—  SHORT COURSE #21  —

Mesenchymal Neoplasms of the Female Genital Tract

Case 5 - Disseminated Peritoneal Leiomyomatosis

Teri Longacre, Esther Oliva and Robert Soslow


Introduction
Disseminated peritoneal leiomyomatosis (DPL) is a rare condition characterized by widespread nodules of histologically benign smooth muscle in the omentum and peritoneum, often numbering in the tens to hundreds. The nodules are usually small, firm, gray-to-white, and cover the peritoneal surface of the uterus, uterine ligaments, ovaries, fallopian tubes, small and large intestine, cul de sac, mesentery, and retroperitoneum, clinically simulating a disseminated malignancy. DPL typically occurs during the reproductive years and many patients are pregnant at the time of diagnosis. Most cases are discovered incidentally at laparotomy. The intraoperative appearance of DPL, first described by Willson and Peale and subsequently recognized as a distinct entity in 1965 by Taubert and colleagues, is so alarming that an intraoperative pathological examination with frozen section is often requested to exclude abdominal carcinomatosis. [41, 46] Despite the alarming appearance, DPL is usually associated with an indolent clinical course and can be treated conservatively with long-term follow-up. The condition is rare; less than 150 cases have been reported in the literature.

Clinical Features
DPL is most common in women of reproductive age (mean, 37 years), who are pregnant or have a long-term history of oral contraceptive use or endogenous increased estrogen production. In fact, the initial description of this condition was in a woman with an estrogen-secreting granulosa cell tumor. [46] Rarely, DPL has been reported in postmenopausal women and in men. [10, 23, 25, 27] Familial clustering of DPL in association with Raynaud's syndrome and prurigo nodularis affecting male and female family members has also been reported. [18]

Most patients have uterine leiomyomas at the time of diagnosis. Ascites may be present. Most patients are asymptomatic or develop symptoms resembling adenomyosis or endometriosis; an association with this latter condition has been reported. [44] The most common presenting symptom is vague pelvic pressure, although by report, one patient presented with an acute abdomen due to bowel obstruction. [15]

The development of DPL has been attributed to elevated hormonal stimulation and/or an enhanced responsiveness to steroid hormones and the nodules in DPL appear to either regress or show no growth once the hormonal stimulus is removed (cessation of pregnancy, removal of estrogen-secreting ovarian tumors, etc.). Extensive surgery is not usually recommended, except for symptomatic relief or patients who have completed childbearing. Despite these recommendations, many patients have been treated with surgical debulking and total hysterectomy with bilateral oophorectomy. Because of the strong association with increased hormonal production in some cases, treatment with gonadotropin-releasing hormone agonists (GnRH) has been advocated. [19]

Rarely , DPL is associated with a more aggressive clinical course. [8] Two young women, both nulligravid and with no history of oral contraceptive use, developed rapidly progressive abdominal disease and died within a two year period after an initial diagnosis of DPL. One of the cases was associated with a large unresectable mass at presentation, which exhibited high-grade leiomyosarcoma on subsequent histologic examination, while the other was interpreted as a histologically low-grade sarcoma at the time of recurrence. [1, 3] Eight other patients with sarcomatous transformation of conditions resembling DPL have also been reported, three of which occurred in men. [10, 27, 38] In most of these cases, there was no history of exposure to estrogen and only one was pregnant at the time of diagnosis. None have had associated uterine leiomyomas. In all cases, a large smooth muscle tumor, 6 to 40 cm in size, exhibiting features of leiomyosarcoma (= cellularity, nuclear atypia, tumor cell necrosis, increased mitotic index and infiltrative growth) was identified, either at the initial presentation or within 12 months of initial presentation of DPL.

The mean age of patients with these aggressive forms does not differ significantly from the more typical DPL (range, 20 to 48 years) although one occurred in a 70-year-old man and another in a 55-year-old postmenopausal woman. [40, 47] Most die within two years of initial presentation. Whether these cases represent true sarcomatous transformation of DPL, inadequate sampling and/or histologically non-informative sarcomatous tumor nodules, or a coincidental occurrence of two independent smooth muscle processes is not known, but the short interval between diagnosis of DPL and development of diagnosable sarcoma indicates that the two may represent related, but distinct entities. [8]

Histologic Features
In most cases, the nodules in DPL measure 2 to 3 mm in size, but nodules measuring 3 to 4 cm may occur and nodules as large as 10 cm have been reported. The cut surface of the nodules is typically that of a benign smooth muscle neoplasm - and consists of a whorled pattern with no necrosis, hemorrhage or soft, fleshy foci. Sections typically show histologically benign appearing smooth muscle (= spindle-shaped cells with elongated blunt-ended nuclei arranged in intertwining bundles); occasionally, foci of endometriosis or sex cordlike elements are also present. [26, 29, 44] A case report of "disseminated adenomyomas" probably represents an extreme example of DPL with endometrial tissue. [9] Foci of decidualization in pregnant patients and/or hyalinization may be present. Nuclear pleomorphism and hypercellularity are absent. Mitotic figures are inconspicuous and if present, number < 3 MF/10 HPF. The nodules are situated immediately beneath the peritonealized surfaces and unattached to blood vessels. A single case of possible DPL that was centered on medium-sized blood vessels has been reported in a postmenopausal woman, but this is not a typical feature of the disease. [31] Lymph node involvement has been reported. [22]

Immunohistologic Features
DPL expresses desmin, smooth muscle actin and CD10. [2] In addition, most express ER and PR, often at higher levels than the corresponding myometrium. [6, 13] Aggressive variants typically do not express hormone receptors.

Molecular Features
The etiology of DPL is unknown. A metaplastic transformation of the subperitoneal mesenchyme has been proposed, based on the contribution of this tissue to the formation of the uterine myometrium during embryogenesis. Cases that also feature endometrium have been compared to miniature uteri. [26] The presence of fibroblastic and myofibroblastic tissue and the disposition of the nodules amidst the decidua in pregnant patients led to the interpretation by Parmley and colleagues that DPL may be a reparative, fibrosing response rather than a neoplastic smooth muscle process. [33] Experimental studies in guinea pigs have demonstrated smooth muscle proliferations similar to DPL in response to high dose estrogen and progesterone. These proliferations regress following removal of the hormonal stimulus. [14]

Clonality has been demonstrated based on non-random X chromosome inactivation patterns. [35] Clonality in this setting may reflect metastatic spread from a unicentric disease, or an underlying predisposition to a specific clonal abnormality, as is seen in some uterine leiomyomas. Cytogenetic abnormalities involving chromosomes 7, 12, and 18 have also been reported.

Clinical Management
Since many cases appear to regress without treatment, complete excision of all nodules is not indicated as long as the diagnosis has been confirmed, usually by intra-operative frozen section. Adequate sampling of all large nodules should be performed to exclude potentially more clinically malignant smooth muscle neoplasms (see Differential Diagnosis), especially in those patients with unusual clinical features (e.g. older age, absence of exogenous or endogenous hormone exposure, nodules > 2 cm). Despite the apparent hormonal responsiveness of the tumors in DPL, oophorectomy is not indicated.

Differential Diagnosis
A variety of other smooth muscle proliferations simulate DPL by virtue of their distribution of disease. These include leiomyosarcoma, intravenous leiomyomatosis, benign metastasizing leiomyoma, lymphangioleiomyomatosis, parasitic leiomyoma, and malignant gastrointestinal stromal tumor (GIST). In most instances, malignant variants are easily excluded and the remaining entities are distinguished on the basis of a variety of clinical and locational attributes.

Gastrointestinal Stromal Tumor vs DPL
Gastrointestinal stromal tumors (GIST) may on occasion present as multiple nodules dispersed throughout the abdomen, but they are typically not as diffuse or as widespread as in DPL. [37] GIST is usually centered on the bowel wall as opposed to the subperitoneum, but approximately 10% of GIST are extra-intestinal and present in the omentum, mesentery, retroperitoneum or pelvis. Spindle and/or epithelioid histology may be present. Since the mitotic index and nuclear atypia are often minimal in GIST, smooth muscle tumors form the primary differential diagnostic consideration in most cases. DPL is excluded on the basis of distinctive clinical presentation and absence of CKIT (CD117), whereas 85 to 90% of GIST express this marker. GIST may contain areas of necrosis, a feature that is conspicuously absent in DPL.

Benign Metastasizing Leiomyoma vs DPL
Benign metastasizing leiomyoma (BML) is a condition consisting of histologically benign smooth muscle tumors in the lungs, lymph nodes or abdomen that appear to originate from a benign uterine leiomyoma, which typically is removed many years prior to the development of extra-uterine disease. [20] The distinctions between BML and DPL involve a constellation of clinicopathologic and definitional features. BML usually presents as one or more pulmonary nodules; when it occurs within the pelvis and abdomen, there are usually only one or two nodules, the nodules are larger, and they tend to be distributed near the region of the round ligament or iliac veins. Additional sites of involvement have included bone, skull base and spine, and heart. A history of previously resected leiomyoma or less commonly, a concomitant uterine leiomyoma is present in the case of BML. [16, 36] DPL is usually discovered incidental to some other procedure, often during pregnancy and is also typically associated with uterine leiomyoma. In most cases, the differential diagnosis can be resolved by attention to the clinical and distributional features. However, caution should be exercised during intraoperative consultation in problematic cases. Some surgeons may not proceed further with a frozen section biopsy diagnosis of DPL since progression is rare and many cases appear to regress without treatment. On the other hand, BML, which is persistent, is usually resected.

Metastatic Leiomyosarcoma vs DPL
Because of the extensive disease within the peritoneum, the unwary pathologist may confuse DPL with metastatic leiomyosarcoma. However, the typical gross appearance of metastatic leiomyosarcoma is that of large, fleshy and necrotic tumor masses and there is significant cytologic atypia and mitotic activity on microscopic examination. In addition, in most cases of metastatic leiomyosarcoma there will be a history of a previously resected leiomyosarcoma or a concomitant, large uterine mass. Metastatic leiomyosarcoma is often concentrated in the pelvis with distribution in the vicinity of the round ligament and iliac veins, whereas DPL is scattered throughout the abdomen. [21] In some instances, the metastatic nodules may not exhibit characteristic features of malignancy and additional sampling of other nodules, particularly the larger lesions is required. At least some of the reports of DPL with malignant change may represent leiomyosarcoma with these histologically non-informative metastases. [27, 38]

Intravenous Leiomyomatosis vs DPL
Intravenous leiomyomatosis (IVL) is another rare and unusual smooth muscle condition that tends to occur in premenopausal, often parous women. [30] Characterized by intravenous intrusion of histologically benign smooth muscle, IVL is notorious for its ability to grow into the right heart, causing cardiopulmonary insufficiency. When confined to the pelvis, the condition is recognized as worm-like protrusions of smooth muscle from veins at the parametrial margin of hysterectomy specimens. The smooth muscle in IVL resembles smooth muscle tumors in the uterus in every respect and may feature epithelioid, myxoid, and sex cord features. [12] Patients may be asymptomatic, but more commonly present with a pelvic mass clinically indistinguishable from a typical uterine leiomyoma. IVL is treated by complete extirpation of the involved veins. Recurrence is uncommon.

Although IVL has been reported to occur in association with BML, there is no clear association with DPL. [5, 24] Extension into the smaller pelvic veins may simulate the peritoneal distribution of DPL on initial inspection, but DPL only involves subperitoneal surfaces and invasion or involvement of the lumens of blood vessels does not occur. As in DPL, uniclonality has been demonstrated. [34] Rearrangements of the HMGA2 gene have also been reported. [34]

Retroperitoneal Leiomyosarcoma vs DPL
Malignant smooth muscle tumors of the retroperitoneum may feature less cellularity and cytologic atypia than those arising in the uterus. Conventional criteria for uterine smooth muscle tumors do not apply to these neoplasms and recent criteria for malignancy includes mitotic index > 3 MF/50 HPF. [32, 45] Small, nodular metastases of these tumors may not always demonstrate classic histologic features of malignancy. A key distinguishing feature is the presence of a large dominant mass in association with the smaller metastatic nodules in retroperitoneal leiomyosarcoma. Many of these tumors arise in association with blood vessels, although a vascular origin may be difficult to identify on histologic examination. Retroperitoneal leiomyosarcoma is more common in older age groups. Hormone receptor expression is often present in retroperitoneal leiomyomas, but is only variably present in the leiomyosarcomas.

Parasitic Leiomyoma vs DPL
Pedunculated leiomyomas have been reported to detach from their subserosal point of uterine attachment due to torsion and necrosis of the pedicle. Reattachment to other sites in the pelvis or omentum then generates a secondary parasitic vascular supply. This phenomenon, if it occurs at all, is uncommon and is not associated with the presence of multiple smooth muscle nodules scattered throughout the abdomen. Typically, there is one or only a few such tumor nodules in parasitic leiomyoma and the nodules are often larger than those usually seen in DPL. [20]

Lymphangioleiomyomatosis vs DPL
Lymphangioleiomyomatosis (LAM) is a rare condition occurring in women of reproductive age characterized by a nodular, often widespread proliferation of myoid cells along lymphatic channels with involvement of lung and lymph nodes. Sites of affected lymph nodes include mediastinum, retroperitoneum, and pelvis, where enlarged masses forming lymphangiomas and lymphangiomyomas may be seen. [43] Occasionally, uterine involvement is also present. [17, 28] LAM is usually sporadic but patients with tuberous sclerosis complex are often affected. The constituent cells are spindle and clear with epithelioid features. Immunoreactivity for desmin and actin, as well as HMB-45 is present. The predominant involvement of lymph nodes and association with lymphatic channels distinguishes LAM from DPL, where the nodules are scattered throughout the peritoneum and associated with the subperitoneum. Additionally, involvement of pulmonary parenchyma is not a feature of DPL.

Reactive Nodular Fibrous Pseudotumor vs DPL
There are several reactive processes that can present with multiple nodular lesions in the peritoneal cavity, which have been variously designated as "peritoneal fibrous nodules," "calcifying fibrous pseudotumor," and "reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery". [11, 39, 48] Histologically, these lesions are characterized by fibrocollagenous nodules composed of sparse spindle cells within a hyalinized, keloid-type collagen, with or without a chronic lymphocytic or plasmacellular inflammatory infiltrate. These lesions may occur in men as well as women, and may be associated with endometriosis when presenting in women during the reproductive years. The nodules in reactive nodular fibrous pseudotumor are often larger than those usually encountered in DPL and do not typically express desmin, although expression of CKIT (CD117) has been reported. Often, a prior history of surgery or peritoneal inflammatory disorder is present.

Hereditary Leiomyomatosis
The presence of multiple leiomyomas in the uterus in conjunction with multiple cutaneous leiomyomas may occur in the setting of familial leiomyomatosis. Mutations in the fumarate hydratase (FH) gene, an enzyme involved in the mitochondrial tricarboxylic acid cycle, are associated with an autosomal dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomas. [4, 7, 42] The cutaneous leiomyomas may be diffuse or segmental and may develop before or after the uterine leiomyomas. Benign smooth muscle tumors also develop in the skin of affected males. Unlike DPL, no intra-abdominal involvement has been reported. The leiomyomas are histologically and clinically benign, but a subset of affected patients develops type II renal cell papillary carcinoma (hereditary leiomyomatosis and renal cell cancer).

A Managerial Approach
Efforts to correctly diagnose and classify neoplasms exhibiting standard smooth muscle differentiation anywhere in the female genital tract should be directed towards two goals: 1) distinguishing clinically malignant neoplasms (i.e., leiomyosarcoma) from clinically benign neoplasms that feature one or more of the following: alternative differentiation (e.g., myxoid or epithelioid), increased cellularity, marked cytological atypia and necrosis; and 2) distinguishing benign or, at most clinically indolent, smooth muscle proliferations that involve extrauterine sites, and may produce morbidity, but only rarely lead to patient death. [21] These latter proliferations, which are often incidental findings, either present at high stage or recur after initial presentation at low stage, but usually have an indolent clinical course, even when recurrence occurs. This group of tumors includes DPL, intravenous leiomyomatosis, benign metastasizing leiomyoma and lymphangioleiomyomatosis.

Since the criteria for the diagnosis of "leiomyosarcoma" vary depending not only on the differentiated type (standard versus myxoid versus epithelioid), but also on the primary site (e.g., vulva versus uterine corpus versus retroperitoneum), localization is important in the initial assessment of smooth muscle neoplasms. For all tumors that initially present at an extra-uterine site, the possibility of metastasis should be considered before applying the diagnostic criteria relevant to that particular site of presentation. Smooth muscle differentiation should be confirmed and mimics should be excluded (e.g. GIST, other sarcoma types, high grade carcinoma, and melanoma) with appropriate immunohistologic stains, when relevant. Whether or not grading leiomyosarcoma in the female genital tract offers useful prognostic information is debatable. A variety of grading schemes have been described, most of which rely on mitotic index, cellular atypia and necrosis. If a grade is assigned to a leiomyosarcoma, the grading scheme used should be explicitly stated in the pathology report.

The treatment for the second group of important, but clinically benign or indolent smooth muscle tumors differs depending on the diagnosis. The treatment of choice for BML and IVL is complete excision, while the management of lymphangioleiomyomatosis is directed towards estrogen reduction therapies and maintenance of pulmonary functioning. [19] Because of the potentially confusing picture in some cases of DPL and the partial histologic overlap with morphologically non-informative leiomyosarcoma, the nodules in DPL must be at least partially excised, with particular attention to the larger nodules. Extensive sampling of the larger nodules to exclude cellular atypia, necrosis and increased cellularity should also be performed. Since many cases appear to regress without treatment, it is important to bear in mind that a frozen section biopsy diagnosis of DPL may not result in complete excision of all nodules. Despite the apparent hormonal responsiveness of the tumors in DPL, oophorectomy is not indicated.

Women who present with DPL in absence of 1) uterine leiomoymas, 2) exogenous or increased endogenous estrogen exposure, and 3) hormone receptor expression on immunohistochemical studies should be regarded as harboring potentially malignant tumors and followed closely. All discrete tumors exceeding 3 to 4 cm should be excised and extensively sectioned. In addition, any early (= within first year of diagnosis) recurrence or evidence of progression of disease after estrogen has been decreased should probably be regarded as a potentially malignant process and such patients should undergo a full evaluation in order to exclude sarcomatous transformation. [8] To date, all men with DPL-like presentations have had a uniformly aggressive clinical course.

Table 1. Differential Diagnosis of Smooth Muscle Proliferations in the Female Genital Tract

DPL BML IVL LAM LMS
Age
(years) 		Reproductive
(mean, 31) 		Late reproductive
(mean, 43) 		Peri-menopausal
(mean, 47) 		Reproductive
(mean, 35) 		Peri-menopausal
(mean, 50)
Clinical features Pregnancy, steroid hormone exposure Prior benign uterine smooth muscle tumor Uterine leiomyoma with intravascular protrusion Tuberous sclerosis complex may be present Uterine or retroperiotenal leiomyosarcoma
Site Throughout abdomen, subperitoneum Uterus, lung, lymph nodes, abdomen Uterus, pelvic veins, inferior vena cava, right heart Lymphatic channels, lung, lymph nodes of mediastinum, pelvis, retroperitoneum Pelvis or retroperitoneum
Size Usually <2 cm, but larger tumors have been reported Variable, but often >2 cm Worm-like venous intrusions vary, but may be quite large Usually <2 cm, but larger lesions have been reported May be large
Behavior Usually regress Recurrence and metastases with prolonged course Intravenous extension Slowly progressive pulmonary dysfunction Recurrences & metastases common with rapid course
Mitotic index Low Low Low Low May be high (<10/10hpf)
Cellular atypia Absent Absent or minimal Absent - similar to smooth muscle tumors of uterus Spindle and epithelioid (clear) cells Usually severe
Necrosis Absent Absent Absent Absent Present

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