The relationship of myometrial histopathology (metropathy) to myometrial dysfunction and clinical manifestations.

Myometrial morphology and myometrial physiology have been considered to be separate entities; however, observations of myometrial morphology and associated dysfunctions suggest a relationship between myometrial morphology and myometrial physiology that deserves further exploration. Although myometrial electrical activity can be monitored by electrohysterogram, the association of increased myometrial contractions with an increase in electrical activity (due to an increase in gap junctions) is typically not evaluated. Although the association of increased myometrial contractions with increase in pain can be monitored by tocometry and intrauterine pressure catheters, respectively, this is generally not done in the non-pregnant uteri. Although standard morphologic evaluations routinely include evaluation with special stains and immunohistochemistry in other organ systems, such as skeletal and cardiac muscle, these evaluations are not standard or routine for myometrium in hysterectomies. The purpose of this review is to discuss non-neoplastic myometrial histology, with consideration of the potential value of using tools to measure variations in myometrial physiology, in order to reliably correlate myometrial histology with myometrial function (and dysfunction).

Apoplectic leiomyomas: does ethnicity make a difference? a clinicopathologic study.

Apoplectic leiomyomas-benign uterine leiomyomas with morphologic changes including hemorrhage, hypercellularity, mitotic activity, nuclear atypia, and even necrosis-can be difficult to distinguish from uterine leiomyosarcomas. Apoplectic leiomyomas have been associated with hormonal therapy; however, the relationship between apoplectic leiomyomas, hormones, and ethnicity has not received much attention in the literature. We evaluated the relationship of hormonal therapy and ethnicity in 869 women with uterine leiomyomas, 136 of which qualified as apoplectic leiomyomas.Apoplectic leiomyomas were observed in 23.3% (49/210) of women exposed to hormonal therapy compared to 13.2% (87/659) of women not exposed to hormonal therapy (p < 0.0001). Women taking ethinyl estradiol/norethindrone (Lo-Estrin), leuprolide, and medroxyprogesterone were significantly more likely to have apoplectic leiomyomas compared to women taking other hormonal therapies. Apoplectic leiomyomas were observed in 28.9% (44/152) of African-American women compared to 12.4% (79/639) of Caucasian women (p < 0.0001), and this difference remained statistically significant regardless of hormone use. Apoplectic leiomyomas were observed in 22.1% (77/349) of women ≤ 45 years of age compared to 11.3% (59/520) of women > 45 years of age (p < 0.0001), and this difference remained statistically significant regardless of hormone use.This is the largest study to date examining apoplectic leiomyomas in women on known hormonal therapy compared to women with uterine leiomyomas, but not on hormonal therapy. Information about hormonal therapy, ethnicity, and age can be helpful in the diagnostic interpretation of apoplectic leiomyoma.

The pathogenesis of abnormal uterine bleeding in myopathic uteri.

It has been suggested that impaired venous drainage and endometrial vascular ectasia (EMVE), secondary to increased intramural pressure, explains abnormal bleeding in fibroid uteri. Striking EMVE with extravasated red blood cells (ecchymosis) has also been seen in uteri with grossly obvious myometrial hyperplasia (MMH), suggesting that increased intramural pressure can cause EMVE in the absence of fibroids. EMVE with MMH may explain the century old association of clinically enlarged uteri with abnormal bleeding, and this same mechanism may be operative in myopathic uteri with grossly obvious adenomyosis. EMVE with associated thrombosis, ecchymosis, and/or stromal breakdown is commonly seen in random sections of hysterectomies for bleeding. EMVE may also be associated with endothelial hyperplasia, consistent with a reaction to endothelial injury due to impaired venous drainage. This further supports the theory that EMVE bleeds when thrombosis occurs, due to Virchow's Triad (stasis, endothelial injury, and hypercoagulability). EMVE may be "the lesion for which surgery was performed" in hysterectomies with otherwise unexplained bleeding.

A study of dermal melanophages in childhood nevi. Reassessing so-called "pigment incontinence".

In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development.

A Comparison of Hysterectomies for Bleeding With Hysterectomies for Pain.

Objectives. We recently suggested that increased intramural pressure may often explain pain and/or bleeding. Hysterectomies for bleeding tend to have outward bulges and endometrial vascular ectasia, while hysterectomies for pain tend to have deflection of pressure inward by subserosal ridges, which promote inner myometrial elastosis (IME). Study design. We analyzed causes of increased intramural pressure in 58 hysterectomies for pain and/or bleeding, excluding clinically fibroid uteri and prolapsed uteri. Postfixation photographs were used to avoid missing grossly obvious myometrial hyperplasia (MMH). Results. The most common cause of increased intramural pressure was grossly obvious MMH in 40/58 cases (69%). Other causes included clinically occult myomas (3 cases), adenomyosis (6 cases), and multifactorial causes (7 cases). Hysterectomies for bleeding weighed more than hysterectomies for pain (P = .035). Hysterectomies for pain had more IME than hysterectomies for bleeding (P = .029). Conclusions. When subserosal ridges deflect pressure inward, bulky MMH may cause pelvic pain and IME, but when they do not, bulkier MMH in heavier uteri may lead to both outward bulges and abnormal bleeding from endometrial vascular ectasia.

Postablation neuroma of the myometrium-a report of 5 cases.

When hysterectomy is performed for chronic pelvic pain, routine pathology examination often provides no explanation. However, analysis of small uterine nerves using immunostains may help to address this deficiency. Small uterine nerves tend to be sparse or absent in wide areas of normal myometrium. Some studies of uterine nerves have suggested that endometriosis, adenomyosis, and fibroids are not inherently painful, with increased small nerves in the inner uterine wall associated with the history of pelvic pain. Although such areas may appear normal on hematoxylin and eosin (H&E), we have found a subtle inner wall lesion termed inner myometrial elastosis, best detected with trichrome or elastic stains, which may be a reaction to microscopic tears of inner myometrium. Such tears may induce increased inner wall innervation via the generation of nerve growth factor in granulation tissue. In the course of studying uterine nerves with immunostains, we found 5 cases with florid nerve proliferation, after deep endometrial ablation for abnormal uterine bleeding led to increased pelvic pain. We suggest that immunostains for postablation neuromas should be done in hysterectomies when pelvic pain increases after endometrial ablation. This may offer gynecologists and their patients an objective finding with a rational, scientific explanation for the pelvic pain.

The High Multiplicity of Prenatal (Congenital Type) Nevi in Adolescents and Adults.

In the absence of work on prenatal nevogenesis, it has long been necessary to define congenital melanocytic nevi by clinical detection on neonatal skin examination. They are seen in approximately 1% of newborns, with multiplicity in approximately 3% of cases. Melan-A staining of grossly normal fetal skin recently demonstrated fetal nevi, whose features validated certain traditional histologic criteria for "congenital type" nevi that may not have been detectable at birth. This suggested that many clinically acquired nevi actually formed in utero, like congenital nevi. Prenatal nevi has been suggested as a preferred synonym for "congenital type" nevi. Prenatal nevi were detected in 6 of 25 fetuses (24%), a strikingly higher incidence than congenital nevi in newborns. In this series of 354 patients with prenatal (congenital type) nevi encountered in routine practice at a community hospital, over 30% of both adolescents and adults had multiple prenatal nevi; a strikingly higher rate of multiplicity than congenital nevi in newborns. This high multiplicity may reflect origin beneath the epidermis, with many prenatal nevi working their way up to the surface of the skin decades after birth.

Myometrial hyperplasia mimics the clinical presentation of uterine fibroids: a report of 3 cases.

The clinical diagnosis of fibroid uterus is based on physical examination findings and/or ultrasound. However, it is not uncommon for routine pathology examination to report no significant fibroids in such cases. Myometrial hyperplasia (MMH) is a structural variation with irregular zones of hypercellularity and increased nucleus/cell ratio that appears in adolescence, can progress during the childbearing years, and can sometimes cause grossly detectable bulges on pathologic examination. MMH can be inframucosal, intramural (microscopic), or subserosal. Three premenopausal women with a preoperative diagnosis of fibroids on pelvic examination, and/or sonograms, underwent hysterectomies. In all the 3 cases, the Myoma Index (number of fibroids×size of largest fibroid) indicated insignificant fibroids. The pathology simulating fibroids was firm, bulging inframucosal MMH. Firm, bulging MMH can mimic uterine fibroids on ultrasound and physical examination. In hysterectomies for fibroid uterus with a Myoma Index <3.7, it is recommended that pathologists evaluate for MMH as the possible explanation for the findings on physical examination and/or ultrasound.

Adult primary pulmonary primitive neuroectodermal tumor: molecular features and translational opportunities.

Primitive neuroectodermal tumors (PNET) arising directly from the lung are very rare but particularly aggressive neoplasms. We report a case of a 31-y-old man with primary pulmonary neuroectodermal tumor. We review the clinical as well as pathological features. As typical for these tumors, the diagnosis was initially delayed in our patient and prognosis was poor despite aggressive surgical resection, postoperative chemotherapy and local irradiation. Recent biological insights have revealed unique chromosomal translocations crucial to the pathogenesis of these tumors, most notably the EWS-FLI-1 translocation. We provide an overview of the molecular features of the Ewing Sarcoma Family of Tumors (ESFT) including PNET and their potential implications for therapeutic targeting.

A look at uterine wound healing through a histopathological study of uterine scars.

BACKGROUND: Few histopathologic studies of uterine wound healing have been published compared with similar healing in other tissues. Our objective was to examine the histopathology resulting from iatrogenic trauma to the myometrium to acquire a better understanding of possible aberrations in uterine wound healing. METHODS: We studied paired injured myometrium and uninvolved myometrium from 7 hysterectomy specimens. All subjects had either abnormal bleeding or chronic pain following an iatrogenic injury to the myometrium. The time between the initial injury and hysterectomy ranged from 2 months to 13 years. Tissue was evaluated with hematoxylin and eosin (H&E) followed by Masson Trichrome staining for collagen, Weigert-Van Gieson elastic staining, and/or Kreyberg staining for fibrin and glycosaminoglycans or MIB-1 (Ki-67) immunhistochemistry for cell proliferation. RESULTS: Histopathologic examination of the 7 paired tissues revealed evidence of altered healing including myofiber disarray, elastosis, tissue edema, and inflammation. Small fibroids, myometrial hyperplasia, a keloid-like region of scar and adenomyosis were also observed. CONCLUSIONS: Myofiber disarray and elastosis may be markers of aberrancy in wound healing after iatrogenic uterine trauma. Altered myometrial scarring in these cases may have contributed to the clinical outcome necessitating hysterectomies. Myometrial hyperplasia in the region of the scars might also contribute to the clinical presentation as well. Small fibroids found within scars and evidence of a keloid-like structure may also represent alterations in uterine wound healing.

On the development of neurocutaneous units--implications for the histogenesis of congenital, acquired, and dysplastic nevi.

This study of spontaneous abortions and fetal deaths in utero used immunostains to evaluate the structure of developing cutaneous nerves. Melan-A immunostains were also used to screen 25 cases of grossly normal fetal skin for occult fetal nevi. Discrete portions of epidermis were generally supplied by branches emanating from regularly spaced deep cutaneous nerves, producing a wedge shape, interpreted as neurocutaneous units (NCU). Deeper nerves embraced broader portions of epidermis. Some nerves ran parallel to epidermis, especially near the superficial vascular plexus at the junction of superficial and deep dermis. Nerve sheath stem cells in each NCU may supply the melanocytes needed by the corresponding portion of epidermis. Transformed nerve sheath stem cells may lead to formation of occult prenatal nevi, whose histology and histogenesis may best be understood in terms of NCUs. In particular, the size and shape of a nevus may be largely determined by its NCU of origin. Six fetal nevi were detected, and 3 occult lumbosacral Mongolian spots; all in deep dermis, no later than the middle of the second trimester, mainly with a pattern of singly dispersed deep dermal melanocytes. These findings suggest that congenital (prenatal) nevi begin as intradermal nevi. In addition to explaining congenital nevi, these findings have implications for the histogenesis of acquired (postnatal) nevi and dysplastic nevi.

Stem cells for epidermal melanocytes--a challenge for students of dermatopathology.

Many obstacles to belief in stem cells for melanocytes arise in the routine practice of cutaneous histopathology. However, the fundamental principle of stem cell theory says that normal stem cells arise during development, are present in adult organs as tissue-determined stem cells, and are little changed, if at all, from their embryonic counterparts. This paradox can be resolved by focusing on the process of epidermal melanocyte development in utero. Stem cells for melanocytes originate in the neural crest. Although much remains to be learned, this author proposes that these stem cells then take a small step to the paraspinal ganglia and then follow the axonal signposts to the skin provided in the course of normal cutaneous innervation. The epidermis may then induce these stem cells in the nerve sheath to give rise to immature dermal melanocytes, which migrate up into the epidermis. It is proposed that these melanocyte stem cells also persist after birth in the superficial nerve sheath and give rise to transient, immature, inconspicuous dermal migratory melanocytes when replacements for epidermal melanocytes are needed in postnatal skin.

Association of seedling myomas with myometrial hyperplasia.

It is paradoxical that such a presumably quiescent tissue as myometrium, so sheltered from carcinogen exposure, has more neoplasms than any other internal tissue and that, in contrast to cervix and endometrium, pathology textbooks recognize no precursor. Although myometrial dysplasia has been described, it is rare. Myometrial hyperplasia (MMH) is a common structural variation characterized by irregular zones of increased myometrial cellularity, with increased nucleus-cell ratios; but to date, there has been only anecdotal evidence that it may give rise to myomas. We studied the relationship of seedling myomas to MMH in 50 consecutive hysterectomies and found that most seedling myomas (44/63, 70%) arose in MMH--35 in inframucosal MMH, 3 in subserosal MMH, and 6 from intramural MMH. Some seedling myomas were incompletely circumscribed, seeming to arise not only in but also from MMH. We suggest that even seedlings in normal myometrium may arise not from normal myometrial smooth muscle cells but rather from myometaplasia in intramural stromal emboli, with hyperplastic and then neoplastic transformation. These findings may explain the high frequency and multiplicity of uterine leiomyomas. Frequent mucosal injury with stromal repair reactions may release growth factors that promote the high frequency and multiplicity of uterine leiomyomas.

Myometrial dysplasia (atypical myometrial hyperplasia).

Although precursor lesions are well known for cervical and endometrial neoplasms, precursor lesions are not currently recognized for the most common tumor of the uterus-leiomyomas. Myometrial hyperplasia has been recently described and evaluated by morphometry, but its relationship to uterine leiomyomas has not been systematically explored. Myometrial dysplasia (atypical myometrial hyperplasia) has not been previously recognized. We herein report a case of myometrial dysplasia with immunostains for proliferation marker MIB-1 (Ki-67) and for p53. The paradoxical rarity of myometrial dysplasia is considered in comparison to the striking frequency of uterine leiomyomas.

Diffuse uterine leiomyomatosis with uterine rupture and benign metastatic lesions of the bone.

BACKGROUND: We report a case of diffuse uterine leiomyomatosis in pregnancy complicated by uterine rupture and dissemination to the bone. CASE: A 35-year-old nulliparous woman with a history of uterine leiomyoma presented at term with fetal demise. Failed induction of labor and hemodynamic instability due to uterine rupture resulted in a cesarean hysterectomy. A free-air series performed postoperatively to confirm paralytic ileus revealed multiple lytic bone lesions. The diagnosis of diffuse uterine leiomyomatosis with metastasis was made on histology of the resected uterus and fine-needle aspiration biopsy of the bone. She was managed conservatively, and the lesions are now regressing. CONCLUSION: Diffuse uterine leiomyomatosis should be considered in pregnant women with a history of uterine fibroids and peripartum hemorrhage.