Case Studies EXTRAGENITAL GRANULOMA INGUINALE MlMlCKlNG RWIEW OF THE LITERATURE RORERI‘ IJAKNES. MD,
SHAHLA
MASOOD.
MD,
NXK:Y
A SOFT-TISSUE
LAMMERT.
MD.
AND
NEOPLASM: A CASE REPORT AND ROBERT H.
E’O~JNG.
MI)
on permanent
sections, the patient Mas treated with appropriate antibiotics with resolution of the labial lesion. After. discharge from the hospital she was lost to follow-up. RESULTS
Gran&ma inguinale is an indolent but progressive, tllcerative venereal disease that usually affects the stratified squamous epithelium of the external genitalia. Its rarity anrl protean manifestations can provide a diagnostic challenge for the pathologist as well as the clinician even when it presents in its classic fin-m. When it presents as extragenital disease it can mimic other systemic illnesses. and the diagnostic difficulty is compounded. Correct diagnosis is t rucial, as untreated granuloma inguinale can develop into a mutilating illness with significant morbidity and mortalit\ i-ates. (:ASE
REPOR-I
An 1ii-vear-old gravida IV, para III black female who r\as 32 weeks pregnant, presented to the emergency room Ivith a complaint of vaginal bleeding over the previous 2 months. Examination at that time revealed a cervical erosion with minimal bleeding. No treatment was instituted and the patient was referred to the obstetric clinic., where 6 weeks later, she was found to have an ulcerative labial lesion which was clinically suspicious for herpes. Viral cultures of. the lahial lesion were negative; howecer. the patient was admitted to the hospital and underwent elective cesarean section. ‘41 the time of operation, a retroperironeal mass that involved tlhe right ureter and caused unilateral hydronephrosis was discovered. A section of this tissue was submitted for frozen section microscopic examination (Fig 1, left) and interpretecl as “acute xanthomatous inflammation. rule especially malignant fibrous out soft-tissue neoplasm. histiocytoma”. ‘l‘he labial lesion was also submitted for hiopsy at this time. After the diagnosis of extragenital granuloma inguinale involving the retroperitoneum was made Received March 14, 1989, from the Department of Pathology. LTniversirv of. Florida/Jacksonville division; and Department of Patholoev. Ma,isachusetts General Hospital, Harvard Medical School. Bosto:. MA. Accepted for publication September 6. 1989. Kev u~rlr: granuloma inguinale. Donovan bodies. exrragenital, hiqtiocyte. pregnancy. Address correspondence and reprint requests to Shahla Masood. MD. Department of Pathology. University Hospital, 655 M’ 8th St, Jacksonville, FL 32209. 0 1990 hv W.B. Saunders Company. W68 177/90/2 IO.50014$5.0910
The tissue from the retroperitoneum consisted of mutiple pieces of. firm, yellow, fihrofattv tissue measuring 3.0 cm hv 2.0 cm hv 0.5 cm. ‘rhe left labial lesion was tan, with the mucosal surface studded with numerorls papillary projections. The cut surface was smooth with area5 of focal hemorrhage. Microscopic examination of the retroperitoneal tissue revealed intense acute and chronic inflammation and ahundant granulation tissue (Fig 2, top left). The inflammator\ cells consisted of numerous plasma cells which in some areas formed perivascular cuff’s around small vessels, focal collections of neutrophils which formed micl oahscesses (Fig 2. top right). rare multinucleated giant cells, and focal collections of foamy histiocytes. The foamy nature of the histiocytes. due to the presence of numerous cvtoplasmic vacuoles, was suspicious for an infective process, and special stains were ordered. Warthin-Starry stain showed that the vacuoles contained small rod-shaped bacteria with the ty!.lical “closed safety pin” morphology of Donovan bodies (I- IR I, top right). Examination of the labial lesion revealed areas of ulceration with acute and chronic inflammation. her&red by epithelium which showed 1~se~~doel~itheliomatolls hvperplasia (Fig 9, bottom). The inflammatory infiltrate consisted of- neutrophils. plasma cells. and sirn1lar histioc-ytes with “Donovan bodies”. Few lymphoc-yte\ were seen in anv section. By electron microscopy, macrophages with large intrac-ytoplasmic vacuoles filled with oblong hacreria measuring 0.7 pm by I .4 pm were found. These bacteria had a trilaninar membrane and cytoplasmic elects-on dense material that hzas concentrated at the periphery of the cell. There were numerous villifijrm protrusions lining the surface of’ the bacteria. Some bacteria that appeared to he dividing. showed invagination of the cell membrane and cell wall. DISCUSSIoN The exact etiology of granuloma inguinale remains unproven; howel,er, Cal~mmc~tobacterium ,granuiomatir. a gramnegative, periodic acid-Schiff-negative, encapsulated, nonmotile bacteria, is considered the responsible pathogen by the weight of circumstantial evidence.’ Although rare in the Lnited States, granuloma inguinale is endemic in certain areas of the world including New Guinea, the Caribbean, and Central Australia.’ Historically, most cases of granuloma inguinale in the United States have been from the southeastern region,” hut in 1986, 30 of‘ the 61 reported cases came from New York City.:’ The incidence in the United States has fallen possibly because of an improved standard of living and the use of antibiotics; however its ability to simulate other diseases may he partially responsi-
HUMAN PATHOLOGY
Volume 21, No. 5 (May 1990)
FIGURE 1. (Left) Frozen section demonstrating xanthomatous histiocytes with inflammatory cells resembling a fibrous histiocytic neoplasm. (Hematoxylin-eosin stain, magnification x 100.) The top right panel demonstrates “closed safetv pin” morphology [arrow) of C granulomotis. (Bottom right] Organisms are often found lining the periphery [arrow] of the cytoplasmic vacuole. (Right War-thin-Starry stain, magnification x 400.)
incidence of extragenital lesions in patients with granuloma inguinale is approximately 6.6%.“Jj Several reports have described patients with cervical lesions who had recently been pregnant and/or had surgical procedures, and in whom subsequent spread of granuloma inguinale produced severe cachexia and, rarely, death occurring within a few weeks or months.7,8 This may result from hematogenous dissemination. Although multiple systems may be involved, there is a predilection for bones with resulting osteolytic lesions,“-a which may resemble leukemia or multiple myeloma radiologically.7 It is of note that our patient, with extensive extragenital disease, was pregnant. The first definitive histologic description of granuloma inguinale by Pund and Greenblattg emphasized the extensive granulation tissue with abundant plasma cells, numerous polymorphonuclear leukocytes forming focal microabscesses, a remarkable lack of lymphocytes, and epithelial hyperplasia with acanthosis and elongation of rete ridges especially at the margins of the ulcer. We could find no previous description of multinucleated giant cells in granuloma inguinale. Pseudoepitheliomatous hyperplasia is occasionally seen, and the histology becomes distorted as the proliferating granulation tissue entraps islands of keratinized squamous epithelium simulating squamous carcinoma.g The pathognomic feature of granuloma inguinale is the large (25 to 90 km) foamy histiocyte with up to 20 cytoplasmic vacuoles containing rod-shaped Donovan bodies, often in a peripheral location (Fig 1, bottom right).“’ Donovan bodies are difficult to see with hematoxylin and eosin stains, especially in early lesions or in a necrotic
ble for its low reported incidence.” Venereal transmission has been ascribed to granuloma inguinale but its exact transmission remains debatable.4 Granuloma inguinale usually presents as a deceptively innocuous small, painless papule or nodule on the external genitalia. When allowed to progress untreated the initial lesion erodes to form a red, beefy ulcer with a rolled border.” In males, the most common location is on the prepuce* or the coronal sulcus with extension to the genital crural or inguinal folds. In females, it presents most commonly in the labia or forchette and may spread to the perineal or perianal skin.” The ulcer may, heal with formation of a band-like scar around the genitaha with resultant lymphatic obstruction and elephantiasis.‘,‘.5 The initial genital lesion may be followed by “daughter lesions” which are due largely to autoinoculation.” These daughter lesions may coalesce to form extensive ulcerations which may mimic the lesions of chancroid, lymphogranuloma venereum, anogenital cutaneous amebiasis, secondary syphilis, or squamous cell carcinoma.‘.’ Involvement of the subcutaneous tissue of the inguinal region produces a classical picture of serpiginous ulcers. Inguinal lymphadenopathy is unusual in granuloma inguinale,‘.” and helps distinguish granuloma inguinale from lymphogranuloma venereum. If enlarged, lymph nodes show nonspecific reactive changes. Inguinal lymphadenopathy is mimicked by the formation of ” inguinal subcutaneous abscesses that fre“pseudobuboes, quently ulcerate to form inguinal ulcers5 Primary and secondary lesions of granuloma inguinale have been described in numerous extragenital sites.‘.4 The
560
CASE STUDIES
FIGURE 2. pop left] The retroperitoneal tissue consisted of abundant granulation tissue with acute and chronic inflammation and conspicuous foamy histiocytes, some of which are multinucleated. (Hematoxyin-eosin stain, magnification x 400.) pop right] Numerous focal collections of neutrophils forming microabscesses were present In the retroperitoneum and genital ulcer. (Hematoxylineosin stain, magnification x IOO.][Bottom] At the edge of the ulcer the epithelium demonstrates pseudoepitheliomatous hyperplasia. (Hematoxylin-eosin stain, magnification x 100.)
ulcer. I” However, the\ are easily demonstrated with Grmsa, DieterIe. or Warihin-Starry stains, which give them a distinctive bipolar (closed safety pin) appearance. ecial stains allowed the identification of’ the pathognomic Donovan bodies within the vacuoles of large histiocytes. Accurate diagnosis is critical because of the morbidity and mortality rates that can be associated with this treatable disease. It is important to be aware of its rare occurrence at extragenital sites where confusion, both clinically and pathologically, with other lesions is particularl)
likely. A combination of light and electron micros{ opy with clinical correlation should facilitate the dia,qnosis. ilcknou’lu~~~~~“t. ‘The authors Morrow. Conception this manuscript.
Lay. and
gratefullv Ferrante Leath
a~kn~nvlrdge .%nn f’or preparation of
REFERENCES 1. Srhgal \‘N. Prasad Indtol “5:x-16. 19X6
ALS:
Dono\nno~ts
~l,t,-rnt
SHAHLA
MASOOD.
MD,
NXK:Y
A SOFT-TISSUE
LAMMERT.
MD.
AND
NEOPLASM: A CASE REPORT AND ROBERT H.
E’O~JNG.
MI)
on permanent
sections, the patient Mas treated with appropriate antibiotics with resolution of the labial lesion. After. discharge from the hospital she was lost to follow-up. RESULTS
Gran&ma inguinale is an indolent but progressive, tllcerative venereal disease that usually affects the stratified squamous epithelium of the external genitalia. Its rarity anrl protean manifestations can provide a diagnostic challenge for the pathologist as well as the clinician even when it presents in its classic fin-m. When it presents as extragenital disease it can mimic other systemic illnesses. and the diagnostic difficulty is compounded. Correct diagnosis is t rucial, as untreated granuloma inguinale can develop into a mutilating illness with significant morbidity and mortalit\ i-ates. (:ASE
REPOR-I
An 1ii-vear-old gravida IV, para III black female who r\as 32 weeks pregnant, presented to the emergency room Ivith a complaint of vaginal bleeding over the previous 2 months. Examination at that time revealed a cervical erosion with minimal bleeding. No treatment was instituted and the patient was referred to the obstetric clinic., where 6 weeks later, she was found to have an ulcerative labial lesion which was clinically suspicious for herpes. Viral cultures of. the lahial lesion were negative; howecer. the patient was admitted to the hospital and underwent elective cesarean section. ‘41 the time of operation, a retroperironeal mass that involved tlhe right ureter and caused unilateral hydronephrosis was discovered. A section of this tissue was submitted for frozen section microscopic examination (Fig 1, left) and interpretecl as “acute xanthomatous inflammation. rule especially malignant fibrous out soft-tissue neoplasm. histiocytoma”. ‘l‘he labial lesion was also submitted for hiopsy at this time. After the diagnosis of extragenital granuloma inguinale involving the retroperitoneum was made Received March 14, 1989, from the Department of Pathology. LTniversirv of. Florida/Jacksonville division; and Department of Patholoev. Ma,isachusetts General Hospital, Harvard Medical School. Bosto:. MA. Accepted for publication September 6. 1989. Kev u~rlr: granuloma inguinale. Donovan bodies. exrragenital, hiqtiocyte. pregnancy. Address correspondence and reprint requests to Shahla Masood. MD. Department of Pathology. University Hospital, 655 M’ 8th St, Jacksonville, FL 32209. 0 1990 hv W.B. Saunders Company. W68 177/90/2 IO.50014$5.0910
The tissue from the retroperitoneum consisted of mutiple pieces of. firm, yellow, fihrofattv tissue measuring 3.0 cm hv 2.0 cm hv 0.5 cm. ‘rhe left labial lesion was tan, with the mucosal surface studded with numerorls papillary projections. The cut surface was smooth with area5 of focal hemorrhage. Microscopic examination of the retroperitoneal tissue revealed intense acute and chronic inflammation and ahundant granulation tissue (Fig 2, top left). The inflammator\ cells consisted of numerous plasma cells which in some areas formed perivascular cuff’s around small vessels, focal collections of neutrophils which formed micl oahscesses (Fig 2. top right). rare multinucleated giant cells, and focal collections of foamy histiocytes. The foamy nature of the histiocytes. due to the presence of numerous cvtoplasmic vacuoles, was suspicious for an infective process, and special stains were ordered. Warthin-Starry stain showed that the vacuoles contained small rod-shaped bacteria with the ty!.lical “closed safety pin” morphology of Donovan bodies (I- IR I, top right). Examination of the labial lesion revealed areas of ulceration with acute and chronic inflammation. her&red by epithelium which showed 1~se~~doel~itheliomatolls hvperplasia (Fig 9, bottom). The inflammatory infiltrate consisted of- neutrophils. plasma cells. and sirn1lar histioc-ytes with “Donovan bodies”. Few lymphoc-yte\ were seen in anv section. By electron microscopy, macrophages with large intrac-ytoplasmic vacuoles filled with oblong hacreria measuring 0.7 pm by I .4 pm were found. These bacteria had a trilaninar membrane and cytoplasmic elects-on dense material that hzas concentrated at the periphery of the cell. There were numerous villifijrm protrusions lining the surface of’ the bacteria. Some bacteria that appeared to he dividing. showed invagination of the cell membrane and cell wall. DISCUSSIoN The exact etiology of granuloma inguinale remains unproven; howel,er, Cal~mmc~tobacterium ,granuiomatir. a gramnegative, periodic acid-Schiff-negative, encapsulated, nonmotile bacteria, is considered the responsible pathogen by the weight of circumstantial evidence.’ Although rare in the Lnited States, granuloma inguinale is endemic in certain areas of the world including New Guinea, the Caribbean, and Central Australia.’ Historically, most cases of granuloma inguinale in the United States have been from the southeastern region,” hut in 1986, 30 of‘ the 61 reported cases came from New York City.:’ The incidence in the United States has fallen possibly because of an improved standard of living and the use of antibiotics; however its ability to simulate other diseases may he partially responsi-
HUMAN PATHOLOGY
Volume 21, No. 5 (May 1990)
FIGURE 1. (Left) Frozen section demonstrating xanthomatous histiocytes with inflammatory cells resembling a fibrous histiocytic neoplasm. (Hematoxylin-eosin stain, magnification x 100.) The top right panel demonstrates “closed safetv pin” morphology [arrow) of C granulomotis. (Bottom right] Organisms are often found lining the periphery [arrow] of the cytoplasmic vacuole. (Right War-thin-Starry stain, magnification x 400.)
incidence of extragenital lesions in patients with granuloma inguinale is approximately 6.6%.“Jj Several reports have described patients with cervical lesions who had recently been pregnant and/or had surgical procedures, and in whom subsequent spread of granuloma inguinale produced severe cachexia and, rarely, death occurring within a few weeks or months.7,8 This may result from hematogenous dissemination. Although multiple systems may be involved, there is a predilection for bones with resulting osteolytic lesions,“-a which may resemble leukemia or multiple myeloma radiologically.7 It is of note that our patient, with extensive extragenital disease, was pregnant. The first definitive histologic description of granuloma inguinale by Pund and Greenblattg emphasized the extensive granulation tissue with abundant plasma cells, numerous polymorphonuclear leukocytes forming focal microabscesses, a remarkable lack of lymphocytes, and epithelial hyperplasia with acanthosis and elongation of rete ridges especially at the margins of the ulcer. We could find no previous description of multinucleated giant cells in granuloma inguinale. Pseudoepitheliomatous hyperplasia is occasionally seen, and the histology becomes distorted as the proliferating granulation tissue entraps islands of keratinized squamous epithelium simulating squamous carcinoma.g The pathognomic feature of granuloma inguinale is the large (25 to 90 km) foamy histiocyte with up to 20 cytoplasmic vacuoles containing rod-shaped Donovan bodies, often in a peripheral location (Fig 1, bottom right).“’ Donovan bodies are difficult to see with hematoxylin and eosin stains, especially in early lesions or in a necrotic
ble for its low reported incidence.” Venereal transmission has been ascribed to granuloma inguinale but its exact transmission remains debatable.4 Granuloma inguinale usually presents as a deceptively innocuous small, painless papule or nodule on the external genitalia. When allowed to progress untreated the initial lesion erodes to form a red, beefy ulcer with a rolled border.” In males, the most common location is on the prepuce* or the coronal sulcus with extension to the genital crural or inguinal folds. In females, it presents most commonly in the labia or forchette and may spread to the perineal or perianal skin.” The ulcer may, heal with formation of a band-like scar around the genitaha with resultant lymphatic obstruction and elephantiasis.‘,‘.5 The initial genital lesion may be followed by “daughter lesions” which are due largely to autoinoculation.” These daughter lesions may coalesce to form extensive ulcerations which may mimic the lesions of chancroid, lymphogranuloma venereum, anogenital cutaneous amebiasis, secondary syphilis, or squamous cell carcinoma.‘.’ Involvement of the subcutaneous tissue of the inguinal region produces a classical picture of serpiginous ulcers. Inguinal lymphadenopathy is unusual in granuloma inguinale,‘.” and helps distinguish granuloma inguinale from lymphogranuloma venereum. If enlarged, lymph nodes show nonspecific reactive changes. Inguinal lymphadenopathy is mimicked by the formation of ” inguinal subcutaneous abscesses that fre“pseudobuboes, quently ulcerate to form inguinal ulcers5 Primary and secondary lesions of granuloma inguinale have been described in numerous extragenital sites.‘.4 The
560
CASE STUDIES
FIGURE 2. pop left] The retroperitoneal tissue consisted of abundant granulation tissue with acute and chronic inflammation and conspicuous foamy histiocytes, some of which are multinucleated. (Hematoxyin-eosin stain, magnification x 400.) pop right] Numerous focal collections of neutrophils forming microabscesses were present In the retroperitoneum and genital ulcer. (Hematoxylineosin stain, magnification x IOO.][Bottom] At the edge of the ulcer the epithelium demonstrates pseudoepitheliomatous hyperplasia. (Hematoxylin-eosin stain, magnification x 100.)
ulcer. I” However, the\ are easily demonstrated with Grmsa, DieterIe. or Warihin-Starry stains, which give them a distinctive bipolar (closed safety pin) appearance. ecial stains allowed the identification of’ the pathognomic Donovan bodies within the vacuoles of large histiocytes. Accurate diagnosis is critical because of the morbidity and mortality rates that can be associated with this treatable disease. It is important to be aware of its rare occurrence at extragenital sites where confusion, both clinically and pathologically, with other lesions is particularl)
likely. A combination of light and electron micros{ opy with clinical correlation should facilitate the dia,qnosis. ilcknou’lu~~~~~“t. ‘The authors Morrow. Conception this manuscript.
Lay. and
gratefullv Ferrante Leath
a~kn~nvlrdge .%nn f’or preparation of
REFERENCES 1. Srhgal \‘N. Prasad Indtol “5:x-16. 19X6
ALS:
Dono\nno~ts
~l,t,-rnt
