A Rare Case of Adenocarcinoma With Micropapillary Structure and Apocrine Differentiation Arising in a Sebaceous Tumor.

ABSTRACT: A 77-year-old Japanese man presented to our hospital with subcutaneous tumors of the right upper arm and axilla. A biopsy revealed a cutaneous adnexal tumor, showing apocrine differentiation, and axillary lymph node metastasis. After chemoradiotherapy to shrink the tumors, both lesions were resected. A resected specimen of the arm tumor showed a variegated histology: (1) a classic sebaceoma with an organoid pattern and sebocytes; (2) a sebaceous tumor with cellular atypia; (3) a papillotubular tumor showing a biphasic pattern of pale eosinophilic cells with apocrine differentiation and basaloid cells; and (4) an invasive adenocarcinoma with a micropapillary structure, reminiscent of an invasive micropapillary carcinoma of the breast. The axillary tumor was regressed. To our knowledge, this is the first reported case of an adnexal tumor of the skin with an invasive micropapillary structure arising in a sebaceous tumor.

Hyperplastic melanocytes with chromosomal aberrations in surrounding skin of subungual melanoma: fluorescence in situ hybridisation analysis using whole-slide digital imaging.

AIMS: Subungual melanoma (SUM) is increasingly being treated with conservative surgery. Consequently, the evaluation of the resection margins has increased in importance. However, in several cases it is difficult to distinguish the in-situ lesion of SUM from hyperplastic melanocytes in the surrounding skin. We examined whether PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry and fluorescence in situ hybridisation (FISH) labelling of CCND1 (11q13), RREB1 (6p25), MYB (6q23), and centromere 6 (CEP6) genes differentiated SUM from hyperplastic melanocytes. METHODS AND RESULTS: We reviewed specimens of 36 SUM cases and compared PRAME immunostains of invasive melanoma, melanoma in situ, and hyperplastic melanocytes. PRAME-positive cases accounted for 90.5% of invasive melanoma, 88.9% of in situ melanoma, and 59.4% of hyperplastic melanocyte specimens. While invasive and in situ melanomas in more than half of the examined cases were diffusely positive, this was found for only 9.4% of hyperplastic melanocyte cases. Four-coloured FISH using whole-slide digital imaging was used to analyse positive detection rates and changes in chromosomal aberrations. The FISH positive detection rate was 100% in invasive melanomas, 94.7% in melanomas in situ, and 66.7% in hyperplastic melanocytes. The number of RREB1 (6p25) signals per cell was significantly amplified following tumour progression. CONCLUSION: Hyperplastic melanocytes in the surrounding skin of SUM, considered morphologically non-neoplastic, showed chromosomal aberrations similar to those in melanoma. Such cells are also thought similar to the field cells of acral melanomas. Thus, whole-slide digital imaging is a technique that allows the evaluation of individual melanocyte lesions by FISH.

Prevalence and molecular characteristics of DNA mismatch repair protein-deficient sebaceous neoplasms and keratoacanthomas in a Japanese hospital-based population.

BACKGROUND: Muir-Torre syndrome (MTS) is currently considered as a clinical variant of Lynch syndrome (LS). The clinical significance of the screening of patients with MTS-associated cutaneous tumors for the identification of LS has not yet been established. In addition, the prevalence and molecular characteristics of mismatch repair (MMR) protein deficiency in such tumors has scarcely been investigated in the Japanese population. METHODS: Immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from 16 sebaceous neoplasms (SNs) resected from 13 patients and 32 keratoacanthomas (KAs) resected from 31 patients at our institution between January 2005 and March 2014. Tumors showing MMR protein loss were further subjected to genetic analysis for detecting the presence of germline and/or somatic alterations of the MMR genes to identify the precise molecular mechanisms underlying the protein loss. RESULTS: Among the 16 SNs resected from 13 patients, eight SNs resected from five patients (38.5%) showed loss of expression of MMR proteins (MLH1/PMS2 loss, one patient; MSH2/MSH6 loss, four patients). Genetic analyses showed a pathogenic germline MSH2 mutation in one patient, somatic hypermethylation of the MLH1 promoter region in one patient, and somatic alterations of MSH2 without detectable germline mutations of MSH2 in three patients. None of the KAs examined in the study showed any loss of MMR protein expression. CONCLUSIONS: The efficacy of routine screening of cutaneous neoplasms known to be associated with MTS by IHC for MMR proteins to identify LS may be fairly limited. MMR protein loss as determined by IHC in SNs is not always diagnostic of LS, and appears, in most cases, to be a result of somatic inactivation of the MMR genes.

Fibrotic focus: An important parameter for accurate prediction of a high level of tumor-associated macrophage infiltration in invasive ductal carcinoma of the breast.

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor-associated macrophage (CD68, CD163 or CD204-positive) infiltration or whether the presence of tumor-associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68-, CD163- or CD204-positive tumor-associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204-positive tumor-associated macrophage infiltration clearly demonstrated that CD204-positive tumor-associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204-positive tumor-associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

A Rare Case of a Primary Cutaneous Desmoplastic Atypical Granular Cell Tumor.

Granular cell tumors are uncommon neoplasms and a small number of these neoplasms have been reported as showing malignant behavior. Here, we report a rare case of a solitary granular cell tumor that exhibited atypical histology, including an extensive desmoplastic stroma, in a 69-year-old woman. The surgical specimen revealed localized areas of spindling cells, areas of cellular pleomorphism, and p53 overexpression. Based on previously published criteria, we classified this lesion as an atypical granular cell tumor. To date, only very few case reports have documented this desmoplastic variant of granular cell tumor. However, the classifications of benign, atypical, and malignant granular cell tumors are still controversial, owing to an overlap of morphological and immunohistochemical profiles and lack of consistent histological criteria. Additionally, it is unknown whether the histology of the desmoplastic variant in the present case is significant for the classification of granular cell tumors and prediction of patient prognosis. Regardless of these issues, awareness, and close follow-up are required because of potential recurrences of this rare variant of granular cell tumor.

Acute acalculous cholecystitis with eosinophilic infiltration.

We report a case of acute acalculous cholecystitis with eosinophilic infiltration. A previously healthy 6-year-old boy was referred with right abdominal pain. Imaging demonstrated marked thickening of the gallbladder wall and peri-cholecystic effusion. Acute acalculous cholecystitis was diagnosed. Symptoms persisted despite conservative treatment, therefore cholecystectomy was performed. Pathology indicated infiltration of eosinophils into all layers of the gallbladder wall. The postoperative course was uneventful and the patient has had no further symptoms. Eosinophilic cholecystitis is acute acalculous cholecystitis with infiltration of eosinophils. The causes include parasites, gallstones, allergies, and medications. In addition, it may be seen in conjunction with eosinophilic gastroenteritis, eosinophilic pancreatitis, or both. An allergic reaction to abnormal bile is thought to be the underlying cause. The present case did not fulfill the diagnostic criteria of eosinophilic cholecystitis, but this may have been in the process of developing.

The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature.

PURPOSE: Growing teratoma syndrome (GTS) is a rare clinical phenomenon defined as the paradoxical growth of mature teratoma components during or after chemotherapy. The mechanism of this phenomenon is not well understood. We present two cases of pineal mixed germ cell tumors that exhibited the similar course to GTS and speculate its pathogenesis. CASE REPORT: The first case was accompanied by slightly elevated alpha-fetoprotein (8.8 ng/ml; normal <6.6 ng/ml). The tumor rapidly grew from 1.5 to 2.7 cm in diameter within 4 weeks. Despite this rapid preoperative growth, thorough pathological investigation found only mature teratoma components along with multiple micro- and macro-cysts. The other case was diagnosed as a pure germinoma based on biopsy and serological examinations. During three courses of chemotherapy, this tumor presented a honeycomb-like appearance on magnetic resonance (MR) images and an exceptionally rapid enlargement. Second-look surgery confirmed the histological diagnosis of a mature teratoma. In both cases, meticulous pathological examination of all whole tumor sections revealed no malignant histological features, and the MIB-1 labeling indices were too low to account for the extremely rapid tumor growth. Instead, both MR images and histological findings demonstrated a predominant formation of multiple cysts. CONCLUSION: We speculate that this paradoxical growth might not be tumorous proliferation but instead the formation and expansion of multiple cysts inside mature teratoma components and that the presence or absence of growth might be a subsidiary phenomenon. Our hypothesis appears consistent with the characteristic radiological findings of GTS reported in the literature.

Application of fluorescence in situ hybridization in distinguishing acral melanoma in situ from acral junctional melanocytic nevus on the volar skin in Japanese patients.

Four-colored fluorescence in situ hybridization (FISH) is an ancillary diagnostic tool for melanoma. However, most studies that have investigated the usefulness of FISH primarily focused on advanced melanomas. The aim of the current study was to evaluate the effectiveness of FISH in distinguishing acral melanoma (AM) in situ from benign acral junctional nevus (AJN), two types of lesions that are difficult to differentiate via traditional clinical means. The authors investigated the usefulness of FISH in 91 acral melanocytic lesions, including 50 lesions with diagnostic discrepancies between dermoscopic and pathologic approaches or difficulty diagnosing between AM in situ and AJN, on the volar skin of Japanese patients. The authors classified the lesions based on the diagnosis of dermatologists and pathologists into four groups: (I) lesions with a unanimous diagnosis by dermatologists and pathologists as AM in situ or AJN (n = 41); (II) lesions with a unanimous diagnosis by dermatologists only as AM in situ or AJN (n = 21); (III) lesions with a unanimous diagnosis by pathologists only as AM in situ or AJN (n = 15); and (IV) all other lesions (n = 14). The dermatologists diagnosed the lesions by clinical and dermoscopic photographs alone, while the pathologists diagnosed the lesions by microscopy of hematoxylin and eosin-stained slides alone. In group I (AM in situ [n = 20] and AJN [n = 21]), four-colored FISH demonstrated 90% sensitivity and 81% specificity in distinguishing AM in situ from AJN. There was a significant correlation between the FISH results and the unanimous diagnoses by pathologists alone (p = 0.03) in group III. However, FISH results were not significantly correlated with the unanimous diagnoses by dermatologists alone (p = 0.33) in group II. In conclusion, the four-colored FISH probe kit was useful in distinguishing between AM in situ and AJN and may be an ancillary method when pathologists who are not experts of dermatopathology diagnose melanocytic lesions.

Bendamustine-induced rash is associated with a favorable prognosis in patients with indolent B-cell lymphoma.

Bendamustine is now recognized as a key drug for indolent B-cell lymphoma (iBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Skin toxicity associated with bendamustine is one of the characteristic adverse effects. We retrospectively examined the relationship between bendamustine-associated drug rashes and disease prognosis of iBCL and MCL at our institution. Between January 2011 and August 2019, 65 patients (39 men and 26 women, median age 68, range 41-84 years) were treated with bendamustine alone (n=11, 120 mg/m2 on days 1 and 2) or a combination of rituximab and bendamustine (n=54, 90 mg/m2 on days 1 and 2). Of these patients, 47 had follicular lymphoma (FL), 10 had MCL and 8 had other iBCLs. Drug rash occurred in 27 (41.5%). Eight cases (29.6%) were grade 1, 5 (18.5%) were grade 2 and 14 (51.9%) were grade 3. The onset was in the first course in 17 (63.0%), 2nd course in 5 (18.5%), 3rd course in 2 (7.4%), 4th course in 1 (3.7%) and 5th course in 2 (7.4%). No treatment was administered in 1 case (3.7%), topical steroid was applied in 10 (37.0%), antiallergic drug was administered in 2 (7.4%), topical steroid and antiallergic drug were administered in 5 (18.5%), and oral and topical steroid and antiallergic drug were administered in 9 (33.3%). The 3-year progression-free survival (PFS) and overall survival (OS) in patients with rash development were 80.0% and 85.5%, respectively, and those in patients without development were 36.4% and 54.0%, respectively (p=0.009 and 0.02, respectively). By multivariate analysis, the development of rash was associated with a better PFS and a diagnosis of iBCL was associated with a better OS. This study revealed that bendamustine-induced rash is associated with a favorable prognosis among patients with iBCL.

A case of dermatofibrosarcoma protuberans with neurofibromatous change.

A 31-year-old man with posterior neck mass visited a hospital. The mass recurred four times on the same location during the past 6 years. Needle biopsy diagnosis was suspicious for benign stromal tumor. Tumor excision was performed 3 months after the biopsy. The tumor size was 8.3 × 4.5 cm and was located at subcutaneous tissue. Histologically, main tumor cells showed comma-shaped nuclei, which are same as neurofibroma. Immunohistochemically, tumor cells were positive for vimentin, CD34, but were negative for S-100. Fluorescence in situ hybridization analysis disclosed a split signal of PDGFB gene. Reverse transcriptase-polymerase chain reaction clarified COL1A1 exon 47/PDGFB exon 2 chimeric gene. Final diagnosis was dermatofibrosarcoma protuberans (DFSP) with neurofibromatous change. DFSP with neurofibromatous change is rare and could be misdiagnosed as benign tumor, especially in a biopsy specimen. Molecular diagnosis is a promising aid in a challenging case and in biopsy specimens.

Distribution of CD1a-positive cells is not different between pseudolymphomatous folliculitis and primary cutaneous marginal zone lymphoma.

Pseudolymphomatous folliculitis (PLF) is a subtype of cutaneous pseudolymphoma that is recognized as an independent disease. PLF is characterized by dermal lymphocytic infiltration surrounding an irregular hyperplastic pilosebaceous unit (i.e., activated pilosebaceous unit). An interstitial distribution of CD1a-positive cells is regarded as an important feature of PLF, especially in distinguishing it from primary cutaneous marginal zone lymphoma (PCMZL), which is associated with a peripheral concentration of CD1a-positive cells. We undertook a clinicopathological investigation of PLF, with a reassessment of CD1a immunohistochemistry. We defined diagnostic criteria for PLF based on past studies and consequently identified 79 cases. In addition, we collected 32 cases of PCMZL and performed detailed clinical, pathological, and immunohistochemical investigations using antibodies to CD3, CD20, and CD1a. We found an interstitial concentration of CD1a-positive cells in 90.2% of PLF and 34.5% of PCMZL cases. The peripheral concentration of CD1a-positive cells was seen in 9.8% of PLF and 34.5% of PCMZL cases. In both diseases, CD1a-positive cells appeared in T-cell nests (88.5% in PLF and 92.9% in PCMZL) but were absent in B-cell nests (0% in both groups). All 79 cases of PLF showed activated pilosebaceous units while 22 of the 32 PCMZL cases displayed pilosebaceous units, although none of these were activated. In summary, regarding the distribution patterns of CD1a-positive cells as a diagnostic feature in distinguishing between PLF and PCMZL is somewhat inconclusive. To differentiate PLF and PCMZL, determining the presence or absence of activated pilosebaceous units is essential.

Normolipemic xanthomatized Sweet's syndrome: A variant of Sweet's syndrome with myelodysplastic syndrome.

We report a rare case of xanthomatized Sweet's syndrome with myelodysplastic syndrome (MDS) in a patient who presented with erythematous plaques on his chest that were elevated and became yellowish. A diagnosis of MDS with single lineage dysplasia was made during the development of the eruption. Bone marrow biopsy showed an increased number of megakaryoblasts. Histopathologically, there was neutrophil infiltration with leukocytoclasia and the infiltration of xanthomatous cells. Immunohistochemical analysis revealed that the xanthomatized cells were predominantly CD163 positive. We propose that our case of xanthomatized neutrophilic dermatosis is a rare clinicopathological variant of Sweet's syndrome associated with a hematologic disorder.

Diagnosis of Pancreatic Solid Lesions, Subepithelial Lesions, and Lymph Nodes Using Endoscopic Ultrasound.

Currently, endoscopic ultrasound (EUS) has become widely accepted and has considerable advantages over computed tomography (CT) and other imaging modalities, given that it enables echostructure assessment in lesions with <1 cm diameter and permits high resolution imaging. EUS-guided tissue acquisition (EUS-TA) provides consistent results under ultrasound guidance and has been considered more effective compared to CT- or ultrasound-guided lesion biopsy. Moreover, complication rates, including pancreatitis and bleeding, have been extremely low, with <1% morbidity and mortality rates, thereby suggesting the exceptional overall safety of EUS-TA. The aggressive use of EUS for various lesions has been key in facilitating early diagnosis and therapy. This review summarizes the diagnostic ability of EUS for pancreatic solid lesions, subepithelial lesions, and lymph nodes where it is mainly used. EUS has played an important role in diagnosing these lesions and planning treatment strategies. Future developments in EUS imaging technology, such as producing images close to histopathological findings, are expected to further improve its diagnostic ability. Moreover, tissue acquisition via EUS is expected to be used for precision medicine, which facilitates the selection of an appropriate therapeutic agent by increasing the amount of tissue collected and improving genetic analysis.

Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 4 of the N-acetyl-D-galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS.

Reassessment of histopathology and dermoscopy findings in 145 Japanese cases of melanocytic nevus of the sole: toward a pathological diagnosis of early-stage malignant melanoma in situ.

Recently, dermoscopic visualization has been improved, allowing for the identification of malignant melanoma (MM) of the sole in situ. When the parallel ridge pattern is evident on dermoscopy, the proliferation of solitarily arranged melanocytes in the crista profunda intermedia should be examined histologically, since this may be a clue to the early diagnosis of MM in situ. We reviewed 145 Japanese cases of melanocytic nevus on the sole, and investigated several useful histological features for the diagnosis of MM in situ using a recent proposal as well as several standard histological criteria of MM in situ. Five cases were considered to be an early-stage MM in situ out of 145 cases previously diagnosed as melanocytic nevi of the sole. These cases showed several specific features, including solitarily arranged melanocytes or melanocyte nests comprising fewer than four cells. Our findings indicate that early-stage MM of the sole in situ can be diagnosed by using new dermoscopy-related histological findings. They are (i) irregular distribution of solitary melanocytes at the crista profunda intermedia with or without small nests (up to three melanocytes) on the slope of rete ridges; and (ii) larger melanocytes with a halo around the nucleus.

Primary cutaneous localized/clearly-outlined true histiocytic sarcoma: Two long-term follow-up cases.

Histiocytic sarcoma (HS) is a rare hematopoietic tumor that mainly involves extranodal sites, including the intestinal tract, skin, soft tissues and other organs. It is well known as an aggressive neoplasm that shows a poor response to therapy. However, a subset of patients with resectable disease has shown a favorable outcome with surgical treatment. Primary cutaneous HS is exceedingly rare and, to date, its long-term prognosis has thus not been well described. Here, we highlight two cases of primary cutaneous HS that showed long-term survival. Case 1 was a healthy 47-year-old woman who found a 12-mm tumor on her forehead. Case 2 was a 66-year-old woman, under follow up of a myxoid liposarcoma in her leg, who presented with a 25-mm tumor in her hypothenar eminence. Histologically, the tumors in both cases had a smooth outline with proliferating atypical tumor cells that showed histiocytic differentiation as revealed by immunohistochemistry with antibodies to CD68 (KP-1) and lysozyme in case 1; and CD68, lysozyme and CD163 in case 2. Tumor cells in case 1 had a monotonous appearance. After complete resection, cases 1 and 2 have survived for 10 and 4 years, respectively, without recurrence. To date, such patients are relatively long follow-up cases of survival from HS and highlight how a clear outline of the primary cutaneous HS tumor may be associated with its resectability and be an important factor in the assessment of its curability.

A case of acute cerebral infarction associated with an accessory middle cerebral artery in a patient who underwent thrombectomy.

BACKGROUND: The accessory middle cerebral artery (AMCA) is a middle cerebral artery (MCA) anomaly originating from the anterior cerebral artery. We report our experience of a case in which thrombectomy was undertaken for a patient with hemodynamics that were specific to the AMCA. CASE PRESENTATION: An 84-year-old man with a history of atrial fibrillation developed paralysis of the left upper and lower extremities. Imaging examinations suggested tandem occlusion of the right internal carotid artery and the origin (M2 segment) of the right MCA. An extremely narrow MCA was visualized. Because there was concern regarding development of frontal lobe infarction, thrombectomy was carried out to restore anterograde blood flow, but an AMCA was found. Recanalization of the main MCA in the infarction zone resulted in hemorrhagic infarction, and the patient died of cerebral herniation. CONCLUSION: When a vascular variation like AMCA is suspected, a careful evaluation of hemodynamics is necessary before undertaking endovascular intervention.