Histiocyte-rich rhabdomyoblastic tumor: a report of two cases and a review of the differential diagnoses.

Histiocyte-rich rhabdomyoblastic tumor is a recently described skeletal muscle neoplasm of uncertain malignant potential, characterized by slow growth, a fibrous capsule containing peripheral lymphoid aggregates, spindle-to-epithelioid cells with a rhabdomyoblastic immunophenotype, and a dense histiocytic infiltrate. It most commonly arises within the muscles of the lower legs and trunk in young-to-middle-aged men, and initial reports suggest indolent behavior. In this paper, we present two additional cases of histiocyte-rich rhabdomyoblastic tumor with similar clinicopathologic features and discuss the differential diagnosis including its overlap with inflammatory leiomyosarcoma.

"Inflammatory Leiomyosarcoma" and "Histiocyte-rich Rhabdomyoblastic Tumor": a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as "Inflammatory Rhabdomyoblastic Tumor".

Inflammatory leiomyosarcoma (ILMS), defined as "a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization", is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of "histiocyte-rich rhabdomyoblastic tumor" (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as "inflammatory rhabdomyoblastic tumor", a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.

Rosai-Dorfman Disease of the Digestive System-Beware Vasculopathy: A Clinicopathologic Analysis.

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytic proliferation that occurs in nodal and extranodal sites. Rare examples of the disease involving the digestive system have been described. To characterize the digestive tract manifestations of this disease, 12 specimens from 11 patients with extranodal RDD affecting the digestive organs were analyzed. Hematoxylin and eosin sections and available immunohistochemical stains were reviewed, and the clinical information was obtained from patients' electronic or submitted records. Eight patients were female and 3 male (median age, 65 y; range, 17 to 76 y). Abdominal pain was the most frequent symptom. Six patients had an associated immunologic or malignant disease. Nine lesions arose in the gastrointestinal tract (1 involving the appendix, 2 right colon, 6 left colon), 2 in the pancreas, and 1 in the liver. Two patients had the coexistent nodal disease, and 1 had bone and soft-tissue involvement. The lesions were generally composed of polygonal to spindle-shaped histiocytes with eosinophilic to clear cytoplasm admixed with lymphoplasmacytic cells. The inflammatory cells formed lymphoid aggregates in 7 cases and included focally scattered or small collections of neutrophils in 6 cases. Fibrosis was variable, and 4 cases had a storiform pattern. Vasculopathy in the form of a thickened capillary wall, medium-sized arterial wall infiltration by lesional and inflammatory cells and phlebitis was seen in 10, 5, and 2 cases, respectively. All cases were reactive for S100-protein. Of the 5 patients with follow-up, 1 developed immunoglobulin A nephropathy and died of renal failure.

Rosai-Dorfman disease of the trachea: an extremely rare benign tumor.

Rosai-Dorfman disease or sinus histiocytosis is a nonmalignant disease chiefly presenting as a painless cervical lymphadenopathy, although extranodal involvement is also frequent. Involvement of the tracheobronchial tree is extremely rare, and there are no clear guidelines on management. Rosai-Dorfman disease usually presents as a tracheal tumor, although it may also present with extraluminal compression. Only 12 cases have been reported in the English language literature. Histopathology is required to confirm the diagnosis. We describe what we think is India's first reported case of histologically proven tracheal Rosai-Dorfman disease in a 40-year-old otherwise healthy lady.

Langerhans Cell Histiocytoma: A Benign Histiocytic Neoplasm of Diverse Lines of Terminal Differentiation.

Langerhans cell (LC) histiocytoma is a neonatal tumor that often consists of a single, ulcerated nodule. Systemic involvement is rare, and LC histiocytoma is considered to be a variant of congenital, self-healing LC histiocytosis (also referred to as Hashimoto-Pritzker disease). In view of its low prevalence, LC histiocytoma is not always diagnosed in a clinical examination and requires histological confirmation. Furthermore, the histological and molecular features of LC histiocytoma have not been well characterized. Here, we report on 6 cases of this rare disease and review the corresponding literature. LC histiocytoma differs from classical self-healing LC histiocytosis with regard to the pathological features; we found that LC histiocytoma was associated with massive infiltration by histiocytes of various sizes and shapes (although often large) throughout the dermis and the superficial subcutis. Epidermotropism was rare, mitotic figures were not inconspicuous, and necrotic or calcified areas were often present. Immunohistochemical assessment revealed a mixture of different types of histiocytes (with CD1a CD207, CD1a CD207, and CD1a CD207 CD163 cells). Genetic testing was performed in 5 cases; it revealed a BRAF mutation (p.V600E and p.485_490delinsF) in 2 cases, a HRAS mutation (p.T58I) in 1 case, a combination of 2 PTEN mutations in another case (p.I224M and p. R234W), and no mutations in the fifth case. All the lesions regressed spontaneously, and none recurred during follow-up.

PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

Orbital presentation of Rosai-Dorfman disease. / Presentación orbitaria de enfermedad de Rosai-Dorfman.

OBJECTIVE: To report a case of orbital mass and proptosis, diagnosed as Rosai-Dorfman disease (RDD). METHODS: Clinical case report based on the review of clinical charts, radiological images, and histopathology. RESULTS: A 42-year-old male with orbital mass and proptosis of the right eye. A surgical biopsy was performed, and the diagnosis of RDD was established using microscopy and immunohistochemistry. Definitive management included open tumour cytoreduction, with good response. DISCUSSION: The RDD is a rare, benign, proliferative condition of unknown origin. It rarely affects the cranial cavities, with the orbital presentation being very unusual. Diagnostic confirmation is essential for the best surgical management.

Intralymphatic Histiocytosis: A Report of 2 Cases. / Histiocitosis intralinfática, a propósito de 2 casos.

Intralymphatic histiocytosis is a benign condition characterized by poorly defined erythematous plaques (sometimes forming a reticular pattern) as well as the presence of nodules and vesicles. Its etiology and pathogenesis appear to be related to chronic inflammation in the affected area, prior surgery, or systemic disease, particularly rheumatoid arthritis. We report on 2 new cases, both associated with joint surgery in the affected area and osteoarticular disease (primary synovial osteochondromatosis and rheumatoid arthritis). This is a chronic disease and there is no specific treatment. Different treatment options were chosen in the 2 cases described. A spectacular response to treatment with oral pentoxifylline and topical tacrolimus was observed in 1 of the patients.

Are CD68 and Factor VIII-RA Expression Different in Central and Peripheral Giant Cell Granuloma of Jaw: An Immunohistochemical Comparative Study.

OBJECTIVE: Central giant cell granuloma and peripheral giant cell granuloma of the jaw and oral cavity are identical in histopathologic features, although they are different in pathogenesis and clinical behavior. The aim of present study was to compare CD 68 and factor VIII related antigen (VIII-RA ) immunoreactivity in central giant cell granuloma and peripheral giant cell granuloma to determine the biologic nature and clinical behavior of these lesions which may lead to a better or new treatment modality. MATERIAL AND METHOD: CD68 and factor VIII-RA expression were examined immunohistochemically in 22 cases of central giant cell granuloma (10 aggressive and 12 non- aggressive ) and 19 cases of peripheral giant cell granuloma. The Kruskal-Wallis test followed by the Dunn test was used for data analysis. RESULTS: CD68 expression was observed in approximately 100% of multinucleated giant cells and 50% of mononuclear cells. Overexpression of factor VIII-RA in the endothelial cells of capillary like vessels in the periphery of the lesions was prominent. A statistical significant difference for CD68 intensity score in mononuclear cells among three groups (P=0.016) was observed. Indeed, factor VIII-RA intensity score in the endothelial cells of central giant cell granuloma and peripheral giant cell granuloma showed significant difference (P=0.004). CONCLUSION: These findings support the histiocyte/macrophage nature of multinucleated giant cells and mononuclear cells. Overexpression and high intensity score of CD68 in mononuclear cells and the high intensity score of factor VIII-RA in endothelial cells represent less aggressive behavior in central giant cell granuloma.

Cutaneous Apocrine Carcinoma With an In Situ Component and Histiocytoid and Signet-Ring Cells.

We present a case of cutaneous apocrine carcinoma arising in the axilla of a 71-year-old man. The tumor had a significant component of histiocytoid and signet-ring cells as well as in situ carcinoma within the apocrine glands. The cells expressed GATA3, gross cystic disease fluid protein 15, androgen receptor, and E-cadherin. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 were negative. Clinical correlation was required to rule out a metastasis from the breast or the gastrointestinal tract. Although most cutaneous apocrine carcinomas do not behave aggressively, our patient developed bone metastases and eventually died of his disease. It is debated whether histiocytoid and signet-ring cell cutaneous carcinomas should be classified as apocrine neoplasm. The presence of in situ carcinoma associated with this kind of tumor has been reported only once in the literature. This characteristic and the immunohistochemical profile are in favor of apocrine differentiation.

Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.

Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Metformin-Induced Generalized Fixed Drug Eruption With Cutaneous Hemophagocytosis.

Fixed drug eruption (FDE) consists of recurrent dusky-red to brownish macules or patches at the same sites after the readministration of the causative drug. It usually presents as a solitary lesion, but generalized eruptions have been described. The most frequently implied drugs are antibiotics, anticonvulsants, and analgesics. Only 2 cases due to metformin have been reported. Histopathologic features of FDE include vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphocytic infiltrate. Cutaneous hemophagocytosis in the context of a FDE has not been previously reported. We describe the case of an 86-year-old man who developed a pruritic generalized macular eruption of reddish to violaceous patches. Skin biopsy was performed and the dermal infiltrate was immunohistochemically studied. Histopathology showed interface dermatitis with vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphohistiocytic infiltrate. In deep dermis, histiocytes with engulfed cells inside their cytoplasm were seen. Lymphoid enhancer binding factor 1 immunostain demonstrated that most of these cells were lymphocytes. We present the first case with cutaneous hemophagocytosis in the context of a metformin-induced generalized FDE. In this particular case, hemophagocytosis was just a histopathologic finding with no systemic consequences for the patient.

Primary Signet-Ring Cell/Histiocytoid Carcinoma of the Eyelid: A "Binocle" Presentation of the "Monocle Tumor".

Primary cutaneous signet-ring cell carcinoma is a rare and aggressive neoplasm which diffusely involves dermis and subcutis of the eyelid or axillae. Neoplastic cells show a signet-ring cell or histiocytoid morphology in variable number, and can be found intermingled among collagen bundles, sparing the epidermis. This neoplasm typically appears in the eyelids of elderly men, in the form of a painless infiltration and swelling but with no other specific clinical feature, and frequently causes diagnostic retardation and worse prognosis. Frequent involvement of both eyelids of the same eye has given it the name of monocle tumor. Only 29 cases have been described in English literature to date, of which 7 developed metastases, mainly on regional lymph nodes. The authors present a case of involvement of contralateral eyelid, which has only been described previously in 2 cases. The immunohistochemical profile of the involvement in the contralateral eye, and the absence of other metastasis, suggest that it is locally spread from the initial lesion. However the possibility of being a second primary tumor or metastasis cannot be readily ruled out.