Abnormal Uterine Involution May Lead to Atony and Postpartum Hemorrhage: A Hypothesis, With Review of the Evidence.

Uterine involution has 2 major components-(1) involution of vessels; and (2) involution of myometrium. Involution of vessels was addressed by Rutherford and Hertig in 1945; however, involution of myometrium has received little attention in the modern literature. We suggest that the pathophysiology of myometrial involution may lead to uterine atony and postpartum hemorrhage. The myometrium dramatically enlarges due to gestational hyperplasia and hypertrophy of myocytes, caused by hormonal influences of the fetal adrenal cortex and the placenta. After delivery, uterine weight drops rapidly, with physiologic involution of myometrium associated with massive destruction of myometrial tissue. The resulting histopathology, supported by scientific evidence, may be termed "postpartum metropathy," and may explain the delay of postpartum menstrual periods until the completion of involution. When uterine atony causes uncontrolled hemorrhage, postpartum hysterectomy examination may be the responsibility of the perinatal pathologist.Postpartum metropathy may be initiated when delivery of the baby terminates exposure to the hormonal influence of the fetal adrenal cortex, and may be accelerated when placental delivery terminates exposure to human chorionic gonadotrophin (HCG). This hypothesis may explain why a prolonged third stage of labor, and delays in management, are risk factors for severe hemorrhage due to uterine atony.

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).

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.

Recurrence of Basal Plate Myofibers, with Further Consideration of Pathogenesis.

OBJECTIVES: Basal plate myofibers (BPMF) may indicate morbid adherence. We assessed recurrence and clinical progression of BPMF. METHODS: In 5 years, 135 BPMF placentas were reported. Controls were the first 50 placentas in 2009, none of which had reported BPMF. RESULTS: 32% of BPMF patients had other placentas, with a recurrence rate of 100%. Actin stains were needed for diagnosis in 117/179 cases (65%). These cases had clinical features suggestive of morbid adherence in 69/117 (59%). 23/47 (49%) of BPMF recurrences progressed in severity, 5 to hysterectomy (11%). Thinning of the basal plate, perforating vessels, gaps in the basal plate, and villi under the basal plate were observed in BPMF placentas. CONCLUSIONS: These findings appear to validate screening for BPMF. The 100% recurrence rate suggests evaluation for a heritable factor, i.e., protease inhibitor deficiency, which may explain pre-delivery basal plate damage.

Placenta Increta Presenting as Retained Placenta: A Report of 3 Cases.

OBJECTIVES: Morbid adherence is a risk factor for retained placenta (RP). We encountered three cases of placenta increta presenting clinically as delayed postpartum hemorrhage. METHODS: This was a retrospective study of three cases of placenta increta presenting as RP. RESULTS: One "routine" term placenta had heavy bleeding 2 weeks later; one missed abortion at 16 weeks with fetal and placental tissue submitted, had heavy bleeding 6 weeks later; and one elective abortion (no tissue submitted), had delayed postpartum bleeding leading to a curettage with blood only, then 6 weeks later a hysterectomy for menorrhagia. All 3 pathology specimens showed necrotic villi. However, all three also showed myometrium with keratin-positive interstitial trophoblasts in a zone of damaged myometrium, consistent with increta. All three cases had basal plate myofibers (BPMF) in the placenta, with BPMF recurrence in the two cases with another pregnancy. CONCLUSION: RP may be a presenting clinical manifestation of placenta increta.

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.

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.

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.

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.

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.

A Review and Reconsideration of Nonneoplastic Myometrial Pathology.

From 1861 to 1962, clinicopathologic research tried to explain the association of abnormal uterine bleeding with uterine enlargement. The etiology was theorized as metropathy, suggesting that myometrial dysfunction may predispose to abnormal uterine bleeding. Research reached a nadir in 1962, when a major review dismissed myometrial hypertrophy as a plausible explanation after prior rejections of the theories of chronic myometritis, fibrosis uteri, and subinvolution as causes of bleeding. Subsequent to this arose a crusade against unnecessary hysterectomies in the 1970s. Although myometrial hyperplasia was proposed in 1868, it is only in the past 25 years that tangible evidence has supported that idea. It now appears that clinically enlarged uteri are due to globoid outward bulging of the uterus, caused by increased intramural pressure-often unrelated to either uterine weight or myometrial thickness. Abnormal (dysfunctional) uterine bleeding may often be due to spontaneous rupture of thrombosed dilated endometrial vessels, due to the combined effects of obstructed venous drainage by increased intramural pressure, and Virchow's triad. Despite a century-old known association of parity with naturally occurring outer wall myometrial scars (fibrosis uteri with elastosis), it was not previously suggested that these may reflect healing reactions to muscle tears during labor and delivery. We now suggest that smaller, similar inner wall elastotic scars in the nerve-rich inner myometrium may explain many cases of pelvic pain. This review suggests that diverse pressure-related lesions may be present in clinically abnormal uteri that have been called "normal" since the crusade against unnecessary hysterectomy.

Association of Retroplacental Blood With Basal Plate Myofibers.

Objectives Diagnosed clinical abruption showing blood clot should be signed out in the pathology report as retroplacental hemorrhage with or without parenchymal indentation, and submitted clot separate from the placenta should be weighed. In our experience, some cases sent as clinical abruptions have been cases of morbid adherence. This study was undertaken to evaluate the association of retroplacental blood with basal plate myofibers (BPMF). Methods One hundred fifty-six placentas reviewed by a board-certified pediatric pathologist at a community hospital were evaluated for significant retroplacental blood. Basal plates were reviewed for deviations from normal. Results Of the 156 placentas, 33 (21%) had significant retroplacental blood; 21/156 (13%) had a separate clot, of which 11/21 (52%) had BPMF. Eleven BPMF-associated separate clots ranged from 10.5 to 60 g (average 23), while the clots of 10 cases with no demonstrated BPMF ranged from 19 to 440 g (average 82), tending to be larger ( p < .03). Basal plate damage prior to delivery was noted in both sets of placentas. BPMF placentas could have myometrial damage prior to delivery. Conclusions Since BPMF may confer a risk for accreta in a subsequent pregnancy, submission of a separate clot with the placenta should lead the pathologist to evaluate for basal plate myofibers on H&E and consider if there is an evidence-based indication to do an actin stain, before presuming a diagnosis of abruption.

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.

Placenta Increta Presenting as Exaggerated Placental Site Reaction.

Exaggerated placental site (EPS) is usually an incidental finding seen in curettings after an abortion. Placenta increta is, by definition, a disease that damages and destroys myometrium; however, prior literature has not paid sufficient attention to the role of myometrium in its pathogenesis and diagnosis. We present an unusual case of placenta increta in a hysterectomy performed for uterine perforation after curettage for the termination of pregnancy at 18 weeks. The initial histologic section of the implantation site suggested EPS. Actin stains showed degenerated inflamed muscle at the EPS-like site, keratin stains showed interstitial trophoblast in the zone of myometrial damage, and the wall of the corpus was grossly thinned under the placenta. The myometrial damage may have softened the wall, predisposing to uterine perforation by the curettage procedure.

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.

Placenta Accreta and Placenta Increta: An Approach to Pathogenesis Based on the Trophoblastic Differentiation Pathway.

Morbid adherence remains a puzzling disease. This paper suggests that normal and morbidly adherent placentation may be viewed best in terms of trophoblastic stem cells and the mutually exclusive branches of the trophoblastic differentiation pathway-villous trophoblast (VT), interstitial and endovascular nonvillous trophoblast (NVT) at the implantation site, and a positional variation in the chorion. Based on cases of hysterectomies for morbid adherence seen over 30 years at a community hospital, analyzed with routine keratin stains, with actin and trichrome stains as indicated, and with attempts at ultrasonography-pathology correlation, we present selected observations. In true accreta, the site of morbid adherence was to dilated basal plate vessels infiltrated by endovascular NVT, with scant interstitial NVT, and normal myometrium. It appeared that excess blood flow into the placenta was due to excessively deep keratin-positive endovascular NVT that spread-independently of interstitial NVT-in an angiocentric fashion in both accreta and increta. Retroplacental abnormalities were due to myometrial destruction by interstitial NVT in increta, sometimes requiring actin stains for detection; and to an admixture of markedly dilated endometrial glands and vessels in true accreta, best appreciated with keratin stains. Variations of depth and extent in increta may be due to variations in myometrial tone, and in the protease-antiprotease balance. Morbidly adherent fetal membranes are described, and the role of caesarean section scars in incretas is addressed.

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.

A Study of Myometrial Growth and Development.

STUDY OBJECTIVE: To evaluate myometrial growth and development. DESIGN: Thirty-five autopsy uteri, ranging from 10 weeks' gestation to age 18 years, acquired over 3 decades from 2 hospitals, were studied based on specimen availability, photographed for documentation, and reviewed at the end of the study. Most were embedded in toto, with 1 block and 1 slide per case. Some were immunostained for actin, CD10, MIB-1, and/or trichrome stain for collagen and muscle. Myometrial thickness was measured by ocular micrometry when sections were nontangential and analyzed by paired-sample t tests and bivariate linear regression. SETTING: Two university-affiliated hospitals. RESULTS: From 20 to 34 weeks, lateral wall corpus thickness increased 6-fold, with a 4- to 6-fold perinatal burst of growth (P < .01) and a drop in thickness after the neonatal period (P = .013). The corpus was thicker than the dome (P < .01) but less thick than the lower uterine segment (P = .087). The lower uterine segment was fully muscular in the second trimester, becoming more fibrous near term. Intramural, subserosal, and inframucosal myometaplasia were observed, as primitive stromal cells turned into muscle cells. Myometrial proliferation was brisk in the second trimester but greatly diminished in the perinatal period. Pressure effects from myometrial tone were observed during development. There was a pubertal burst of inframucosal myometaplasia. CONCLUSIONS: Myometaplasia accounted for most myometrial growth, especially in the perinatal and pubertal bursts of growth. Pressure effects, related to myometrial tone, appeared to affect myometrial development. True endocervix, with a fibrous wall and mucinous epithelium, appeared late in development.