Introduction
Signet-ring cell carcinomas (SRCC) are poorly-differentiated neoplasms that generally
arise from gastrointestinal or breast tissue and are associated with poor prognosis.
1
Malignant signet-ring cells contain abundant cytoplasmic mucin and a peripherally
displaced nucleus. Of note, these neoplasms have an unusual tendency to infiltrate
surrounding tissues, which is thought to be due to the loss of E-cadherin.
2
This is clearly illustrated by the gastric SRCC variant, known as “linitis plastica,”
which can result in the thickening of the stomach wall.
3
Similarly, SRCC can metastasize to the peritoneum, leading to omental caking, a classic
radiologic pattern describing the infiltration of omental fat by soft-tissue material
(eg, Krukenberg tumors). Dermatologists seldom identify SRCC in practice, most probably
due to a combination of their sporadic prevalence and wide-ranging cutaneous manifestations.
Here, we report a remarkable case of SRCC presenting with massive anasarca diagnosed
solely via skin biopsy.
Case report
A 63-year-old woman with a history of basal cell carcinoma, hypothyroidism, and tobacco
use presented to the emergency department from her nursing home complaining of bilateral
lower extremity edema coupled with a rapid decline in overall health. Edema of the
lower extremities inexplicably began about 5 months prior to admission. During the
interim, she experienced gradual weight loss from her face and upper body, diffused
hair loss from the scalp, and significant orthopnea, ultimately requiring her transfer
to a skilled nursing facility. While there, she suffered a pulmonary embolism and
had several inconclusive workups for her gross deterioration. Aggressive diuresis
failed to provide any significant relief from edema, which prompted her hospital admission.
On physical examination (Fig 1, A and B), she had a massive indurated edema of the
lower body extending to the inframammary area, which stood in stark contrast to the
cachectic appearance of the upper extremities, chest, head, and neck. The lower extremity
skin was thickened and leathery, with very faint overlying scattered erythema on the
pretibial areas alone. No frank nodularity, papules, ulcerations, or violaceous lesions
were found.
Fig 1
Clinical presentation. A, Indurated edema of bilateral lower extremities. B, Edema
extending to the inframammary area with cachexia of upper extremities and thorax.
Initial diagnostic workup revealed hemoglobin of 7.9 g/dL, elevated erythrocyte sedimentation
rate (89 mm/hr), and elevated thyroid-stimulating hormone (18.6 mIU/mL) with depressed
free T4 (0.72 ng/dL). A computed tomography scan showed evidence of diffuse body wall
edema and skin thickening with hypertrophy and calcification of the proximal lower
extremity musculature. These changes were uniformly distributed, although slightly
worse in dependent areas (sacrum and proximal thighs). When taken together with hypothyroidism,
these imaging findings suggested a diagnosis of Hoffman's syndrome, a rare form of
hypothyroid myopathy presenting with muscular pseudohypertrophy. Nevertheless, clinical
uncertainty necessitated further evaluation.
The dermatology department was consulted and a skin biopsy was performed from the
most superior region of the anterior abdominal wall. This location was chosen as it
was typical of the edematous changes seen throughout, as well as to avoid the static
changes that can occur after lower leg biopsies. On histopathologic examination (Fig
2, A and B), there was tremendous edema with scattered cells having a signet-ring
morphology within the deep reticular dermis and subcutis. Lesional cells stained positive
with pancytokeratin, CK7, SATB2, and CDX-2, which was suggestive of a non-cutaneous
primary malignancy. GATA3, CK20, and neuroendocrine markers, synaptophysin and chromogranin,
were negative. Colloidal iron highlighted mucin within atypical cells and no lymphovascular
invasion was observed. Collectively, the histopathologic and immunophenotypic findings
pointed to a metastatic SRCC of gastrointestinal origin.
Fig 2
Histopathology. A, Signet-ring cells. (Hematoxylin-eosin stain; original magnification:
×200.) B, Tissue stained with CK-7 (colorectal). (Original magnification: ×100.)
Subsequently, the patient underwent abdominal ultrasonography, esophagogastroduodenoscopy,
colonoscopy with biopsy, and fluorodeoxyglucose-positron emission tomography with
computed tomography. Tumor marker studies were notable for elevated CEA, CA 19-9,
CA 15-3, and CA 125 antigen. Imaging studies, as well as tissue biopsies of colonic
and esophageal mucosa, failed to identify a primary SRCC.
The patient was transferred to the medical oncology department for further management,
with a diagnosis of metastatic adenocarcinoma due to the presence of signet-ring cells.
She tolerated inpatient folinic acid, 5-fluorouracil, and oxaliplatin therapy and
was referred to a skilled nursing facility with plans for outpatient follow-up. Regrettably,
she succumbed to septic shock soon after discharge and no autopsy was performed.
Discussion
We present a remarkable case where a patient with immense edema of the abdomen and
lower extremities was diagnosed with metastatic visceral adenocarcinoma (SRCC) solely
via skin biopsy.
Physicians must consider several pathophysiologic mechanisms when evaluating skin
thickening and lower extremity edema. Iatrogenic culprits include medications (ie,
dihydropyridine calcium channel blockers) or surgical lymph node dissections. Infectious
etiologies (eg, lymphatic filariasis) should be ruled out in those with pertinent
travel histories. Infiltrative processes, such as amyloidosis, myxedema, or sarcoidosis,
present unique challenges when they are not accompanied by classic symptoms (weight
gain/loss, fatigue) or other typical features (hair/nail changes, uveitis). These
features can prolong arriving at the correct diagnosis, which is worrisome for both
patient and physician. Our case determined that SRCC is the infiltrative process responsible
for anasarca, which has not yet been reported.
In prior literature, cutaneous metastases from SRCC are described as papulonodular,
sclerodermoid, or inflammatory-appearing lesions.
4
Illustrative examples of these reactionary patterns include carcinoma en cuirasse
and carcinoma erysipeloides, often in the setting of metastatic gastric or breast
SRCC.
4
,
5
These distinct morphologies can provide strong clues for the dermatologist but are
scarcely observed in common practice. Furthermore, SRCC can mimic benign processes,
such as allergic contact dermatitis,
6
or appear as localized, asymptomatic scarring.
7
In addition to obtaining a comprehensive history and performing a full body skin examination,
these reports on cutaneous manifestations of SRCC emphasize that the clinician must
harbor a high index of suspicion and a low threshold for accepting skin biopsy results
to avoid delays in diagnosis and treatment.
After a biopsy, gross histopathologic evaluation and targeted immunostaining are essential
and will often help in identifying the primary cancer. Painter et al provided a concise
review of relevant immunohistochemical markers that dermatologists may encounter.
8
In our case, the presence of signet-ring cells prompted immunostaining for common
gastrointestinal malignancies with CK-7/CK-20, SATB2, and CDX-2, in addition to GATA3
for breast and bladder primaries.
6
Negative synaptophysin and chromogranin militated against a neuroendocrine etiology.
To summarize, dermatologists should consider a diagnosis of SRCC when faced with a
confusing clinical picture that could be explained by an infiltrative process. Moreover,
this case underscores the powerful diagnostic utility of a skin biopsy, which provided
the only evidence for an internal malignancy in this case.
Conflicts of interest
Dr Musiek reports the following: Kyowa - advisory board; Helsinn - advisory board;
Elorac, Sologenix, miRagen, Connect, Pfizer, and Menlo - investigator. Author Raval
and Drs Shmuylovich, Strickley, Chen, and Rosman have no conflicts of interest to
report.