrated 20.8% +/- 1.6% (mean +/- standard error) of telogen hairs in the alopecia group compared with 9.5% +/- 2.8% of the control group (P < 0.05). The hair density in the alopecia group was 52.8 +/- 4.1/cm2 and 79.6 +/- 14.3/cm2 in the control group. Skin biopsies in affected monkeys demonstrated increased telogen follicles, with no fibrosis or inflammation. There were no statistically significant differences in the dominance behavioral analysis. The findings are consistent with chronic telogen effluvium (CTE). A number of organic, behavioral, and dominance-related stress causes of CTE were excluded. CTE appears to be predominantly age-related in this population. CTE in female squirrel monkeys may serve as an animal model for human diffuse alopecia.

Histomorphologic assessment of formalin substitute fixatives for diagnostic surgical pathology.

CONTEXT: In 1987, the Formaldehyde Standard became law in the United States, alerting laboratory workers to the potential carcinogenicity of formaldehyde. As a result, a variety of proprietary fixatives were developed for use in surgical pathology. OBJECTIVE: To assess histomorphology with different formalin substitute fixatives. DESIGN: Four experienced board-certified surgical pathologists examined 7 specimens (hepatocellular carcinoma, ovarian sex cord/stromal tumor, myxoid liposarcoma, uterine endometrioid adenocarcinoma, splenic follicular hyperplasia, infiltrating mammary carcinoma, and cecal signet ring carcinoma) fixed with formalin and 5 proprietary fixatives advertised as formalin replacements. In a blind study, the pathologists rated cellular outlines, cytoplasmic detail, nuclear detail, erythrocyte integrity, lymphocyte integrity, overall morphology, and overall staining in each case. RESULTS: Formalin received the highest overall morphology and staining scores, followed by Glyo-Fixx, STF-Streck, Omnifix, Histochoice, and Histofix. Formalin also received the highest scores in cellular outline and erythrocyte integrity. Individually, some fixatives performed better in different areas than others. Glyo-Fixx performed as well as formalin for overall morphology and provided highest nuclear detail and lymphocyte appearance scores. Omnifix II gave best results for cytoplasmic detail. CONCLUSION: In this blind study, formalin fixation provided the highest histomorphologic quality for tissue stained with hematoxylin-eosin and examined for diagnostic surgical pathology. Should the use of formalin be discontinued, pathologists will have to familiarize themselves with a different set of microscopic details associated with the replacement fixatives.

Dual CD117 expression in gastrointestinal stromal tumor (GIST) and paraganglioma of Carney triad: a case report.

Carney triad is a rare syndrome, with only 20 complete cases reported. We report a 36-year-old white woman with complete Carney triad, including metastatic gastric stromal tumor (GIST), pulmonary chondroma, and nonfunctioning extra-adrenal paraganglioma. Immunohistochemistry was positive for CD34 and CD117 (c-kit) in the GIST, and positive for chromogranin and CD117 in the paraganglioma. Ultrastructural studies demonstrated skeinoid fibers in the GIST. To our knowledge, this is the 21st complete Carney triad case reported and the first report of dual expression CD117 in both GIST and paraganglioma, a finding with intriguing pathogenetic implications related to the organization of the autonomic nervous system.

Basal cell carcinoma and World War II-era cathode ray oscilloscope exposure.

BACKGROUND: There is a high prevalence of skin cancer in World War II servicemen stationed in the Pacific theater as a result of various risk factors such as exposure to ultraviolet radiation and genetic predisposition. OBJECTIVE: We sought to describe whether a possible association exists between basal cell carcinoma (BCC) development and the use of high-voltage cathode ray tube (CRT) oscilloscopes manufactured around 1940 to 1955, which were a source of X-radiation. METHODS: We present a case series of 9 men aged 65 to 93 years who presented with similar head and neck distributions of BCC and a history of extensive use of early CRT oscilloscopes during and shortly after the World War II era. The patients were interviewed and their medical records reviewed to determine CRT exposure times and BCC location, subtype, and treatment. Representative BCC histologic sections were reviewed. RESULTS: A total of 230 BCCs of the head and neck region were identified and mapped. Questionnaires determined a minimum exposure of 600 (range, 624-9600) hours within a 60-cm distance of early CRT screens in all patients. The average number of aggressive histologic subtypes was 23.5%. The average number of Mohs micrographic surgery layers required to obtain negative margins was 1.99 compared with 1.63 in the control group treated by the same Mohs micrographic surgeon (P < .002). CONCLUSION: This descriptive study is the first to suggest that ionizing radiation from early CRT oscilloscopes may be a factor in the development of multiple BCCs of the head and neck with increased subclinical spread.

Lumbosacral ectopic nephrogenic rest unassociated with spinal dysraphism.

Nephrogenic rests (NRs) are thought to originate from persistent nephrogenic blastema and are considered precursor lesions of Wilms' tumor (WT). These rests usually occur as perilobar and intralobar lesions in the kidney and, rarely, in ectopic sites. We report a midline lumbosacral ectopic NR in a healthy full-term newborn male with no family history of WT or WT-associated syndromes. The NR presented as a soft polypoid mass covered by normal skin. An MRI study revealed no lumbosacral spine abnormalities and no communication with the vertebral canal. The resected mass measured 3 cm and contained fat and had a central 1.2-cm solid nodule. The nodule was composed of blastema, epithelial elements (mature tubules and nephrons), and abundant stroma. No other somatic tissue elements were identified after complete microscopic examination. There are 4 cases of NRs reported in the lumbosacral area associated with spinal dysraphism, and only 2 cases, in addition to our report, unassociated with spinal abnormalities. The pathogenesis of heterotopic immature nephrogenic tissue remains a source of conjecture and speculation. If these lesions are heterotopic rests, their potential for neoplastic progression is probably quite limited, but if a monodermal teratoma, then more scrupulous clinical follow-up is warranted.