Questions/Discussion
Fig. 1 , Fig. 2 show one of the ovaries. Describe the gross and histologic features.
A gross examination of this ovary shows a mass (6 × 5 cm) that is predominantly solid and partially cystic. The center of the solid area is friable with purulent material. Microscopic sections (hematoxylin and eosin stain) show clumps of filamentous bacteria consistent with Actinomyces colonies. The bacterial colonies display a dark staining eosinophilic rim at the periphery, referred to as the “ Splendore-Hoeppli” phenomenon, caused by immune complex deposits and cell debris. 5 The bacterial colony is surrounded by suppurative inflammation, with the presence of numerous polymorphonuclear neutrophils. Fig. 1 Gross exam shows one of the bisected ovaries with predominantly solid areas (SA) with suppuration (S) and partly cystic (C) at the periphery. The attached part of the fallopian appears thickened (FT). Fig. 1 Fig. 2 Section of ovary stained with H&E. Microscopy (10X) shows Actinomyces bacterial colonies (A) displaying Splendore-Hoeppli phenomenon (S) surrounded by suppurative inflammation with abundant polymorphonuclear neutrophils (PMN). Fig. 2
Gross exam shows one of the bisected ovaries with predominantly solid areas (SA) with suppuration (S) and partly cystic (C) at the periphery. The attached part of the fallopian appears thickened (FT).
Section of ovary stained with H&E. Microscopy (10X) shows Actinomyces bacterial colonies (A) displaying Splendore-Hoeppli phenomenon (S) surrounded by suppurative inflammation with abundant polymorphonuclear neutrophils (PMN).
Gross and microscopic images show features of PID with tubo-ovarian actinomycosis and abscess, consistent with the diagnosis of pelvic actinomycosis.
PID refers to an infectious and inflammatory disorder of the female upper reproductive system. It involves the endometrium, fallopian tubes, ovaries, or the pelvic peritoneum. 6 Infections are acquired either by ascending route from the vagina and cervix (most commonly) or hematogenous through the bloodstream. The infection is deep-seated and often presents subtle clinical signs and symptoms. Clinically, PID is classified as either acute, subacute (subclinical), or chronic. 6 , 7
Acute PID is an infection with a shorter duration. The vast majority (85%) of these infections are sexually transmitted and spread through the ascending route from the lower reproductive system to the pelvic area. Infection commonly occurs in sexually active young women, with the most frequent causative agents being N. gonorrhoeae and C. trachomatis . A minority of infections occur in the puerperium, tend to be poly-microbial, and include bacterial vaginosis pathogens ( Gardnerella , Peptostreptococcus species, and Bacteroides species). 6 Chronic PID is an infection of longer duration and is associated with Mycobacterium tuberculosis or Actinomyces species. 6 , 7 Fungal and parasitic infections are rare causes of PID. Fungal infections include those caused by Cryptococcus and Blastomyces, and parasitic infections include those caused by Schistosoma, Enterobius, Toxoplasma gondii, and Entamoeba histolytica . 8
Gonococcal infections involve the mucosal surfaces, commencing from the endocervical mucosa and extending to the uterine endometrium and spreading to the tubo-ovarian region. Non-gonococcal infections ascend to the uterus and do not show mucosal inflammation because they are likely to spread through lymphatic and venous channels. 6 , 9 Bacterial vaginosis pathogens produce enzymes that degrade cervical mucus, and antibacterial proteins disrupt the cervical barrier, resulting in tubo-ovarian spread. 6 , 7
Immunocompromised patients are predisposed to opportunistic fungal infections that may affect the reproductive tract. 8
Cryptococcus and Blastomyces may cause granulomatous inflammation making it difficult to distinguish from tuberculosis. Serology, culture, and special stains are often necessary to confirm a diagnosis. 8
Genitourinary infections caused by Schistosoma are acquired through travel to endemic countries and contact with contaminated water. Perianal parasites, such as Enterobius vermicularis migrate, causing vulvovaginitis and, rarely, upper genital infections. 8 Toxoplasmosis is a protozoal parasitic infection caused by the accidental ingestion of oocysts from cat feces or eating raw meat. Toxoplasma induces endometritis and predisposes neonates to congenital transplacental spread during pregnancy. 8
Acute PID refers to infections that last less than 30 days in duration. 6 Most infections are caused by sexually transmitted pathogens, whereas others occur in the puerperium.
Clinically, most patients with acute PID present with an acute onset of fever, lower abdominal pain, abnormal vaginal discharge, uterine bleeding, dyspareunia, and dysuria. 6 , 9 A bimanual examination can elicit cervical motion and uterine or adnexal tenderness. 6 , 9
Gross examination of the reproductive organs in severe acute PID reveals inflammation of the uterus and hyperemia of the serosa coated with fibrinous exudate. Inflammation and purulent exudate distort the tube and ovaries. A tubo-ovarian abscess or mass develops with both structures entangled in adhesions ( Fig. 3 ). Fig. 3 This image depicts an inflamed uterus and ovary removed due to the presence of an ovarian abscess in a case of pelvic inflammatory disease (PID) and caused by an undisclosed anaerobic bacterium. (Image attribution: Image # 17,605, public health image library, CDC/Jim Pledger. https://phil.cdc.gov/default.aspx permission as an open-access source.) Fig. 3
This image depicts an inflamed uterus and ovary removed due to the presence of an ovarian abscess in a case of pelvic inflammatory disease (PID) and caused by an undisclosed anaerobic bacterium. (Image attribution: Image # 17,605, public health image library, CDC/Jim Pledger. https://phil.cdc.gov/default.aspx permission as an open-access source.)
Subacute or subclinical PID refers to an asymptomatic infection related to the same pathogens that cause acute PID. It occurs in women with previously diagnosed or undiagnosed acute PID. Infection results in structural and functional damage to the fallopian tubes. Clinically, most patients present with infertility. 6 , 7
Chronic PID can last for more than 30 days and is caused by a chronic infection due to Mycobacterium tuberculosis or Actinomyces species. 6 , 7 Clinically, it is insidious and may present with chronic or intermittent pelvic pain, pelvic masses, abnormal uterine bleeding, low-grade fever, weight loss, and gastrointestinal and renal symptoms. 3 , 7 , 10 Adnexal masses detected by clinical examination and imaging studies are often mistaken for neoplastic disease. 3 , 7 , 10 The salient features of acute and chronic PID are presented in Table 1 . Table 1 Main features of acute and chronic pelvic inflammatory disease (PID). Table 1 Clinical type Acute PID Chronic PID Causative agent Sexually transmitted pathogens: C. trachomatis, N. gonorrhoeae Bacterial: Mycobacterium tuberculosis or Actinomyces species Puerperal infections: Pathogens causing bacterial vaginosis ( Gardnerella, Peptostreptococcus species, Bacteroides species), Staphylococci, streptococci, coliforms, Clostridium perfringens Fungal: Cryptococcus, Blastomyces Parasitic: Schistosoma, Enterobius, Toxoplasma gondii, Entamoeba histolytica Clinical features Fever, lower abdominal pain Chronic or intermittent pelvic pain, pelvic mass Abnormal vaginal discharge Abnormal uterine bleeding Uterine bleeding Low-grade fever Dyspareunia Weight loss Dysuria Gastrointestinal and renal symptoms Pelvic exam Cervical motion tenderness, uterine tenderness Adnexal mass felt on bimanual examination Adnexal tenderness Differential diagnosis Ovarian torsion, acute appendicitis Ovarian tumors, cysts, uterine myoma, adenomyosis Diverticulitis Inflammatory bowel disease Endometriosis Diverticulitis Ectopic pregnancy Endometriosis Cystitis Tuberculosis
Main features of acute and chronic pelvic inflammatory disease (PID).
Actinomyces are obligate anaerobic gram-positive bacilli. They are non-acid-fast and slow growing. There are several species of which Actinomyces israelii is the most common cause of disease in humans 10 , 11 , 12 , 13 . Actinomyces reside as commensals in the human mouth, urogenital tract, and gastrointestinal tract. When mucosal barriers are breached, they invade and become pathogenic. The disease state of this infection is referred to as actinomycosis. Gram staining of the infected tissue reveals the branched filamentous nature of Actinomyces with radially arranged peripheral hyphae. Owing to the presence of filaments or hyphae, Actinomyces was originally thought to be a fungus. 11 , 12
Actinomyces is classified as a true bacteria because it lacks mitochondria and a nuclear membrane. 10
Actinomyce s co-exists with as many as 5–10 companion bacteria, and the colonies contain a mixture of cocci and rods 10 , 11 , 12 , 13 .
Actinomyces is an opportunistic pathogen that is characterized by suppurative and granulomatous inflammation. 11 , 13
Actinomyces lesions typically form multiple abscesses with draining sinus tracts. On closer inspection, the abscesses may contain yellow granules resembling grains of sand termed “sulfur granules” 10 , 11 , 12 , 13 . Although the sulfurous content of the lesion is debatable, the granules represent masses of filamentous bacteria bound by calcium phosphate. 12 Microscopy and H&E staining reveal cauliflower-shaped eosinophilic bacterial colonies. The colonies have a dark staining eosinophilic rim at the periphery, displaying the “ Splendore-Hoeppli ” phenomenon. This phenomenon is not unique to Actinomyces and has been observed in other bacterial infections, including nocardiosis and botryomycosis. This feature has also been reported in fungal and parasitic infections. 5
As Actinomyces is an opportunistic pathogen, progression to a clinical infection requires a breach of the mucosal barrier caused by trauma, surgery, or a foreign body. 3 , 11 , 14
Companion bacteria produce toxins, weaken host defenses, reduce oxygen tension, and facilitate Actinomyces infection. 13 In the reproductive tract, an infection caused by bacterial vaginosis pathogens and the associated loss of normal vaginal lactobacilli elevates the pH, resulting in less acidity 6 , 8 and creating an anaerobic environment favoring the growth of Actinomyces . 14
The “ Splendore-Hoeppli ” phenomenon provides a resistance mechanism to evade the host immune system and inhibit phagocytosis. 10 , 13
The most common clinical presentation is cervicofacial actinomycosis which accounts for 60% of infections and presents as “lumpy jaw” syndrome. 10 , 12 , 13 It characteristically involves the skin and soft tissues in the jaw, presenting as a painless indurated mass that breaks down into multiple abscesses and sinus tracts that drain yellow sulfur granules. 10 , 12 , 13 Microscopically, the suppurative areas are surrounded by fibrosing granulation tissue, which gives the lesion a hard consistency. 12 This leads to mandibular osteomyelitis with or without a sinus tract. Bisphosphonate-related severe osteonecrosis of the jaw, which was once considered a non-infectious disease, has now been reported to be associated with Actinomyces spp. 10
The urogenital tract is the second most common site of Actinomyces infections. A common form of the disease is pelvic actinomycosis, particularly in women with a history of IUD insertion. 3 , 14 , 15 It presents with pelvic pain, tubo-ovarian mass, and vaginal discharge. However, fever is not a common symptom. These clinical symptoms and findings are often mistaken for gynecological tumors. Bladder involvement can mimic the symptoms of bladder carcinoma with dysuria and hematuria. 10 , 13 , 14 , 15
Thoracic actinomycosis is the third most common type of disease. Lung involvement can present with symptoms similar to those of chronic lung infection and cancer. Thoracic actinomycosis manifests as chronic productive cough, hemoptysis, dyspnea, and chest pain. Abscesses present as cavitary lesions with sinus tracts. 10
Abdominal actinomycosis commonly affects the appendix, cecum, and colon. It may present with non-specific symptoms, such as low-grade fever, weight loss, nausea, and changes in bowel habits. Abscesses may form abdominal fistulas. 10
Localized involvement of the skin and soft tissues in the extremities manifests as mycetoma. This type of infection is commonly observed in tropical and subtropical regions. Mycetoma presents as a large painless soft tissue swelling that may be destructive and extend to the bone. 16
Central nervous system actinomycosis is a rare clinical presentation of the disease, presenting as a cerebral abscess or meningitis. 10 , 12
Actinomyces is an organism with low virulence and becomes invasive when the mucosal barrier breaks down. The infection is further facilitated by companion bacteria. Cervicofacial actinomycosis is caused by odontogenic infections. Poor dental hygiene, dental caries, dental surgery, and systemic illnesses, such as diabetes, are predisposing factors for this infection. 10 , 13 Pulmonary actinomycosis results mainly from the aspiration of gastrointestinal secretions. Predisposing factors for these infections include alcohol abuse and seizure disorders. Chronic lung diseases, such as tuberculosis and obstructive and restrictive lung diseases, damage the mucosal defenses, predisposing Actinomyces infection. In women, IUD use increases the risk of pelvic actinomycosis. Prior surgery for appendicitis and colonic diverticulitis may be a risk factor for gastrointestinal actinomycosis. Immunosuppressive conditions, such as HIV infection, organ transplantation, treatment with biologics, and malignancy, are other risk factors. 10 , 13
Pelvic actinomycosis occurs predominantly in women using IUDs. 3 , 14 , 15 Studies have shown that Actinomyces -like organisms reside in the cervix, vulva, and perineum. 11 IUD insertion results in a small portion of the attached strings to normally protrude through the ectocervix ( Fig. 4 ). These wires or strings may aid microbial growth and cause ascending infection. 14 IUD insertion traumatizes the epithelium, disrupts the mucosal barrier, and causes erosion, which may predispose to Actinomyces invasion. 10 In addition, pre-existing infection by bacterial vaginosis pathogens can induce an anaerobic environment that favors the growth of Actinomyces 14 . IUD insertion also alters carbohydrate metabolism in the endometrial cells, resulting in inflammation that facilitates spread to the fallopian tubes and ovaries. 14 Fig. 4 Photo of vagina and cervix (with visible IUD strings) during a speculum exam illustrating normal vaginal discharge. The image was republished under CC BY-SA 4.0 ( https://creativecommons.org/licenses/by-sa/4.0 ), via Wikimedia Commons. “Normal cervix and vaginal discharge” By VeeBabzel from https://commons.wikimedia.org/wiki/File:Normal_cervix_and_vaginal_discharge.jpg . Fig. 4
Photo of vagina and cervix (with visible IUD strings) during a speculum exam illustrating normal vaginal discharge. The image was republished under CC BY-SA 4.0 ( https://creativecommons.org/licenses/by-sa/4.0 ), via Wikimedia Commons. “Normal cervix and vaginal discharge” By VeeBabzel from https://commons.wikimedia.org/wiki/File:Normal_cervix_and_vaginal_discharge.jpg .
Most actinomycoses associated with IUD insertion results in tubo-ovarian abscess. 11 Inflammation can cause adhesions that may involve adjacent structures, such as the peritoneum, small bowel, and bladder. As they present as a chronic illness with vague symptoms, such as intermittent lower abdominal pain and weight loss, they are detected late. In imaging studies, tubo-ovarian abscesses are likely to be mistaken for ovarian tumors. 3 , 15 Therefore, the diagnosis of pelvic actinomycosis is often made postoperatively. 11 , 14
The risk of acquiring Actinomyces infection increases proportionately with the duration of IUD use, especially over four years. 3 , 11 The presence of Actinomyces -like organisms has been reported in up to 7% of Pap smears in women using IUD. 3 , 11 Types of IUD associated with Actinomyces infection include the Lippes loop, Dalkon shield device, copper IUD, and hormonal IUD. 3 Unfortunately, Pap tests that are positive for Actinomyces cannot predict the likelihood of these women presenting with pelvic actinomycosis. 11 Although little data are available, the risk of future symptomatic infection is estimated to be less than 1/1000. 11 Some studies have recommended changing the IUD every three–five years. 10 , 14 Women who choose IUD as a form of contraception should be informed of the low potential risk of actinomycosis. 11
Laboratory tests, such as a complete blood count, are likely to show leukocytosis with neutrophilia. Levels of inflammatory markers, such as ESR and CRP, are likely to be elevated. Levels of tumor marker CA-125 may be slightly elevated, making it difficult to rule out ovarian tumors. 2 , 4 , 10 Pap smears may detect Actinomyces -like organisms but cannot differentiate between colonization and infection. 10 , 11 , 13 , 14
CT, ultrasound, and other imaging studies are useful in detecting pelvic masses but may be difficult for distinguishing between chronic inflammatory conditions and cancer. These can detect lymphadenopathy as seen in 50% of patients with pelvic actinomycosis. 12 , 13 They are also helpful for retrieving guided biopsies or aspiration. 3 , 10 , 14
The gold standard for the diagnosis of actinomycosis is a histopathological examination and bacterial culture from a tissue biopsy or aspirated material. Bacterial culture is a slow process and may take 15–20 days. Strict anaerobic processing is also required. When grown, colonies of Actinomyces israelii appear like a “molar tooth” 10 , 12 ( Fig. 5 ). Fig. 5 This photograph shows a close view of a Petri dish culture plate containing a growth medium of blood heart infusion (BHI) agar that gave rise to two irregularly-shaped, rough-type bacterial colonies derived from Actinomyces israelii bacteria. (Image attribution: Image # 21,816, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.) Fig. 5
This photograph shows a close view of a Petri dish culture plate containing a growth medium of blood heart infusion (BHI) agar that gave rise to two irregularly-shaped, rough-type bacterial colonies derived from Actinomyces israelii bacteria. (Image attribution: Image # 21,816, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.)
Histological evaluation of the infected tissue may show suppurative and granulomatous inflammation along with granulation tissue and Actinomyces bacterial colonies displaying the Splendore-Hoeppli phenomenon 14 ( Fig. 2 ). Gram staining shows the presence of filamentous gram-positive rods ( Fig. 6 ). Bacterial colonies can also be visualized using immunofluorescence techniques 10 ( Fig. 7 ). Molecular techniques using 16S rRNA sequencing are further useful methods for identification. 10 , 14 Fig. 6 This photomicrograph (900X) depicts a gram-stained culture specimen, which had grown these gram-positive and rod-shaped Actinomyces naeslundii . Note the long strands of bacteria attached end-to-end, resembling a branched network of hyphal-like filaments, much like those seen in fungal organisms. (Image attribution: Image # 21,572, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.) Fig. 6 Fig. 7 This photomicrograph revealed the morphology of Actinomyces sp. bacteria, which had originated as a pus smear from clinical material, and stained using a fluorescent antibody (FA) technique, then viewed under fluorescent light. (Image attribution: Image # 21,734, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.) Fig. 7
This photomicrograph (900X) depicts a gram-stained culture specimen, which had grown these gram-positive and rod-shaped Actinomyces naeslundii . Note the long strands of bacteria attached end-to-end, resembling a branched network of hyphal-like filaments, much like those seen in fungal organisms. (Image attribution: Image # 21,572, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.)
This photomicrograph revealed the morphology of Actinomyces sp. bacteria, which had originated as a pus smear from clinical material, and stained using a fluorescent antibody (FA) technique, then viewed under fluorescent light. (Image attribution: Image # 21,734, public health image library, CDC/Dr. Lucille K. Georg. https://phil.cdc.gov/default.aspx permission as an open-access source.)
Actinomyces spp. are sensitive to penicillin G and beta-lactams. Other antibiotics, such as clindamycin, macrolides, tetracycline, and doxycycline, are also effective and used in patients allergic to penicillin or displaying antibiotic resistance. IUDs should also be removed in patients with IUD-associated pelvic actinomycosis. The usual length of treatment is 6–12 months. 10 , 13 , 15 Patients in an uncomplicated clinical course may be managed with antibiotics to avoid surgical intervention and maintain future fertility. 3 Surgical intervention supplemented with antibiotics offers a cure for the most complicated cases. 10 , 17 Therapy may be shortened to three months if the patient undergoes surgical removal of the infected site. 10 , 13 , 15
Acute PID caused by gonorrhea is associated with severe inflammation spreading to the fallopian tubes (acute salpingitis) and ovaries (salpingo-oophoritis). Eventually, pus accumulation results in the formation of a tubo-ovarian abscess. Inflammation and pus may spill into the peritoneum, causing peritonitis. A further extension to the upper abdomen along the hepatic capsule results in peri-hepatitis (Fitz-Hugh-Curtis syndrome). 7 When the inflammation subsides, it resolves and forms a fluid-filled distention of the tubes (hydrosalpinx). 7 , 18 In contrast, acute PID caused by pathogens related to puerperal infections shows less evident mucosal inflammation. This is associated with severe inflammation of the deeper layers and systemic spread, resulting in septicemia, endocarditis, and meningitis. 18
Long-term complications are associated with chronic inflammation and scarring. In the fallopian tubes, the ciliated columnar epithelium lining is damaged, causing reparative scarring and adhesion, which affects tubal patency. Consequently, acute PID impairs fertilization and implantation, greatly enhancing the risk of infertility and ectopic gestation. 7 , 19
Similarly, the inflammation of the peritoneum results in the development of adhesions and fibrous bands that involve the adjacent organs. This can account for chronic pelvic pain and, in severe cases, may cause ureteral or bowel obstruction. 7 , 18
The patient is successfully treated with a three-month course of antibiotics after surgery and is doing well thereafter. She is advised to follow-up and is recommended to undergo hormone replacement therapy. With the elevation of inflammatory markers and IUD use, the awareness of the variation in CA-125 levels in pre- and postmenopausal women and investigation with ultrasound-guided fine-needle aspiration cytology could potentially avoid the need for surgery.