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A Distinctive Myointimal Proliferation (`Myointimoma') Involving the Corpus Spongiosum of the Glans Penis: A Clinicopathologic and Immunohistochemical Analysis of 10 Cases

Fetsch, John F. M.D.; Brinsko, Robert W. M.D.; Davis, Charles J. Jr. M.D.; Mostofi, F. Kash M.D.; Sesterhenn, Isabell A. M.D.

American Journal of Surgical Pathology: November 2000 - Volume 24 - Issue 11 - pp 1524-1530
Original Articles

This study details the clinicopathologic and immunohistochemical features associated with 10 cases of a distinctive myointimal proliferation involving the corpus spongiosum of the glans penis. Patients ranged in age from 2 to 61 years old (mean age, 29 yrs) and presented with a mass that varied in size from 0.5 to 1.9 cm in greatest dimension. The process was said to be present from 4 days to more than 6 months before surgical intervention. In each case, microscopic examination revealed almost identical histology. There was a prominent, often occlusive, fibrointimal proliferation with plexiform architecture involving the vasculature of the corpus spongiosum. The proliferation consisted of stellate-shaped and spindled cells embedded in abundant fibromyxoid matrix. Occasional lesional cells had well-developed myoid characteristics with moderately abundant eosinophilic cytoplasm, blunt-ended nuclei, and juxtanuclear vacuoles. Foci with degenerative changes, including [ldquo]ghost cell[rdquo] morphology, were also present. The myointimal process was extensively immunoreactive for [agr]-smooth muscle actin, muscle-specific actin (HHF-35), and calponin, but it was minimally reactive for the D33 and D-ER-11 desmin clones. In contrast, native vascular smooth muscle encompassing the proliferation was strongly immunoreactive for all five markers. The myointimal cells were nonreactive for CD34, S-100 protein, and keratin. Factor VIIIrAg, CD31, and CD34 highlighted intact endothelial cells lining suboccluded vessels, scattered capillaries that penetrated the proliferation, and the normal uninvolved vasculature. The examined specimens were punch, incisional, or excisional biopsies, and in each instance, the process microscopically extended to the tissue margin. Followup data are available for 8 cases (median follow-up interval, 5 yrs 8 mos)[colon] one incompletely excised lesion with 6 months follow-up is stable but persistent, one lesion with 10 years follow-up regressed spontaneously after a punch biopsy, and the remaining six lesions have not recurred. A differential diagnosis of myofibroma, late-stage intravascular (nodular) fasciitis, vascular leiomyoma, and plexiform fibrohistiocytic tumor is discussed.

From the Departments of Soft Tissue Pathology and Genitourinary Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, U.S.A.

The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army, Navy, or Defense.

This is a U.S. Government work and, as such, is in the public domain in the United States of America.

Address correspondence and reprint requests to John F. Fetsch, MD, Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, U.S.A.

The penis is an uncommon site for soft tissue lesions. This report describes 10 cases of a rare but highly distinctive intravascular proliferation involving the corpus spongiosum of the glans penis. The process occurs over a wide age range and appears to develop over a relatively short period of time. We are aware of four previously published examples, reported as an intravascular leiomyoma, 4 intravascular leiomyomatosis, 8 intravascular myofibroblastic proliferation suggestive of late-stage intravascular fasciitis, 11 and a solitary cutaneous myofibroma. 16 The differential diagnosis revolves primarily around the latter two entities and a potential relationship to these is discussed.

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Cases accessioned to the Genitourinary and Soft Tissue Departments of the Armed Forces Institute of Pathology (AFIP) between 1970 and 2000 were the sole source of material for this study. Lesions involving the penis and coded as an organizing thrombus, intravascular fasciitis, fibrointimal proliferation, intravascular myofibroblastic proliferation, myofibroma, vascular leiomyoma, intravascular leiomyomatosis, or neurofibroma were retrieved for evaluation. Ten lesions with nearly identical histology were identified and are the basis for this report.

All hematoxylin and eosin-stained sections were reviewed. In eight cases, formalin-fixed, paraffin-embedded material was also examined with immunohistochemistry using the avidin-biotin complex (ABC) immunoperoxidase technique. Table 1 lists the immunohistochemical antibodies, their sources and dilutions. Enzymatic digestion at 37[deg]C with protease (either Type VIII or Type XIV, see Table 1) was used to unmask antigenic sites before incubation with primary antibodies directed against keratin, muscle-specific actin, calponin (a calmodulin, F-actin, and tropomyosin binding protein expressed in smooth muscle, myoepithelial, and myofibroblastic populations), and Factor VIIIrAg. Tissue sections to be examined for [agr]-smooth muscle actin, D-ER-11 desmin, D33 desmin, and CD31 were microwaved in 10 mM sodium citrate buffer (pH 6.0) at or near boiling for 20 minutes and cooled for 45 minutes in the buffer before incubation with the primary antibodies.

Primary antibodies were incubated with the histologic sections at room temperature for 1 hour. After incubation with a biotinylated secondary antibody, the immunohistochemical reaction was visualized using the avidin-biotin-peroxidase complex with either diaminobenzidine tetrahydrochloride or the Vector VIP substrate kit for peroxidase (Vector Laboratories, Burlingame, CA, USA) as the chromogen. Appropriate controls were tested simultaneously.

Follow-up data was obtained by telephone conversation with the patients or their urologists.

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Clinical Findings

The clinical features of the study group are summarized in Table 2. The patients ranged in age from 2 to 61 years old (median age, 29 yrs; mean age, 31 yrs) and presented with a solitary mass involving the glans penis. Four of the lesions involved the corona of the glans, and one occurred in close proximity to the meatus. The duration of the process was documented in seven instances and ranged from a purported 4 days to more than 6 months. The lesion of longest duration grew from 0.4 cm at first recognition to 1.1 cm at the time of resection. There were no symptoms associated with the masses in five instances. However, one patient noted mild tenderness. No patient related a history of trauma to the penis, and there was no documented evidence of diabetes, collagen-vascular disease, or autoimmune disease.

Management included an excisional biopsy (n [equals] 7), a biopsy of unspecified type (n [equals] 2), and a punch biopsy for diagnosis (n [equals] 1).

The differential diagnosis provided by the contributing pathologists included intravascular leiomyomatosis, multiple vascular leiomyomas, penile fibromatosis, fibrointimal hyperplasia, intravascular fasciitis, arteriovenous malformation, extensive venous occlusion (not otherwise specified), extraskeletal chondrosarcoma, schwannoma, and neuroma (1 each).

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Gross and Microscopic Findings

A partial or complete gross description was available for all 10 cases. The lesions ranged in size from 0.5 to 1.9 cm in greatest dimension (mean size, 0.9 cm) at the time of the surgical procedure. A firm consistency and beige or white color were reported.

Histologic examination revealed a complex myointimal proliferation involving the vasculature of the corpus spongiosum of the glans penis (Figs. 1, 2, and 3A). At low magnification, the process often had plexiform architecture. At higher magnification, the proliferation was noted to contain stellate-shaped and spindled cells embedded in abundant fibromyxoid matrix (Fig. 4A). Some lesional cells had well-developed myoid properties with moderately abundant eosinophilic cytoplasm, blunt-ended nuclei, and juxtanuclear vacuoles. However, other cells were more fibroblast-like in appearance. There was mild nuclear variability among the cells, but no atypia was present and mitotic figures were absent. All cases contained occasional cells with degenerative features, including [ldquo]ghost cell[rdquo] morphology (Fig. 3B). Inflammation was minimal and consisted primarily of perivascular lymphocytes.

With Masson's trichrome stain, the myointimal cells exhibited eosinophilic or amphophilic cytoplasm, and they were separated by abundant basophilic collagen. Longitudinal cytoplasmic striations were sparse. In contrast, native vascular smooth muscle surrounding the intimal proliferation often had more intense cytoplasmic eosinophilia and better defined longitudinal cytoplasmic striations.

A Verhoeff-van Gieson stain failed to demonstrate elastic fibers within the intimal proliferation (Fig. 4B). However, the surrounding vessel wall contained a fine meshwork of elastic fibers, and coarse elastic fibers were present to a variable extent in the adjacent soft tissue.

In seven specimens, skin was present for examination; in two of these, rare dermal vessels exhibited a similar myointimal proliferation. In one specimen, the surface epithelium was hyperkeratotic. Of note, the intimal process extended to involve the tissue margin in all 10 cases.

The myointimal proliferation was extensively immunoreactive for muscle-specific actin, [agr]-smooth muscle actin, and calponin, but it was only minimally reactive for the D33 and D-ER-11 desmin clones (Table 3;Fig. 5). While some myointimal cells with desmin expression were detected in most cases, the percent of immunoreactive cells was always less than 20[percnt] and usually less than 5[percnt]. In contrast, native vascular smooth muscle cells were strongly and diffusely immunoreactive for all five markers. Oftentimes, native smooth muscle reacted more intensely for muscle-specific actin, [agr]-smooth muscle actin, and calponin than the myointimal cells. No immunoreactivity was detected in the lesional cells for S-100 protein or a cytokeratin cocktail (AE1/AE3). CD31, CD34, and Factor VIIIrAg were expressed by endothelial cells lining normal vessels, vessels that were subtotally involved by the intimal proliferation (Fig. 5F), and capillary channels that penetrated the process. CD34 also reacted with perivascular stromal cells that were often accentuated around the affected vessels.

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Follow-Up Data

Follow-up data ranging from 3 months to 13 years (median follow-up interval, 5 yrs 8 mos) were obtained for eight patients. One patient, who was 6 months postbiopsy, had a persistent but stable nodule [ldquo]one-half the size of a pea.[rdquo] Another with 10 years of follow-up had complete regression of his lesion after undergoing only a punch biopsy. The remaining six patients were all considered disease-free. However, one individual was only 3 months postoperative and had noted some local tenderness at the operative site.

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We have described a highly distinctive intravascular proliferation involving the corpus spongiosum of the glans penis. The process is intimately associated with, and appears to be derived from, the intimal cells of blood vessels. It typically exhibits complex architecture, and it has morphologic and immunohistochemical features consistent with myofibroblastic differentiation. Our group of 10 patients ranged in age from 2 to 61 years. At presentation, a relatively small painless mass of stable size, or with a history of slow enlargement, was usually evident.

This myointimal proliferation has morphologic similarities to the plump, smooth muscle-like element with stromal hyalinization that is seen in so-called myofibromas. However, we have chosen not to classify our cases as the latter for several reasons. First, classic examples of myofibroma, as seen in the pediatric population (i.e., infantile myofibroma/myofibromatosis), have a peripherally situated myoid element arranged in short fascicles around a central hemangiopericytoma-like component. 2 Whereas this architecture is often less well-defined in the adult variant of myofibroma, a hemangiopericytoma-like element is nevertheless typically present. 3,7,13,15,18 None of the penile lesions, including three examples from pediatric patients, had a hemangiopericytoma-like component. Second, although myofibromas may involve vessels, it is very uncommon for a fully typical example of this process to be confined to the lumen of one or more vessels. 2 Our cases were strictly intravascular. Third, the designation [ldquo]myofibroma[rdquo] makes no reference to a vascular origin, which has been conclusively demonstrated for the penile lesions presented in this study.

Another myofibroblastic entity that must be considered in the differential diagnosis is a late fibrosing stage of intravascular (nodular) fasciitis. 6,12 While it is difficult to exclude a possible relationship to fasciitis, the penile myointimal lesions lacked a number of features commonly associated with this process, including loose tissue culture-like growth with mitotic activity, acellular mucoid pools, and a sprinkling of intralesional lymphocytes. 1,6,10,12,17

It is noteworthy that two previously published examples of this process were interpreted as smooth muscle tumor variants (i.e., an intravascular leiomyoma and intravascular leiomyomatosis). 4,8 While our findings support myoid differentiation, we believe the intraluminal location, along with the morphology and immunoprofile of the lesional cells, favors a myofibroblastic cell type over true smooth muscle.

One additional entity warrants brief mention in the differential diagnosis because of its growth pattern, the plexiform fibrohistiocytic tumor. 5,9 This process also has myofibroblastic differentiation, but it differs from the penile myointimal lesions by having greater proliferative activity with at least some degree of cytologic atypia. In addition, it frequently contains scattered osteoclast-like giant cells and is never predominantly intravascular in location. From a biologic perspective, the plexiform fibrohistiocytic tumor is a borderline neoplasm that rarely metastasizes. 5,14

Although there is no doubt that the myointimal proliferation described in this report is benign, it is unclear if it is reactive or neoplastic. At present, this issue remains unresolved for a variety of lesions with myofibroblastic differentiation, including the so-called myofibroma. 7 Nevertheless, our findings suggest that this process is self-limiting with a tendency to stabilize, and in some instances, even regress. This view is based on our follow-up data, as well as certain histologic observations, including a lack of mitotic activity, a tendency to accumulate collagen, and the presence of some degenerative cellular changes. As a result, management should be conservative.

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The authors thank Denise Y. Young for her outstanding immunohistochemical assistance.

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Immunohistochemistry; Intravascular fasciitis; Intravascular leiomyomatosis; Myofibroma(tosis); Myointimal proliferation; Penis; Plexiform fibrohistiocytic tumor; Soft tissue tumors; Vascular leiomyoma; Vascular tumors

[copy] 2000 Lippincott Williams [amp] Wilkins, Inc.