Peptide vaccinations elicited strong immune responses that were reboosted by anti-PD1 therapy in a patient with myxofibrosarcoma.

Peptide-based immunotherapy does not usually elicit strong immunological and clinical responses in patients with end-stage cancer, including sarcoma. Here we report a myxofibrosarcoma patient who showed a strong clinical response to peptide vaccinations and whose immune responses were reboosted by anti-PD1 therapy combined with peptide vaccinations. The 46-year-old man showed a strong response to the peptide vaccinations (papillomavirus binding factor peptide, survivin-2B peptide, incomplete Freund's adjuvant, and polyethylene glycol-conjugated interferon-alpha 2a) and subsequent wide necrosis and massive infiltration of CD8+ T cells in a recurrent tumor. The patient's immune responses weakened after surgical resection; however, they were reboosted following the administration of nivolumab combined with peptide vaccinations. Thus, anti-PD1 therapy combined with peptide vaccinations might be beneficial, as suggested by the observations in this sarcoma patient.

Experimental models of pancreatic cancer desmoplasia.

Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.

Dendritic fibromyxolipoma: a variant of spindle cell lipoma with extensive myxoid change, with cytogenetic evidence.

Dendritic fibromyxolipoma (DFML), a rare, recently described distinct benign soft tissue tumor, has many clinicopathological features reminiscent of spindle cell lipoma and solitary fibrous tumor with myxoid change. It is distinguished histologically from both entities by the presence of spindle and stellate cells with dendritic cytoplasmic prolongations, prominent myxoid stroma with abundant keloidal collagen and occasional small plexiform vascular proliferation. We describe a case of histologically confirmed DFML of the left shoulder in a 67-year-old male, in which subsequent cytogenetic analysis revealed deletion involving 13q14.3 region in all the tumor cells, typically detected in spindle cell lipoma. In the presence of many clinicopathological similarities between DFML and spindle cell lipoma including chromosomal abnormalities, we postulate that DFML is merely a rare variant of spindle cell lipoma with extensive myxoid degeneration, and may not be considered as a separate entity. The possible differential diagnosis and their distinguishing features are briefly discussed.

Superficial acral fibromyxoma: a clinicopathological and immunohistochemical analysis of 12 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes.

AIM: Superficial acral fibromyxoma (SAFM) is a rare soft tissue tumor, recently delineated and documentated as a separate entity. We report 12 cases of SAFM observed in our department from June 2004 to June 2010 and highlight pathological features and differential diagnosis. METHODS: Radiographic examination of the affected digit was performed in all patients. All the tumors were surgically excised under local anesthesia. Follow-up was made every 6-8 months for a maximum period of five years. RESULTS: The patients consisted of 8 men and 4 women, age range 28-76 years (mean 51), presenting with a solitary mass or nodule located in the toes and fingers. Histologically the lesions were well circumscribed dermal nodules composed of stellate and spindle cells, arranged in a myxoid matrix. Very low grade atypia and a few mitotic figures were found in only one case. Neoplastic cells showed immunoreactivity for CD34 (12 patients). In contrast focally positive or negative staining was shown for the epithelial membrane antigen (EMA) and CD 99. Actin, S100 protein, HMB45 and cytokeratin were negative. In three cases marked hyperkeratosis and acanthosis of the epidermis was present. Pathological analysis confirmed the diagnosis of superficial acral fibromyxoma. No recurrences were observed even in a long term, 2-5 year follow-up. CONCLUSION: Complete surgical excision of the tumors and a careful follow-up is suggested, despite the benign course previously reported.

Cowden's syndrome: a clinical, immunological, and histopathological study.

BACKGROUND: Cowden's syndrome is a rare, autosomal dominant condition characterized by hamartomas of the gastrointestinal tract and cancer of the breast and thyroid. This study describes the clinical, immunological, and histopathological status of four Cowden's syndrome cases from two different families. METHODS: Biopsies were taken from different skin, mucous membrane, and intestinal lesions in all patients. Blood samples from patients and their parents were also examined. RESULTS: Two brothers in the first family had more flexural distribution of papular and warty skin lesions as well as other manifestations of the syndrome, including recurrent pyogenic and fungal infections. Flow cytometric study revealed decreased total T and B-cell percentages and abnormal helper: suppressor ratios in these patients. The other two patients from the second family showed the classical picture of the syndrome and normal immunological parameters. Histopathologically, most skin lesions of the face showed trichilemmomas, and all oral and some of the other skin lesions showed benign fibromas with giant cells (Cowden's fibroma). Examination of intestinal biopsies revealed hamartomatous and hyperplastic polyps. CONCLUSIONS: Some cases of Cowden's syndrome may be associated with prominent flexural skin lesions, recurrent pyogenic and fungal skin infections, decreased total T and B-cell counts, and an abnormal helper:suppressor ratio.

Superficial acral fibromyxoma: a clinicopathological study of new 41 cases from the U.K.: should myxoma (NOS) and fibroma (NOS) continue as part of 21st-century reporting?

BACKGROUND: Superficial acral fibromyxoma (SAF) remains poorly recognized by general pathologists and dermatopathologists, partly attributable to its relatively uncommon occurrence and recent documentation. OBJECTIVES: To examine a series of SAF and document the U.K. experience with this new entity. METHODS: We reviewed 771 tumours reported between 1970 and 2006 in seven different U.K. hospitals and coded as myxoma, not otherwise specified (NOS), fibroma (NOS) or dermatofibroma (NOS) presenting at acral sites. Forty-one cases of SAF were studied. RESULTS: The patients comprised 27 men and 14 women, age range 19-91 years (mean 50, median 47), presenting with a solitary mass or nodule with a mean size of 1.92 cm. The common clinical sites were the toes (n=29) and fingers (n=11) as well as the palm (n=1), with more than 75% of cases close to or involving the nail bed. All cases presented with a painless mass except for four cases where pain was the presenting complaint. A history of trauma was reported in only two cases. Histologically, all cases presented as proliferation of spindle-shaped and/or stellate cells with a storiform and fascicular pattern embedded in a fibromyxoid/collagenous stroma with conspicuous mast cells. Multinucleated cells were observed (n=22), increased number of blood vessels in the stroma and extravasation of red blood cells (n=4). The characteristic immunophenotype was CD34+, CD99+/-, epithelial membrane antigen+ focally/-, S100-, desmin-, smooth muscle actin-, HMB45- and cytokeratin-. CONCLUSIONS: We describe a large series of 41 cases of SAF showing that it is a distinct entity with typical clinical, histological and immunohistochemical features. Follow-up was available only in 12 patients, precluding a firm comment on recurrence. However, complete excision and follow-up review is recommended.

Apolipoprotein D in CD34-positive and CD34-negative cutaneous neoplasms: a useful marker in differentiating superficial acral fibromyxoma from dermatofibrosarcoma protuberans.

More recent techniques to characterize the genetic profile of soft-tissue tumors include the use of gene arrays. Using this technique, Apolipoprotein D (Apo D), a 33-kDa glycoprotein component of high-density lipoprotein, has been found to be highly expressed in dermatofibrosarcoma protuberans. To corroborate these results, we sought to ascertain the utility of Apo D by investigating its sensitivity and specificity in a variety of CD34-positive and CD34-negative cutaneous neoplasms including superficial acral fibromyxoma, sclerotic fibromas, and cellular dermatofibromas. Of interest, we found absence of Apo D expression in all four cases of superficial acral fibromyxoma. Of the remaining CD34-positive lesions, Apo D expression was noted in 35/36 (97%) cases of dermatofibrosarcoma protuberans, 3/5 (60%) giant-cell fibroblastomas, 4/4 (100%) sclerotic fibromas, 8/8 (100%) neurofibromas, and 1/1 (100%) solitary fibrous tumor. Of the CD34-negative lesions, Apo D expression was noted in 2/22 (9%) regular dermatofibroma, 23/45 (51%) cellular dermatofibroma, 10/10 (100%) malignant fibrous histiocytoma, 9/10 (90%) atypical fibroxanthoma, 7/8 (86%) cellular neurothekeoma, 9/9 (100%) malignant melanoma, 8/8 (100%) melanocytic nevi (100%), 0/2 superficial angiomyxoma, 0/15 fibromatosis, 0/1 nodular fasciitis, and 1/2 (50%) desmoplastic fibroblastomas. In summary, our findings indicate that Apo D expression is not specific to dermatofibrosarcoma protuberans. Its principal use as an immunohistochemical adjunct lies in its utility in differentiating superficial acral fibromyxoma from dermatofibrosarcoma protuberans. Although strong positive staining of Apo D in a markedly atypical fibrohistiocytic lesion is suggestive of atypical fibroxanthoma and/or malignant fibrous histiocytoma, further studies with the inclusion of other atypical spindled cell neoplasms are required to conclusively prove the same.

CD99 immunoreactivity in atypical fibroxanthoma and pleomorphic malignant fibrous histiocytoma: a useful diagnostic marker.

Atypical fibroxanthoma (AFX), a benign lesion, and pleomorphic malignant fibrous histiocytoma (MFH) are thought to represent points along the same neoplastic spectrum but with different prognoses and treatments. Diagnosis based on histology and clinical parameters alone is sometimes difficult, and a reliable cost-effective immunohistochemical marker to help distinguish these lesions would be beneficial. The diagnosis of AFX or MFH was based upon published clinical and microscopic criteria. Formalin-fixed, paraffin-embedded tissues of 17 cases of AFX and 26 cases of MFH were immunostained with monoclonal antibody to CD99. For all cases, CD99 expression was scored on a four-tiered scale: negative, weak (1+), moderate (2+), or strong (3+). Two pathologists blinded to tumor diagnoses and type of immunostain evaluated each case independently. The interobserver correlation coefficient was calculated. Seventeen patients with AFX (16 males and one female; mean age = 79) and 26 patients with MFH (16 males and 10 females; mean age = 60) were included. AFX lesions were from the head and the face, mean size = 1.5 cm, and MFH lesions were from the head, the neck, the trunk, and the upper/lower extremities, mean size = 5.2 cm. The 17 cases of AFX demonstrated moderate or strong (2 to 3+) immunoreactivity with CD99, compared to nine of 26 (35%) MFH cases (chi-square = 18.38; p < 0.001; interobserver correlation coefficient = 0.83). Of these, 16 of 17 (94%) AFX cases stained diffusely with CD99, while only four of 26 (15%) MFH cases stained diffusely. Control slides were adequate. Our study demonstrated that CD99 can help distinguish AFX from MFH, in addition to other immunohistochemistry as well as clinical and histologic criteria.

Giant-cell fibroblastoma in a patient with a bone-marrow transplant.

A case of an epigastric giant-cell fibroblastoma is reported in a 6-year-old girl who had undergone a bone-marrow transplant for severe combined immunodeficiency secondary to adenosine deaminase deficiency. A small subcutaneous nodule had been excised from the epigastrium at age 12 months.

Solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for O13 (CD99) and CD34.

BACKGROUND: Solitary sclerotic fibroma (SF) presents as a well circumscribed dermal nodule, composed of sparse spindle cells with alternating wavy collagen fibers arranged in a storiform pattern. The histogenesis and nature of this histologically distinct lesion are uncertain. Whether this peculiar tumor represents a true hamartoma or a degenerating end of various fibrous lesions such as pleomorphic fibroma (PF), dermatofibroma, or angiofibroma is still controversial. High proliferating index of spindle cells in SF argues against the possibility of being a degenerating end product of another lesion. METHODS: We studied morphological features and immunoprofile of eight SFs, in comparison with four PFs, one collagenized dermatofibroma, two angiofibromas, and two periungual fibromas. Immunostains for CD34, CD31, O13 (CD99), Factor XIIIa, S-100, CD68 (KP-1), and MIB-1 were carried out using a labeled streptavidin-biotin method with DAKO-automated immunostainer. Paraffin blocks of two SFs were reprocessed for electron microscopic studies. Clinical data of all patients with SF were also reviewed. RESULTS: Spindle cells and pleomorphic cells in SF and PF showed diffuse immunoreactivity for CD34 and O13 but were negative for CD31, S-100, and CD68. Spindle cells in one dermatofibroma and one angiofibroma were positive for Factor XIIIa. Proliferating index (MIB-1) was very low in all cases of SF, contradicting some previous reports. CONCLUSIONS: SF is a fibrotic lesion with cells positive for CD34 and O13. It shares a common immunoprofile with PF but is distinct from dermatofibroma and other common spindle cell lesions of skin. O13 expression in SF has not been previously described.

Superficial collagenous fibroma: immunohistochemical, ultrastructural, and flow cytometric study of three cases, including one pemphigus vulgaris patient with a dermal mass.

Collagenous fibroma (desmoplastic fibroblastoma) is an extremely rare benign soft tissue tumor of fibroblastic origin. The majority of reported cases have been located in the deep subcutis, fascia, aponeurosis, or skeletal muscle of the extremities, limb girdles, or head and neck regions. There has been no mention of underlying diseases in patients who developed this tumor. We here report an additional three cases of superficial collagenous fibroma, one of which was a dermal lesion occurring in the abdomen of a 26-year-old male patient with a 5-year history of pemphigus vulgaris prior to development of the tumor. To the best of our knowledge, an association between collagenous fibroma and pemphigus vulgaris has not previously been reported. The remaining two tumors were located in the superficial subcutaneous tissue of the infrascapular area and right foot, respectively. There was no tumor recurrence or metastasis during follow up of 18, 25, and 47 months, respectively. All three tumors were well-circumscribed and unencapsulated without infiltrating borders. Histologically, the common denominator of all three cases was paucicellular proliferation of spindle or stellate fibroblasts enmeshed within an extensively collagenous background. Immunohistochemically, there was diffuse strong staining for vimentin and intense focal reaction for smooth muscle actin in two tumors tested. Electron microscopy revealed features consistent with a fibroblastic or myofibroblastic lineage. Flow cytometry in two cases demonstrated a diploid DNA content with low S-phase fractions, which correlated with minimal MIB-1 nuclear labeling (less than 1%) and benign behavior of this entity.

Expression of CD34 in sclerotic ("plywood") fibromas.

CD34 antigen is expressed in normal human skin on endothelium, in spindle cells located around adnexal structures, and in a subset of interstitial cells in the reticular dermis. CD34 expression has also been identified in a number of fibrohistiocytic neoplasms, such as dermatofibrosarcoma protuberans and solitary fibrous tumors of soft tissue. CD34 expression has not previously been described in sclerotic, or "plywood" fibromas. Here presented are three lesions from three patients, in which histologic examination revealed a well-circumscribed dermal nodule composed of spindled cells with focal nuclear pseudo-inclusions. There was extensive fibrosis with hypocellular, storiform areas, characteristic of sclerotic fibroma. The spindled cells strongly expressed CD34, but not factor XIIIa or markers of melanocytic, neural, or muscular differentiation. A diagnosis of Cowden syndrome was considered in one of the cases. These cases provide evidence that CD34 expression can occur in sclerotic fibromas, either solitary or associated with Cowden syndrome. When diagnosing a sclerotic fibroma, one should comment in the report regarding the possibility of Cowden syndrome.

Chemokine gene expression in human oral mucosa.

In order to gain further understanding of the role of chemokines in healthy oral mucosa, we analyzed mRNA expression of the alpha (CXC)-family chemokines IL-8 and GROgamma as well as of the beta (CC)-family chemokines MIP-1alpha, MIP-1beta and MCP-1 in twenty young and healthy subjects with good oral hygiene. Twenty biopsies were taken from clinically healthy oral mucosa before surgical removal of impacted wisdom teeth. In addition, five biopsies from patients presenting with specific oral lesions were studied. RNA was purified, quantitated and utilized as substrate for competitive reverse transcription-polymerase chain reaction (RT-PCR). In healthy tissue, IL-8 and MCP-1 mRNA was constitutively expressed in all biopsies, whereas GROgamma, MIP-1alpha, and MIP-1beta were significantly lower. These findings suggest that IL8 and MCP-1 play a significant role in oral tissue homeostasis. The few samples from pathological conditions encourage exploring diseased tissue in more detail.