John F. Fetsch

Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.

Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KIT, and PDGFRA mutation status and long-term prognosis of patients with GIST in NF1 are incompletely characterized. In this study, we analyzed 45 patients who had NF1 and GIST. There were 26 females and 19 males with a median age of 49 years (10 years lower than the median age of GIST patients in general). A great majority of tumors occurred in the jejunum or ileum, with multiple tumors occurring in 28 cases. Ten patients had a duodenal and one had a gastric GIST. The most common presentations were gastrointestinal bleeding and anemia, and many patients had intermittent bleeding over several years. The majority of the tumors were small and mitotically inactive; only 7 had mitotic activity >5/50 HPFs and 15 tumors were >5 cm. Associated Cajal cell hyperplasia was common. One patient had an intraabdominal peri-intestinal neurofibroma. Five of 35 patients with follow-up died of metastatic disease; all of these had a tumor >5 cm, mitotic rate >5/50 HPFs, or both; three of these tumors were located in the duodenum. The presence of multiple small tumors was not associated with progressive disease. Most patients with long-term follow-up enjoyed a good prognosis; 2 died of other NF1-associated tumors (malignant peripheral nerve sheath tumors, brain tumor). None of the 16 tumors from 15 patients had a KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as is typically seen in sporadic GISTs, indicating that GISTs in NF1 patients have a different pathogenesis than sporadic GISTs.

Calcifying fibrous pseudotumor

We report 10 cases of a distinctive benign fibrous lesion characterized by the presence of abundant hyalinized collagen with psammomatous or dystrophic calcificatons and a lymphoplasmacytic infiltrate. The lesions were prsent from 2 months to 10 years before resection and ranged in size from 2.5 to 15 cm. They involved subcutaneous and deep soft tissues and, although relatively well-circumsribed, occasionally infiltrative borders or entrapped structures were seen on microscopic examination. The lessions were located in the extremities (three cases), trunk (two cases), scrotum (two cases). groin (one case), neck (one case), and axilla (one case). Both sexes were equally affected. the man and median ages of the patients were 16.2 and 18.5 years, respectively (range, 1 to 33 years). All cases were initially managed by simple local excision. Follow-up ranging from 2 months to more than 10 years (median, 41.5 months) was available in six cases and revelaed a local recurrence in one instace; this became clinically apparent about 7.5 years after the initial resection. Morphologic features and follow-up data suggest this may be a unique from of fibrous pseudotumor.

Sclerosing perineurioma: a clinicopathologic study of 19 cases of a distinctive soft tissue lesion with a predilection for the fingers and palms of young adults.

This report describes 19 cases of a distinctive sclerosing perineurial tumor of the hands. Fourteen patients were male and five were female (age range 9-55 years; median age 24.5 years). The process typically presented as a painless mass and was present from 6 months to 40 years before resection. Sites of involvement were the thumb (n = 6); index (n = 3), middle (n = 4), and ring (n = 4) fingers; and the palm (n = 2). The lesions were generally well marginated but nonencapsulated. They had a firm, fibrous consistency and ranged in size from 0.7 to 3.3 cm in maximum dimension. Microscopic examination showed abundant dense collagen and variable numbers of small, epithelioid, and spindled cells exhibiting corded, trabecular, and whorled (onion bulblike) growth patterns. Immunoreactivity was present for epithelial membrane antigen (15 of 15); a cytokeratin cocktail containing AE1, AE3, and CK1 (four of 14); CAM 5.2 (one of 12); vimentin (12 of 12); muscle-specific actin (nine of 14); alpha-smooth muscle actin (six of 14); collagen IV (six of six); laminin (five of six); and CD99 (three of five). Ultrastructural features consistent with perineurial cells were noted. All of the lesions were locally excised. Follow-up was obtained for seven patients, with mean and median follow-up intervals of 12 years 7 months and 10 years 6 months, respectively. None of the lesions have recurred. This study advances the morphologic spectrum of perineurioma, a rare tumor of nerve sheath derivation. Familiarity with this distinctive subtype should help to avoid confusion with other processes, including a fibroma of tendon sheath, the sclerotic fibroma associated with Cowdens disease, an epithelioid neurofibroma, a late stage of tenosynovial giant cell tumor, and sclerosing adnexal tumors.

Neurothekeoma : An analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information

This report describes the clinicopathologic findings in 176 patients who presented with 178 tumors currently referred to as neurothekeomas. Our study group included 64 males and 112 females, ranging from 20 months to 85 years old at the time of their first surgical procedure (median age: 17 y). Twenty-four percent of patients were ≤10 years of age and only 20% of patients were ≥30 years of age at initial diagnosis. The patients typically presented with a solitary, superficial, slow-growing, and relatively asymptomatic mass in the 0.3 to 2.0 cm size range. One patient had multiple tumors. More than 75% of the lesions involved the head (n=63), upper extremities (n=44), and shoulder girdle (n=27) regions. The tumors were evident a few weeks to 4 years (median duration: ≈7 mo) before surgical resection was sought. Histologically, the lesions involved the dermis and/or subcutis, and they formed multinodular masses with varying amounts of myxoid matrix and peripheral fibrosis. On the basis of the amount of myxoid matrix, the tumors were subclassified as cellular (n=63), mixed (n=67), or myxoid (n=48). All cases had spindled and epithelioid mononuclear neoplastic cells with relatively abundant cytoplasm and indistinct cell borders. The majority of cases also had occasional multinucleated tumor cells. The lesional cells had a strong tendency for whorled growth, and oftentimes, focal fascicular growth was also present. Nuclear atypia was minimal in 62 cases, mild in 73 cases, at least focally moderate in 41 cases, and focally marked in 2 cases. Mitotic activity ranged from 0 to 124 mitotic figures/25 wide-field high power fields (WHPFs) (median mitotic count: 4 mitotic figures/25WHPFs). Twenty-five lesions had >10 mitotic figures/25WHPFs. A total of 16 cases (9%) had atypical mitotic figures. Osteoclastlike giant cells were detected in 39% of cases. Immunoreactivity was typically present for vimentin, NKI/C3, CD10, microphthalmia transcription factor, and PGP9.5, and focal reactivity was sometimes noted for smooth muscle actin and CD68. All tumors tested were negative for S100 protein, glial fibrillary acidic protein, and Melan A. The overwhelming majority of cases had involvement of the tissue margins. A complete follow-up record is available for 71 patients (40.3%) with follow-up intervals ranging from 3 years 2 months to 34 years 9 months (median: 17 y 9 mo). Limited or incomplete follow-up information is also available for an additional 14 patients with follow-up intervals ranging from weeks to approximately 10 years (median: 5 mo). Regrowth of tumor after biopsy or local excision was reported in 13 patients, one of whom had 2 recurrences. However, because of the nature of our consultation practice and a tendency for clinicians to specifically send us cases with a complex clinical course, this is believed an overestimation of the true recurrence rate. Neurothekeomas are morphologically and immunohistochemically distinct from true nerve sheath myxomas. An origin from fibroblastic cells with the ability to differentiate into myofibroblasts and a tendency to recruit histiocytic cells is postulated.

A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis.

The tumor described here as lipofibromatosis is a rare pediatric neoplasm that has been variously interpreted as a type of infantile or juvenile fibromatosis, a variant of fibrous hamartoma of infancy, and a fibrosing lipoblastoma. This report details the clinicopathologic features associated with 45 cases of this soft tissue entity. The study group consisted of 32 males, 12 females, and one person of unstated gender. The patients presented with a soft tissue mass (range, 1–7 cm) involving the hand (n = 18), arm (n = 8), leg (n = 7), foot (n = 6), trunk (n = 5), or head (n = 1). Eight tumors were evident at birth. The individuals ranged in age from 11 days to 12 years (median age, 1 yr) at the time of initial biopsy or resection. Microscopic examination revealed abundant adipose tissue with a spindled fibroblastic element that chiefly involved the septa of fat and skeletal muscle. The process generally did not cause extensive architectural effacement of fat as is common with conventional fibromatoses, and it did not have a primitive nodular fibromyxoid component as is characteristic of fibrous hamartoma of infancy. The fibroblastic element exhibited focal fascicular growth and typically had limited mitotic activity (≤1 mitosis/10 high-power fields) and cytologic atypia. Oftentimes, small collections of univacuolated cells were present at the interface between some of the fibroblastic fascicles and the mature adipocytes. The tumors entrapped vessels (n = 45), nerves (n = 44), skin adnexa (n = 16), and skeletal muscle (n = 18). Focal immunoreactivity was present in some tumors for CD99, CD34, &agr;-smooth muscle actin, BCL-2, and less frequently, S-100 protein, muscle actin (HUC 1-1), and EMA. However, no reactivity was detected for desmin (D33 and D-ER-11 clones), keratins, or CD57. Follow-up data were available for 25 individuals (median follow-up period, 6 yrs 7 mos) with regrowth of the tumor or persistent disease documented in 17 (72%). The following events were more common in the group with recurrent or persistent disease: congenital onset, male sex, hand and foot location, incomplete excision, and mitotic activity in the fibroblastic element. Although it is likely this tumor comprises part of the spectrum of what has been referred to in the literature as infantile/juvenile fibromatosis, its clinicopathologic features and, in particular, its distinctive tendency to contain fat as an integral component, warrant separate classification as a “lipofibromatosis.”

Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate.

This report describes the clinicopathologic findings in 57 cases of nerve sheath myxoma. Our study group included 34 males and 23 females, ranging from 8 to 72 years of age at the time of their first surgical procedure (mean, 36 years; median, 34 years). The patients typically presented with solitary, superficial, multinodular masses in the 0.5- to 2.5-cm size range. Eighty-six percent of cases occurred in the extremities, with the most common locations being the hand/fingers (n = 22), knee/pretibial region (n = 10), and ankle/foot (n = 7). Only 7 cases (12.3%) involved the trunk or head and neck region. The tumors were generally slow growing, and often, they were present for many years before surgical resection was sought. In the majority of instances, the lesions were painless. Histologically, the tumors involved the dermis and/or subcutis, and they formed distinct multinodular/multilobular masses with abundant myxoid matrix and a peripheral fibrous border. All cases had small epithelioid Schwann cells in corded, nested, and/or syncytial-like aggregates, a variable number of Schwann cells with a ring-like appearance, and scattered spindled and stellate-shaped Schwann cells. These cells often had cytoplasmic-nuclear invaginations, and they were immunoreactive for S-100 protein, glial fibrillary acidic protein, neuron specific enolase, and CD57. They were also bordered by collagen IV. Epithelial membrane antigen-positive perineurial cells were typically present in small numbers, primarily in the fibrous tissue directly adjacent to the myxoid nodules. CD34-positive intraneural fibroblasts were generally sparse. Mitotic figures were uncommon. All cases were initially managed by simple excision, and in almost all instances, tumor extended to the tissue edge. Follow-up information is available for 34 patients (follow-up range, 8 months to 28 years; median follow-up interval, 14 years 3 months). Sixteen patients (47%) had one (n = 11) or more (n = 5) local recurrence of their tumor, and 2 additional patients had findings suspicious for a recurrence. Nerve sheath myxomas are morphologically distinct peripheral nerve sheath tumors with a peak incidence in the fourth decade of life and a strong predilection for the extremities. These tumors have a relatively high local recurrence rate when managed by simple local excision. They appear to be unrelated to so-called cellular and mixed-type neurothekeomas.

Collagenous fibroma (desmoplastic fibroblastoma): A clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with stellate-shaped fibroblasts

Sixty-three cases of collagenous fibroma (desmoplastic fibroblastoma) from the files of the Armed Forces Institute of Pathology were analyzed. These tumors occurred mostly in men (80%) with a median age of 50 years (range, 16 to 81 years). The lesions had a wide anatomic distribution and involved the arm (24%), shoulder girdle (19%), posterior neck or upper back (14%), feet or ankles (14%), leg (14%), hand (8%), and abdominal wall and hip (6%). The patients typically presented with a history of a painless, slowly growing mass, often of relatively long duration. The tumors ranged in size from 1 to 20 cm (median, 3.0 cm). The lesions were predominantly subcutaneous, but fascial involvement was common, and 27% of cases involved skeletal muscle. Gross examination typically showed an elongated, lobulated, or disc-shaped mass with a firm consistency and a homogeneous pearl-gray color. Histologically, the tumors often appeared well marginated on low-power examination, but most (78%) infiltrated fat or, less commonly, skeletal muscle. The lesional cells were relatively bland stellate and spindle-shaped fibroblasts separated by a collagenous or myxocollagenous matrix. Mitotic activity was absent or minimal. Some of the lesional cells had a myofibroblastic immunophenotype, as evidenced by focal reactivity for muscle-specific and alpha-smooth muscle actins. In a few cases, rare actin-positive cells were also positive for keratins. Desmin, S100 protein, and CD34 were not expressed. None of the 39 patients with follow-up (median, 11 years) developed a recurrence. Collagenous fibroma is a benign fibroblastic/myofibroblastic proliferation. The large size of some of these tumors coupled with slow growth and persistence favors a neoplastic process over a peculiar reactive proliferation. The differential diagnosis includes a variety of reactive and neoplastic fibroblastic lesions, most importantly fibromatosis and low-grade fibromyxoid sarcoma. Simple, conservative excision is the treatment of choice for collagenous fibroma.

Pigmented (melanotic) neurofibroma: a clinicopathologic and immunohistochemical analysis of 19 lesions from 17 patients.

Neurofibromas with melanin-laden pigmented cells are rare, accounting for less than 1% of all neurofibromas accessioned to the Soft Tissue Registry of the Armed Forces Institute of Pathology between the years 1970 and 1996. This study analyzes the clinicopathologic features associated with 19 specimens removed from 17 patients. Eleven males and six females, ranging in age from 2 to 61 years (median, 28 years), participated in the study. Nine of 15 patients whose race was provided were black. Eight patients (47%) are known to have neurofibromatosis, and two others (12%) are strongly suspected of having this disorder; two patients have similarly affected family members. Eight patients were noted to have multiple skin tumors, and in each of two cases, two pigmented neurofibromas were available for review. Two patients had hypertrichosis and cutaneous hyperpigmentation resembling a hairy nevus, and one had a café au lait spot directly overlying a pigmented neurofibroma. Tumors ranged in size from 1.7 to 50 cm in greatest dimension and involved the buttock or leg (n = 6), head or neck (n = 8), trunk (n = 2), wrist or hand (n = 2), and an unspecified site (n = 1). The neurofibromas exhibited diffuse (n = 15), combined diffuse and plexiform (n = 2), combined diffuse and intraneural epithelioid (n = 1), and nonspecific (n = 1) growth patterns. The process involved the skin (n = 14), subcutis (n = 18), and/or skeletal muscle (n = 3). Wagner-Meissner-like bodies were identified in 11 tumors, and mitoses (average, less than one mitosis per 10 high-power fields) were present in three lesions. All examples contained scattered pigmented cells with dendritic, tadpole-shaped, spindled or epithelioid morphology. These cells were positive with Fontana-Masson (nine of nine) and Warthin-Starry (pH, 3.2; four of four) stains, and were depigmented with a melanin bleach method (two of two). An iron stain was negative. The tumors had immunoreactivity for S-100 protein (11 of 11), HMB-45 ( 10 of 11), Melan-A (four of four), tyrosinase (four of four), and CD34 (four of four). Although recurrences are documented, none of the tumors are known to have undergone malignant transformation. A pigmented neurofibroma can be confused with a pigmented dermatofibrosarcoma protuberans (Bednár tumor) because the melanin-laden cells of both processes are similar. However, the latter entity exhibits a more extensive storiform growth, has greater immunoreactivity for CD34, and lacks a diffuse proliferation of S-100 protein-positive Schwann cells.

Superficial angiomyxoma (cutaneous myxoma): a clinicopathologic study of 17 cases arising in the genital region.

SummarySeventeen cases of superficial angiomyxoma (cutaneous myxoma) of the genital region are reported. Thirteen patients were female (age range: 15–33 years; mean: 21 years) and four were male (age range: 18–55 years; mean: 39 years). The sites of involvement in females were the labium majus or labium, not otherwise specified (n = 6), vulva (n = 4), groin (n = 2), and mons pubis (n = 1). All lesions in male patients involved the scrotum. The tumors were present from 2 months to 4 years before resection and ranged from 0.9 to 6 centimeters in maximal dimension; 10 tumors were 3 centimeters or less in size. The predominant reason for seeking medical attention was a slow growing painless mass. All lesions were locally excised. Follow-up was obtained for 9 patients with a mean and median follow-up interval of 135 and 95 months, respectively. A recurrence developed in three patients at 8 months, 7 years 11 months, and 20 years. No patient has been shown to have Carneys complex. The tumors were immunoreaetive for vimentin (11/11), CD34 (11/11), muscle-specific actin (8/12), smooth muscle actin (9/11), S100 protein (5/13), and Factor Xllla (5/9). No immunoreactivity was present fordesmin (DE-R-11), glial fibrillary acidic protein, estrogen receptor or progesterone receptor. Superficial angiomyxomas are probably derived from fibroblast-like cells capable of antigen modulation.

Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases.

Reticulohistiocytoma and multicentric reticulohistiocytosis are designations for uncommon, incompletely characterized histiocytic proliferations of the skin or soft tissues. In this study, we analyzed a uniform group of 44 lesions composed of epithelioid histiocytes, comprising a subset of lesions originally designated as reticulohistiocytoma, and propose designating them as “solitary epithelioid histiocytoma” (SEH), in line with the recently published classification proposal for histiocytic disorders. There were 26 males and 18 females with a median age of 35 years (range, 2.5–74 years). All patients had a superficial, circumscribed, mildly elevated, solitary lesion (size range, 1.5–11 mm; median, 4 mm), located in the trunk wall (n=16), lower extremity (n=12), head and neck (n=8, including 2 in the oral cavity), upper extremity (n=6), penis (n=1), and an unspecified site (n=1). Histologically, the lesions typically involved upper and mid-dermis and were not ulcerated. They were composed of large epithelioid histiocytes with a varying number of lymphocytes and neutrophils. The histiocytes had abundant, typically densely eosinophilic, cytoplasm and mostly mild, if any, nuclear atypia. Multinucleated forms with randomly oriented nuclei were also present. The histiocytes had low mitotic activity (range, 0–4 mitoses per 10 wide HPFs; median, 1 mitosis per 10 HPFs). The lesions contained varying numbers of CD3-positive T cells, whereas B lymphocytes, plasma cells, eosinophils, and mast cells were scant, if present at all. Immunohistochemically, the epithelioid histiocytes were positive for CD163, CD68, lysozyme (variably), and vimentin. They often had focal nuclear immunoreactivity for microphthalmia transcription factor, and they sometimes had focal reactivity for Factor XIIIa and S-100 protein. Membrane positivity for CD31, CD43, and CD45 was variable. The epithelioid histiocytes were consistently negative for CD3, CD20, CD30, HMB45, and keratins. All 12 patients with follow-up information had an uneventful clinical course with no recurrences (median, 13 years). SEH is a benign, probably reactive, histiocytic proliferation of unknown etiology. It needs to be distinguished from Rosai-Dorfman disease, juvenile xanthogranuloma, a variety of granulomatous conditions, and some malignant neoplasms, including histiocytic sarcoma, melanoma, and epithelioid sarcoma.